CN117241780A - Biological delivery system - Google Patents
Biological delivery system Download PDFInfo
- Publication number
- CN117241780A CN117241780A CN202180093685.7A CN202180093685A CN117241780A CN 117241780 A CN117241780 A CN 117241780A CN 202180093685 A CN202180093685 A CN 202180093685A CN 117241780 A CN117241780 A CN 117241780A
- Authority
- CN
- China
- Prior art keywords
- delivery vehicle
- mole
- acid
- lipid
- cationic lipid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
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- 238000012384 transportation and delivery Methods 0.000 title claims abstract description 605
- 210000004027 cell Anatomy 0.000 claims abstract description 106
- 238000000034 method Methods 0.000 claims abstract description 55
- 210000003097 mucus Anatomy 0.000 claims abstract description 47
- 210000001035 gastrointestinal tract Anatomy 0.000 claims abstract description 20
- -1 cationic lipid Chemical class 0.000 claims description 487
- 150000002632 lipids Chemical class 0.000 claims description 425
- 239000002105 nanoparticle Substances 0.000 claims description 223
- 239000003833 bile salt Substances 0.000 claims description 201
- 239000003613 bile acid Substances 0.000 claims description 121
- KXGVEGMKQFWNSR-LLQZFEROSA-N deoxycholic acid Chemical compound C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 KXGVEGMKQFWNSR-LLQZFEROSA-N 0.000 claims description 116
- 229940009976 deoxycholate Drugs 0.000 claims description 103
- 102000039446 nucleic acids Human genes 0.000 claims description 99
- 108020004707 nucleic acids Proteins 0.000 claims description 99
- 229920001223 polyethylene glycol Polymers 0.000 claims description 97
- HSINOMROUCMIEA-FGVHQWLLSA-N (2s,4r)-4-[(3r,5s,6r,7r,8s,9s,10s,13r,14s,17r)-6-ethyl-3,7-dihydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-17-yl]-2-methylpentanoic acid Chemical compound C([C@@]12C)C[C@@H](O)C[C@H]1[C@@H](CC)[C@@H](O)[C@@H]1[C@@H]2CC[C@]2(C)[C@@H]([C@H](C)C[C@H](C)C(O)=O)CC[C@H]21 HSINOMROUCMIEA-FGVHQWLLSA-N 0.000 claims description 91
- 150000007523 nucleic acids Chemical class 0.000 claims description 89
- 239000002245 particle Substances 0.000 claims description 76
- 108020004414 DNA Proteins 0.000 claims description 75
- 239000000203 mixture Substances 0.000 claims description 66
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 54
- 239000002202 Polyethylene glycol Substances 0.000 claims description 50
- 108090000623 proteins and genes Proteins 0.000 claims description 47
- 239000003814 drug Substances 0.000 claims description 37
- 125000003729 nucleotide group Chemical group 0.000 claims description 37
- JZNWSCPGTDBMEW-UHFFFAOYSA-N Glycerophosphorylethanolamin Natural products NCCOP(O)(=O)OCC(O)CO JZNWSCPGTDBMEW-UHFFFAOYSA-N 0.000 claims description 36
- 239000002773 nucleotide Substances 0.000 claims description 35
- 239000002253 acid Substances 0.000 claims description 34
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 34
- 102000004196 processed proteins & peptides Human genes 0.000 claims description 33
- SMEROWZSTRWXGI-HVATVPOCSA-N lithocholic acid Chemical compound C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)CC1 SMEROWZSTRWXGI-HVATVPOCSA-N 0.000 claims description 31
- 239000008194 pharmaceutical composition Substances 0.000 claims description 30
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical group CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 claims description 30
- 102000004169 proteins and genes Human genes 0.000 claims description 30
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 claims description 28
- KXGVEGMKQFWNSR-UHFFFAOYSA-N deoxycholic acid Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 KXGVEGMKQFWNSR-UHFFFAOYSA-N 0.000 claims description 28
- 108091032973 (ribonucleotides)n+m Proteins 0.000 claims description 27
- BHQCQFFYRZLCQQ-OELDTZBJSA-N cholic acid Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 BHQCQFFYRZLCQQ-OELDTZBJSA-N 0.000 claims description 27
- 150000008104 phosphatidylethanolamines Chemical class 0.000 claims description 27
- 239000013598 vector Substances 0.000 claims description 26
- NONFBHXKNNVFMO-UHFFFAOYSA-N [2-aminoethoxy(tetradecanoyloxy)phosphoryl] tetradecanoate Chemical compound CCCCCCCCCCCCCC(=O)OP(=O)(OCCN)OC(=O)CCCCCCCCCCCCC NONFBHXKNNVFMO-UHFFFAOYSA-N 0.000 claims description 25
- 230000002496 gastric effect Effects 0.000 claims description 24
- 229920001477 hydrophilic polymer Polymers 0.000 claims description 24
- 229920001184 polypeptide Polymers 0.000 claims description 24
- JAJWGJBVLPIOOH-IZYKLYLVSA-M sodium taurocholate Chemical compound [Na+].C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(=O)NCCS([O-])(=O)=O)C)[C@@]2(C)[C@@H](O)C1 JAJWGJBVLPIOOH-IZYKLYLVSA-M 0.000 claims description 24
- MWRBNPKJOOWZPW-CLFAGFIQSA-N dioleoyl phosphatidylethanolamine Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC(COP(O)(=O)OCCN)OC(=O)CCCCCCC\C=C/CCCCCCCC MWRBNPKJOOWZPW-CLFAGFIQSA-N 0.000 claims description 21
- WTJKGGKOPKCXLL-RRHRGVEJSA-N phosphatidylcholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCC=CCCCCCCCC WTJKGGKOPKCXLL-RRHRGVEJSA-N 0.000 claims description 21
- 239000001294 propane Substances 0.000 claims description 21
- 230000001225 therapeutic effect Effects 0.000 claims description 20
- BHQCQFFYRZLCQQ-UHFFFAOYSA-N (3alpha,5alpha,7alpha,12alpha)-3,7,12-trihydroxy-cholan-24-oic acid Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 BHQCQFFYRZLCQQ-UHFFFAOYSA-N 0.000 claims description 19
- 239000004380 Cholic acid Substances 0.000 claims description 19
- 229960002471 cholic acid Drugs 0.000 claims description 19
- 150000003904 phospholipids Chemical class 0.000 claims description 19
- 229940124597 therapeutic agent Drugs 0.000 claims description 19
- 125000000217 alkyl group Chemical group 0.000 claims description 18
- AWUCVROLDVIAJX-UHFFFAOYSA-N alpha-glycerophosphate Natural products OCC(O)COP(O)(O)=O AWUCVROLDVIAJX-UHFFFAOYSA-N 0.000 claims description 18
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 18
- RFDAIACWWDREDC-FRVQLJSFSA-N glycocholic acid Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(=O)NCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 RFDAIACWWDREDC-FRVQLJSFSA-N 0.000 claims description 18
- 229910052757 nitrogen Inorganic materials 0.000 claims description 18
- 230000014509 gene expression Effects 0.000 claims description 17
- SNKAWJBJQDLSFF-NVKMUCNASA-N 1,2-dioleoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/CCCCCCCC SNKAWJBJQDLSFF-NVKMUCNASA-N 0.000 claims description 16
- 108010007979 Glycocholic Acid Proteins 0.000 claims description 16
- ATUOYWHBWRKTHZ-UHFFFAOYSA-N Propane Chemical compound CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 claims description 16
- 235000019416 cholic acid Nutrition 0.000 claims description 16
- 108091070501 miRNA Proteins 0.000 claims description 16
- 239000013612 plasmid Substances 0.000 claims description 16
- 159000000000 sodium salts Chemical class 0.000 claims description 16
- RUDATBOHQWOJDD-BSWAIDMHSA-N chenodeoxycholic acid Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)CC1 RUDATBOHQWOJDD-BSWAIDMHSA-N 0.000 claims description 15
- 229960003964 deoxycholic acid Drugs 0.000 claims description 15
- 230000000149 penetrating effect Effects 0.000 claims description 15
- ATBOMIWRCZXYSZ-XZBBILGWSA-N [1-[2,3-dihydroxypropoxy(hydroxy)phosphoryl]oxy-3-hexadecanoyloxypropan-2-yl] (9e,12e)-octadeca-9,12-dienoate Chemical compound CCCCCCCCCCCCCCCC(=O)OCC(COP(O)(=O)OCC(O)CO)OC(=O)CCCCCCC\C=C\C\C=C\CCCCC ATBOMIWRCZXYSZ-XZBBILGWSA-N 0.000 claims description 14
- ZFFZMGJMZGAGMF-SXAUZNKPSA-N [7-[4-(dipropylamino)butyl]-7-hydroxy-13-[(Z)-octadec-9-enoyl]oxytridecyl] (Z)-octadec-9-enoate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCCCCCCC(O)(CCCCCCOC(=O)CCCCCCC\C=C/CCCCCCCC)CCCCN(CCC)CCC ZFFZMGJMZGAGMF-SXAUZNKPSA-N 0.000 claims description 14
- 210000000941 bile Anatomy 0.000 claims description 14
- 229940009025 chenodeoxycholate Drugs 0.000 claims description 14
- 235000012000 cholesterol Nutrition 0.000 claims description 14
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 14
- 230000000968 intestinal effect Effects 0.000 claims description 14
- 150000003384 small molecules Chemical class 0.000 claims description 14
- AWDRATDZQPNJFN-VAYUFCLWSA-N taurodeoxycholic acid Chemical compound C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(=O)NCCS(O)(=O)=O)C)[C@@]2(C)[C@@H](O)C1 AWDRATDZQPNJFN-VAYUFCLWSA-N 0.000 claims description 14
- 230000003612 virological effect Effects 0.000 claims description 14
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 13
- RZRNAYUHWVFMIP-KTKRTIGZSA-N 1-oleoylglycerol Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC(O)CO RZRNAYUHWVFMIP-KTKRTIGZSA-N 0.000 claims description 12
- JLPULHDHAOZNQI-JLOPVYAASA-N [(2r)-3-hexadecanoyloxy-2-[(9e,12e)-octadeca-9,12-dienoyl]oxypropyl] 2-(trimethylazaniumyl)ethyl phosphate Chemical class CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C\C\C=C\CCCCC JLPULHDHAOZNQI-JLOPVYAASA-N 0.000 claims description 12
- 201000010099 disease Diseases 0.000 claims description 12
- RZRNAYUHWVFMIP-HXUWFJFHSA-N glycerol monolinoleate Natural products CCCCCCCCC=CCCCCCCCC(=O)OC[C@H](O)CO RZRNAYUHWVFMIP-HXUWFJFHSA-N 0.000 claims description 12
- 239000000816 peptidomimetic Substances 0.000 claims description 12
- 229940099352 cholate Drugs 0.000 claims description 11
- 230000007935 neutral effect Effects 0.000 claims description 11
- KIQFUORWRVZTHT-OPTMKGCMSA-N 3-oxo-5beta-cholanic acid Chemical compound C([C@H]1CC2)C(=O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)CC1 KIQFUORWRVZTHT-OPTMKGCMSA-N 0.000 claims description 10
- RPKLZQLYODPWTM-LVVAJZGHSA-N 5beta-cholanic acid Chemical compound C([C@H]1CC2)CCC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)CC1 RPKLZQLYODPWTM-LVVAJZGHSA-N 0.000 claims description 10
- SYFQYGMJENQVQT-UHFFFAOYSA-N 6-amino-2-[bis(carboxymethyl)amino]hexanoic acid Chemical compound NCCCCC(C(O)=O)N(CC(O)=O)CC(O)=O SYFQYGMJENQVQT-UHFFFAOYSA-N 0.000 claims description 10
- 102000004127 Cytokines Human genes 0.000 claims description 10
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- 230000028327 secretion Effects 0.000 claims description 10
- SLKDGVPOSSLUAI-PGUFJCEWSA-N 1,2-dihexadecanoyl-sn-glycero-3-phosphoethanolamine zwitterion Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(=O)OCCN)OC(=O)CCCCCCCCCCCCCCC SLKDGVPOSSLUAI-PGUFJCEWSA-N 0.000 claims description 9
- PORPENFLTBBHSG-MGBGTMOVSA-N 1,2-dihexadecanoyl-sn-glycerol-3-phosphate Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(O)=O)OC(=O)CCCCCCCCCCCCCCC PORPENFLTBBHSG-MGBGTMOVSA-N 0.000 claims description 9
- 125000003545 alkoxy group Chemical group 0.000 claims description 9
- 239000003102 growth factor Substances 0.000 claims description 9
- QQVIHTHCMHWDBS-UHFFFAOYSA-L isophthalate(2-) Chemical compound [O-]C(=O)C1=CC=CC(C([O-])=O)=C1 QQVIHTHCMHWDBS-UHFFFAOYSA-L 0.000 claims description 9
- 150000003905 phosphatidylinositols Chemical class 0.000 claims description 9
- 239000000243 solution Substances 0.000 claims description 9
- WBWWGRHZICKQGZ-HZAMXZRMSA-N taurocholic acid Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(=O)NCCS(O)(=O)=O)C)[C@@]2(C)[C@@H](O)C1 WBWWGRHZICKQGZ-HZAMXZRMSA-N 0.000 claims description 9
- JEJLGIQLPYYGEE-UHFFFAOYSA-N 1,2-dipalmitoylglycerol Chemical compound CCCCCCCCCCCCCCCC(=O)OCC(CO)OC(=O)CCCCCCCCCCCCCCC JEJLGIQLPYYGEE-UHFFFAOYSA-N 0.000 claims description 8
- 108090000994 Catalytic RNA Proteins 0.000 claims description 8
- 102000053642 Catalytic RNA Human genes 0.000 claims description 8
- 208000022559 Inflammatory bowel disease Diseases 0.000 claims description 8
- 239000004698 Polyethylene Substances 0.000 claims description 8
- 208000029664 classic familial adenomatous polyposis Diseases 0.000 claims description 8
- 150000001982 diacylglycerols Chemical class 0.000 claims description 8
- 229960005160 dimyristoylphosphatidylglycerol Drugs 0.000 claims description 8
- BPHQZTVXXXJVHI-AJQTZOPKSA-N ditetradecanoyl phosphatidylglycerol Chemical compound CCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(=O)OC[C@@H](O)CO)OC(=O)CCCCCCCCCCCCC BPHQZTVXXXJVHI-AJQTZOPKSA-N 0.000 claims description 8
- 239000007850 fluorescent dye Substances 0.000 claims description 8
- OVBPIULPVIDEAO-LBPRGKRZSA-N folic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 claims description 8
- 108091027963 non-coding RNA Proteins 0.000 claims description 8
- 102000042567 non-coding RNA Human genes 0.000 claims description 8
- 108091092562 ribozyme Proteins 0.000 claims description 8
- LVNGJLRDBYCPGB-LDLOPFEMSA-N (R)-1,2-distearoylphosphatidylethanolamine Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[NH3+])OC(=O)CCCCCCCCCCCCCCCCC LVNGJLRDBYCPGB-LDLOPFEMSA-N 0.000 claims description 7
- CITHEXJVPOWHKC-UUWRZZSWSA-N 1,2-di-O-myristoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCCCCCCC CITHEXJVPOWHKC-UUWRZZSWSA-N 0.000 claims description 7
- 102000004190 Enzymes Human genes 0.000 claims description 7
- 108090000790 Enzymes Proteins 0.000 claims description 7
- 201000006107 Familial adenomatous polyposis Diseases 0.000 claims description 7
- 206010028980 Neoplasm Diseases 0.000 claims description 7
- HIHOWBSBBDRPDW-PTHRTHQKSA-N [(3s,8s,9s,10r,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1h-cyclopenta[a]phenanthren-3-yl] n-[2-(dimethylamino)ethyl]carbamate Chemical compound C1C=C2C[C@@H](OC(=O)NCCN(C)C)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HIHOWBSBBDRPDW-PTHRTHQKSA-N 0.000 claims description 7
- 239000002955 immunomodulating agent Substances 0.000 claims description 7
- 229940121354 immunomodulator Drugs 0.000 claims description 7
- 229950004354 phosphorylcholine Drugs 0.000 claims description 7
- NRHMKIHPTBHXPF-TUJRSCDTSA-M sodium cholate Chemical compound [Na+].C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC([O-])=O)C)[C@@]2(C)[C@@H](O)C1 NRHMKIHPTBHXPF-TUJRSCDTSA-M 0.000 claims description 7
- NEZDNQCXEZDCBI-WJOKGBTCSA-N (2-aminoethoxy)[(2r)-2,3-bis(tetradecanoyloxy)propoxy]phosphinic acid Chemical compound CCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(=O)OCCN)OC(=O)CCCCCCCCCCCCC NEZDNQCXEZDCBI-WJOKGBTCSA-N 0.000 claims description 6
- 229920002505 N-(Carbonyl-Methoxypolyethylene Glycol 2000)-1,2-Distearoyl-Sn-Glycero-3-Phosphoethanolamine Polymers 0.000 claims description 6
- 108020004459 Small interfering RNA Proteins 0.000 claims description 6
- 108020004566 Transfer RNA Proteins 0.000 claims description 6
- 235000010445 lecithin Nutrition 0.000 claims description 6
- 239000000787 lecithin Substances 0.000 claims description 6
- 210000004400 mucous membrane Anatomy 0.000 claims description 6
- 108020004418 ribosomal RNA Proteins 0.000 claims description 6
- SRLOHQKOADWDBV-NRONOFSHSA-M sodium;[(2r)-2,3-di(octadecanoyloxy)propyl] 2-(2-methoxyethoxycarbonylamino)ethyl phosphate Chemical compound [Na+].CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCCNC(=O)OCCOC)OC(=O)CCCCCCCCCCCCCCCCC SRLOHQKOADWDBV-NRONOFSHSA-M 0.000 claims description 6
- BHTRKEVKTKCXOH-BJLOMENOSA-N taurochenodeoxycholic acid Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(=O)NCCS(O)(=O)=O)C)[C@@]2(C)CC1 BHTRKEVKTKCXOH-BJLOMENOSA-N 0.000 claims description 6
- HRXKRNGNAMMEHJ-UHFFFAOYSA-K trisodium citrate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 claims description 6
- GHCZAUBVMUEKKP-UHFFFAOYSA-N ursodeoxycholic acid glycine-conjugate Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(=O)NCC(O)=O)C)C1(C)CC2 GHCZAUBVMUEKKP-UHFFFAOYSA-N 0.000 claims description 6
- JFBCSFJKETUREV-UHFFFAOYSA-N 1,2 ditetradecanoylglycerol Chemical compound CCCCCCCCCCCCCC(=O)OCC(CO)OC(=O)CCCCCCCCCCCCC JFBCSFJKETUREV-UHFFFAOYSA-N 0.000 claims description 5
- NRJAVPSFFCBXDT-HUESYALOSA-N 1,2-distearoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCCCCCCCCCCC NRJAVPSFFCBXDT-HUESYALOSA-N 0.000 claims description 5
- LVNGJLRDBYCPGB-UHFFFAOYSA-N 1,2-distearoylphosphatidylethanolamine Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(COP([O-])(=O)OCC[NH3+])OC(=O)CCCCCCCCCCCCCCCCC LVNGJLRDBYCPGB-UHFFFAOYSA-N 0.000 claims description 5
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 claims description 5
- JLLBPEUXSDBMIZ-UHFFFAOYSA-N 2,5-dibromobenzene-1,4-dicarbonitrile Chemical compound BrC1=CC(C#N)=C(Br)C=C1C#N JLLBPEUXSDBMIZ-UHFFFAOYSA-N 0.000 claims description 5
- NEZDNQCXEZDCBI-UHFFFAOYSA-N 2-azaniumylethyl 2,3-di(tetradecanoyloxy)propyl phosphate Chemical compound CCCCCCCCCCCCCC(=O)OCC(COP(O)(=O)OCCN)OC(=O)CCCCCCCCCCCCC NEZDNQCXEZDCBI-UHFFFAOYSA-N 0.000 claims description 5
- 241000282472 Canis lupus familiaris Species 0.000 claims description 5
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- 108091007412 Piwi-interacting RNA Proteins 0.000 claims description 5
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- 125000001124 arachidoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 5
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Landscapes
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Abstract
Delivery vehicles and methods of making and using the same to reach epithelial cells, such as cells in a mucus-containing environment, as well as delivery vehicles having improved stability in harsh environments, including the gastrointestinal tract, are provided.
Description
Cross Reference to Related Applications
The present application claims priority from the following applications: U.S. provisional application No. 63/125,075, 2021, U.S. provisional application No. 63/194,315, 2021, month 6, month 11, entitled "composition and method for a biological delivery vehicle", filed 14, 12, 2020, and U.S. provisional application No. 63/282,421, entitled "biological delivery system", filed 23, 2021, 11, each of which is incorporated herein by reference in its entirety.
Statement regarding federally sponsored research
The application is carried out under the support of the U.S. government according to contract number 1846078 of the national science foundation. The government has certain rights in this application.
Sequence listing
The present application is presented with a sequence listing in electronic format. A sequence table file named 2214_1006pct_sl. Txt was created at 12 months 13 of 2021 and is 4,060 bytes in size. The information in the electronic format of the sequence listing is incorporated herein by reference in its entirety.
Background
Despite advances in gene therapy over the last 50 years, there are many diseases that are difficult to treat with traditional methods, particularly where delivery to a target site of gene therapy, such as in the gastrointestinal tract, may present challenges. The present disclosure addresses this need and provides a number of advantages as well.
SUMMARY
The following description and examples detail embodiments of the present disclosure. It is to be understood that the present disclosure is not limited to the particular embodiments described herein, as such may vary. Those skilled in the art will recognize that there are many variations and modifications of this disclosure, which are included within its scope.
In some embodiments, the present disclosure provides a delivery vehicle (delivery vehicle) comprising: at least one bile salt, at least one bile acid, or a combination thereof; at least one cationic lipid; at least one structural lipid; and optionally at least one conjugated lipid.
In some embodiments, the at least one bile salt comprises sulfobromophthalein disodium salt hydrate, taurine-3 beta, 5 alpha, 6 beta-Trihydroxycholanic acid, tauchenodeoxycholic acid sodium salt, taurocholate sodium salt hydrate, taurocholate sodium salt, taurodeoxycholic acid sodium salt, taurocholate deoxycholate, taurocholate sodium salt, taurocholate 3-sulfuric acid disodium salt, taurocholate sodium salt, tauro-beta-mous acid sodium salt, tauroursodeoxycholate sodium salt, tauro-alpha-mous acid sodium salt, tauro-gamma-mous acid sodium salt, tauro-omega-mous acid sodium salt, beta-estradiol 17- (beta-D-glucuronide) sodium salt, lithocholic acid 3-sulfate (disodium salt), chenodeoxycholic acid 3-sulfate (disodium salt) chenodeoxycholic acid 7-sulfate (disodium salt), cholic acid 3-sulfate (disodium salt), cholic acid 7-sulfate (disodium salt), cholic acid sodium salt, deoxycholic acid 3-sulfate (disodium salt), deoxycholic acid disulfate (trisodium salt), phenoxymethyl penicillin potassium salt, chenodeoxycholic acid disulfate (trisodium salt), chenodeoxycholic acid sodium salt cholate, methylcholate, sodium taurocholate hydrate, 1-naphthyl isothiocyanate, deoxycholate, pig deoxycholate, glycocholate, sodium glycochenodeoxycholate, sodium cholate hydrate, taurocholate, taurodeoxycholate, taurochenodeoxycholate, chenodeoxycholate, lithocholic acid salt, isophthalic acid salt, alloisophthalic acid salt (alloisolhocholate), sodium deoxycholate monohydrate, dehydrolithocholic acid salt, sodium glycodeoxycholate, sodium glycocholate hydrate, sodium taurodeoxycholate hydrate, sodium chenodeoxycholate, glycocholate sulfate, glycocholate, sodium taurocholate hydrate, sodium taurocholate, sodium taurodeoxycholate, sodium tauroursodeoxycholate, sodium taurocholate, glycodeoxycholate, and any combination thereof.
In some embodiments, the at least one bile salt comprises cholate, deoxycholate, chenodeoxycholate, lithocholate, and any combination thereof.
In some embodiments, the at least one bile acid comprises 3β,5α,6β -trihydroxy cholanic acid, 12-ketochenodeoxycholic acid, 12-ketolithocholic acid, 3-oxochenodeoxycholic acid, 3-oxodeoxycholic acid, 3-oxocholic acid, 3α,6β,7α,12α -tetrahydroxy bile acid, 3α,6α,7α,12 a-tetrahydroxy bile acid, 4-bromobenzoic acid, 6, 7-diketo-lithocholic acid, 7-ketodeoxycholic acid, 7-ketolithocholic acid, allocholic acid, allo-iso-lithocholic acid, orthocholic acid (delta 14 isomer), arachidyl amidocholanic acid, chenodeoxycholic acid-D4, cholic acid, dehydrocholic acid, dehydrolithocholic acid, deoxycholic acid, dioxo-cholic acid, glyco-12-oxo Dan Danwan acid, glycochenodeoxycholic acid, glycocholic acid hydrate, glycodehydrocholic acid, glycodeoxycholic acid, glycohyodeoxycholic acid, glycolithocholic acid, glycoursodeoxycholic acid, glyco-gamma-murine cholic acid, hyodeoxycholic acid, obeticholic acid, pentadecanoic acid, bear deoxycholic acid, alpha-murine deoxycholic acid, beta-murine cholic acid, omega-murine cholic acid, and any combination thereof.
In some embodiments, the at least one bile acid comprises Xiong Erchun (ursodiol), 5 β -cholanic acid, 3-oxo-cholanic acid, and any combination thereof.
In some embodiments, the delivery vehicle comprises about 5 to about 40 mole% of at least one bile salt or at least one bile acid. In some embodiments, the delivery vehicle comprises about 20 to about 40 mole% of at least one bile salt or at least one bile acid. In some embodiments, the delivery vehicle comprises about 30 to about 40 mole% of at least one bile salt or at least one bile acid. In some embodiments, the at least one bile salt comprises deoxycholate.
In some embodiments, the at least one bile salt comprises chenodeoxycholate. In some embodiments, the at least one bile salt comprises lithocholic acid salt. In some embodiments, at least one bile allobionate. In some embodiments, the at least one bile comprises dehydrolithocholate. In some embodiments, the at least one bile acid comprises bear diol.
In some embodiments, the at least one bile salt comprises isophthalate. In some embodiments, the at least one bile salt comprises dehydrolithocholate. In some embodiments, the at least one bile acid comprises 5- β -cholanic acid. In some embodiments, the at least one bile salt comprises taurodeoxycholate. In some embodiments, the at least one bile comprises tauxe deoxycholate. In some embodiments, at least one bile salt glycocholate. In some embodiments, the at least one bile acid comprises 3-oxo-cholanic acid. In some embodiments, the delivery vehicle comprises deoxycholate and lithocholate.
In some embodiments, the delivery vehicle comprises about 20 to about 30 mole% deoxycholate and about 5 to about 10 mole% lithocholate. In some embodiments, the delivery vehicle comprises at least one bile salt and at least one bile acid.
In some embodiments, the at least one cationic lipid comprises N1- [2- ((1S) -1- [ (3-aminopropyl) amino ] -4- [ bis (3-amino-propyl) amino ] butylcarboxamido) ethyl ] -3, 4-bis [ oleyloxy ] -benzamide (MVL 5), N4-cholesteryl-spermine HCl (GL 67), 1, 2-dioleyloxy-3-dimethylaminopropane (DODMA), N- [1- (2, 3-dioleyloxy) propyl ] -N, N, N-trimethylammonium chloride (DOTMA), [1, 2-bis (oleoyloxy) -3- (trimethylammonio) propane ] (DOTAP), dimethyl Dioctadecyl) Ammonium (DDA), 3β [ N- (N ', N' -dimethylaminoethane) -carbamoyl ] cholesterol (DC-Chol), and dioctadecyl amidoglycinamide (DOGS), 1, 2-dialkyl-sn-3-glycero-3-ethyl-phosphate, 1, 2-dialkyl-3-dimethylammonium propane, 1, 2-dialkyl-3- (trimethylammonio-1, 2-dialkyl-3-dimethylammonium propane, N, 3-dialkyl-dialkyi-3-dioleyl-propan-1, 2-dialkyl-3-dioleyl-2-dioleyl-3-dioleyloxy-carboxamido-amine, n-dimethylammonium, N- (4-carboxybenzyl) -N, N-dimethyl-2, 3-bis (alkoxy) propan-1-ammonium, 1, 2-dialkyl-sn-3- [ (N- (5-amino-1-carboxypentyl) iminodiacetic acid) succinyl ], N1- [2- ((1S) -1- [ (3-aminopropyl) amino ] -4- [ bis (3-amino-propyl) amino ] butylcarboxamido) ethyl ] -3, 4-dialkyl ] -benzamide, 1, 2-dialkoxy-N, N-dimethylaminopropane, 4- (2, 2-dioctyl-9, 12-dienyl- [1,3] dioxolan-4-ylmethyl) -dimethylamine, O-alkyl ethyl phosphorylcholine, (6Z, 9Z,28Z, Z) -heptadecan-6,9,28,31-tetraen-19-yl 3- (dimethylamino) propionate (2), 3 beta- [ N- (N ', N ' -dimethylaminoethane) -carbamoyl ] ethyl ] -3, 4-dialkyl ] -benzamide, 1, 2-dialkyl-2, 2-dicarboxamide, 2-dimethyl-propan-4-dicarboxamide, 2-dimethyl-2-methyl-2-dicarboxyl-propan-1, 3-dicarboxyl-2-dimethy-N-methyl-4-methyl-phosphorylcholine, O-alkyl-ethyl-phosphorylcholine, (6Z, 28Z, Z) -heptadecan-tetraen-19-yl-3- (dimethylamino) propionate (MC 2, 3-beta-N- (N ' -dimethylaminoethyl) -carbamyl-methyl-2-propanoate, 1, 2-di-O-alkyl-3-trimethylammoniopropane, 1, 2-dialkoxy-3-dimethylaminopropane, N-dialkyl-N, N-dimethylammonium, N- (4-carboxybenzyl) -N, N-dimethyl-2, 3-bis (alkoxy) propan-1-ammonium, 1, 2-dialkyl-sn-glycero-3- [ (N- (5-amino-1-carboxypentyl) iminodiacetic acid) succinyl ], N1- [2- ((1S) -1- [ (3-aminopropyl) amino ] -4- [ bis (3-amino-propyl) amino ] butylcarboxamido) ethyl ] -3, 4-di [ alkyl ] -benzamide, 7- (4- (dimethylamino) butyl) -7-hydroxytridecane-1, 13-diyldioleate (CL 1H 6), 7- (4- (diisopropylamino) butyl) -7-hydroxytridecane-1, 13-diyldioleate (4H 6), 1, 2-stearoyl-3-trimethylammonium (DSTAP), 1, 2-diolamide (DSTAP-3-dimethyl-propan-3-dioleyl) propyl (DSTAP-3-diolamide), or any combination thereof. In some embodiments, the saturated cationic lipid may include at least one of the following: 1, 2-dialkyl-sn-glycero-3-ethylphosphocholine, 1, 2-dialkyl-3-dimethylammonium-propane, 1, 2-dialkyl-3-trimethylammonium-propane, 1, 2-di-O-alkyl-3-trimethylammonium propane, 1, 2-dialkoxy-3-dimethylaminopropane, N-dialkyl-N, N-dimethylammonium, N- (4-carboxybenzyl) -N, N-dimethyl-2, 3-bis (alkoxy) propan-1-ammonium, 1, 2-dialkyl-sn-glycero-3- [ (N- (5-amino-1-carboxypentyl) iminodiacetic acid) succinyl ], N1- [2- ((1S) -1- [ (3-aminopropyl) amino ] -4- [ bis (3-amino-propyl) amino ] butylcarboxamido) ethyl ] -3, 4-bis [ alkyl ] -benzamide, and any combination thereof.
In some embodiments, the at least one cationic lipid comprises MVL5; MC2; CL1H6; CL4H6; DODMA, and any combination thereof.
In some embodiments, the delivery vehicle comprises from about 5 to about 90 mole% of at least one cationic lipid. In some embodiments, the delivery vehicle comprises from about 5 to about 60 mole% of at least one cationic lipid. In some embodiments, the delivery vehicle comprises from about 10 to about 60 mole% of at least one cationic lipid. In some embodiments, the delivery vehicle comprises from about 10 to about 50 mole% of at least one cationic lipid. In some embodiments, the delivery vehicle comprises from about 10 to about 30 mole% of at least one cationic lipid.
In some embodiments, the at least one cationic lipid comprises at least one multivalent cationic lipid and at least one ionizable cationic lipid.
In some embodiments, the at least one multivalent cationic lipid comprises MVL5.
In some embodiments, the delivery vehicle comprises from about 5 to about 90 mole% of at least one multivalent cationic lipid. In some embodiments, the delivery vehicle comprises from about 5 to about 60 mole% of at least one multivalent cationic lipid. In some embodiments, the delivery vehicle comprises from about 5 to about 30 mole% of at least one multivalent cationic lipid. In some embodiments, the delivery vehicle comprises from about 5 to about 15 mole% of at least one multivalent cationic lipid. In some embodiments, the at least one multivalent cationic lipid comprises up to about 100 mole% of the at least one cationic lipid.
In some embodiments, the at least one multivalent cationic lipid comprises about 5-75 mole% of the at least one cationic lipid. In some embodiments, the at least one multivalent cationic lipid comprises about 40-60 mole% of the at least one cationic lipid. In some embodiments, the at least one multivalent cationic lipid comprises about 50 mole% of the at least one cationic lipid.
In some embodiments, the at least one ionizable cationic lipid comprises at least one of MC2, CL1H6, CL4H6, DODMA, and any combination thereof.
In some embodiments, the at least one ionizable cationic lipid comprises MC2. In some embodiments, the at least one ionizable cationic lipid comprises CL1H6. In some embodiments, the at least one ionizable cationic lipid comprises CL4H6. In some embodiments, the at least one ionizable cationic lipid comprises DODMA.
In some embodiments, the delivery vehicle comprises from about 5 to about 90 mole% of at least one ionizable cationic lipid. In some embodiments, the delivery vehicle comprises from about 5 to about 60 mole% of at least one ionizable cationic lipid. In some embodiments, the delivery vehicle comprises from about 5 to about 30 mole% of at least one ionizable cationic lipid. In some embodiments, the delivery vehicle comprises from about 5 to about 15 mole% of at least one ionizable cationic lipid. In some embodiments, the ionizable cationic lipid comprises up to about 100 mole% of the at least one cationic lipid.
In some embodiments, the ionizable cationic lipid comprises about 5-75 mole% of the at least one cationic lipid. In some embodiments, the ionizable cationic lipid comprises about 40-60 mole% of the at least one cationic lipid. In some embodiments, the ionizable cationic lipid comprises about 50 mole% of the at least one cationic lipid. In some embodiments, the delivery vehicle comprises about the same amount of at least one multivalent cationic lipid and at least one ionizable cationic lipid.
In some embodiments, the at least one structural lipid comprises at least one neutral lipid, at least one anionic lipid, at least one phospholipid, and any combination thereof.
In some embodiments, the at least one structural lipid comprises Glycerol Monooleate (GMO), dioleoyl phosphatidylethanolamine (DOPC), 1, 2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC), short chain bis-N-heptadecylphospholipid phosphatidylcholine (DHPC), di (hexadecanoyl) phosphoethanolamine (DHPE), 1, 2-dioleoyl-sn-glycero-3-phosphocholine (DLPC), dimyristoyl phosphoethanolamine (DMPE), dimyristoyl phosphatidylglycerol (DMPG), dioleoyl phosphatidylcholine (DOPC), dioleoyl phosphatidylethanolamine 4- (N-maleimidomethyl) -cyclohexane-1-carboxylate (DOPE-mal), dioleoyl phosphatidylglycerol (DOPG), 1, 2-dioleoyl-sn-glycero-3- (phosphol-serine) (DOPS), cell-free fusogenic phospholipid (DPPE), dipalmitoyl phosphatidylcholine (DPPC), dipalmitoyl phosphatidylcholine (dpp), dioleoyl phosphatidylethanolamine (dsppe), stearoyl phosphatidylethanolamine (DSPE), stearoyl phosphatidylethanolamine (dpp-pei), stearoyl phosphatidylethanolamine (DSPE), stearoyl phosphatidylethanolamine (dspeak-phosphatidylethanolamine (DSPE), stearoyl phosphatidylethanolamine (dpp-pei), and (dpp-phosphatidyl), 1, 2-di (undecanoyl) -sn-glycero-phosphocholine (DUPC), lecithin (EPC), hydrogenated soybean phosphatidylcholine (MHPC), hydrogenated Soybean Phosphatidylcholine (HSPC), mannosylated dipalmitoyl phosphatidylethanolamine (ManDOG), 1, 2-dioleoyl-sn-glycero-3-phosphoethanolamine-N- [4- (p-maleimidomethyl) cyclohexane-carboxamide ] (MCC-PE), 1, 2-di-phytoyl-sn-glycero-3-phosphoethanolamine (ME 16.0 PE), 1-myristoyl-2-hydroxy-sn-glycero-phosphocholine (MHPC), 1-oleoyl-2-cholesteryl hemisuccinyl-sn-glycero-3-phosphocholine (OChemsPC), phosphatidic Acid (PA), phosphatidylethanolamine lipid (PE), phosphatidylglycerol (PG), partially hydrogenated soybean phosphatidylcholine (phsp), phosphatidylinositol lipid (PI), phosphatidylinositol-4-phosphate (PIP), palmitoyl phosphatidyl-Phosphatidylethanolamine (PE), phosphatidyl-2-hydroxy-sn-glycero-3-phosphoethanolamine (ME 16.0 PE), 1-myristoyl-2-hydroxy-glycero-3-phosphoethanolamine (pomsc), 1-oleoyl-Phosphatidylethanolamine (PE), stearoyl-2-succinyl-3-phosphocholine (omps), phosphatidylethanolamine (phsp), phosphatidylethanolamine (PE), phosphatidyl), soybean Phosphatidylcholine (SPC), 1, 2-di-arachidonyl-sn-glycero-3-phosphorylcholine, 1, 2-di-arachidonyl-sn-glycero-3-phosphoethanolamine, 1, 2-di (docosahexaenoic acid) -sn-glycero-3-phosphocholine, 1, 2-di (docosahexaenoic acid) -sn-glycero-3-phosphoethanolamine, 1, 2-di-linolenoyl-sn-glycero-3-phosphocholine, 1, 2-di-linolenoyl-sn-glycero-3-phosphoethanolamine, 1, 2-di-oleoyl-sn-glycero-3-phosphoethanolamine, 1, 2-dioleyl-sn-glycero-3-phosphoethanolamine, 1, 2-distearoyl-sn-glycero-3-phosphoethanolamine, and any combination thereof.
In some embodiments, the at least one structural lipid comprises DSPC, DMPC, DOPE, GMO, and any combination thereof.
In some embodiments, the delivery vehicle comprises from about 5 to about 75 mole% of at least one structural lipid. In some embodiments, the delivery vehicle comprises about 30 to about 50 mole% of at least one structural lipid. In some embodiments, the delivery vehicle comprises about 35 to about 45 mole% of at least one structural lipid.
In some embodiments, the delivery vehicle does not comprise cholesterol.
In some embodiments, the at least one conjugated lipid comprises at least one conjugated lipid and at least one hydrophilic polymer. In some embodiments, the at least one hydrophilic polymer comprises polyethylene glycol (PEG). In some embodiments, the at least one conjugated lipid comprises at least one phospholipid, at least one neutral lipid, at least one glyceride, at least one diglyceride, at least one anionic lipid, at least one cationic lipid, and any combination thereof.
In some embodiments, the at least one conjugated lipid comprises 1, 2-dimyristoyl-rac-glycerol (DMG), 1, 2-dimyristoyl-sn-glycero-3-phosphoethanolamine (DMPE), 1, 2-distearoyl-rac-glycerol (DSG), 1, 2-dipalmitoyl-rac-glycerol (DPG), 1, 2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE), diacylglycerol (DAG), 1, 2-dipalmitoyl-sn-glycero-3-phosphoethanolamine (DPPE), and any combination thereof.
In some embodiments of the present invention, in some embodiments, the at least one conjugated lipid comprises DMG-PEG, DMPE-PEG, DSG-PEG, DPG-PEG, DSPE-PEG, DAG-PEG, DPPE-PEG, PEG-S-DSG, PEG-S-DMG, PEG-PE, PEG-PAA, PEG-OH DSPE C18, PEG-DSPE, PEG-DSG, PEG-DPG, PEG-DOMG, PEG-DMPE Na, PEG-DMPE, PEG-DMG2000, PEG-DMG C14, PEG-DMG2000, PEG-DMG, PEG-DMA, PEG-ceramide C16, PEG-C-DOMG, PEG-C-DMNG, PEG-C-DMA, PEG-cDMA, PEGA, PEG-C-DMA, PEG400, PEG2K-DMG, PEG2K-C11, PEG2000-PE, PEG2000-P, PEG-DSPE, PEG2000-DOMG, PEG2000-DMG, PEG2000-C-DMA, PEG 2000' PEG200, PEG (2K) -DMG, PEG DSPE C18, PEG DMPE C14, PEG DLPE C12, mPEG-PLA, MPEG-DSPE, mPEG3000-DMPE, MPEG-2000-DSPE, MPEG2000-DSPE, mPEG2000-DPPE, mPEG2000-DMPE, mPEG2000-DMG, mPPE-PEG 2000, HPEG-2K-LIPD, folic acid PEG-DSPE, DSPE-PEGMA 500, DSPE-PEGMA, DSPE-PEG6000, DSPE-PEG5000, DSPE-PEG2K-NAG, DSPE-PEG2K, DSPE-PEG2000 maleimide, DSPE-PEG2000, DSG-PEGMA, DSG-PEG5000, DPPE-PEG-2K, DPPE-mPEG2000, DPPE-mPEG, DPG-PEGMA, DOPE-PEG2000, DMPE-PEGMA, DMPE-PEG2000, DMPE-mPEG2000, at least one of DMG-PEGMA, DMG-PEG2000, cl8PEG750, CI8PEG5000, CI8PEG3000, CI8PEG2000, CI6PEG2000, CI4PEG2000, C18-PEG5000, C18PEG, C16PEG, C14-PEG-DSPE200, C14-PEG2000, C14-PEG, C14PEG, (PEG) -C-DOMG, PEG-C-DMA, and any combination thereof.
In some embodiments, the at least one conjugated lipid comprises DMG-PEG. In some embodiments, the at least one conjugated lipid comprises DMPE-PEG.
In some embodiments, the delivery vehicle comprises from about 0.5 to about 2.0 mole% of at least one conjugated lipid. In some embodiments, the delivery vehicle does not comprise at least one conjugated lipid.
In some embodiments, the delivery vehicle comprises: at least one bile salt or at least one bile acid; at least one multivalent cationic lipid; at least one ionizable cationic lipid; at least one structural lipid; and at least one conjugated lipid.
In some embodiments, the delivery vehicle comprises: about 5-40 mole% of at least one bile salt or at least one bile acid; about 5 to 90 mole% of at least one multivalent cationic lipid; about 5 to 90 mole% of at least one ionizable cationic lipid; about 5 to 75 mole% of at least one structural lipid component; and about 0.5 to about 2.0 mole% of at least one conjugated lipid component.
In some embodiments, the delivery vehicle comprises: about 5-40 mole% of at least one bile salt or at least one bile acid; about 5 to 60 mole% of at least one multivalent cationic lipid; about 5 to 60 mole% of at least one ionizable cationic lipid; about 5-75 mole% of at least one structural lipid; and about 0.5 to about 2.0 mole% of at least one conjugated lipid.
In some embodiments, the delivery vehicle comprises: about 20-40 mole% of at least one bile salt or at least one bile acid; about 5 to 30 mole% of at least one multivalent cationic lipid; about 5 to 30 mole% of at least one ionizable cationic lipid; about 30-50 mole% of at least one structural lipid; and about 0.5 to about 2.0 mole% of at least one conjugated lipid.
In some embodiments, the delivery vehicle comprises: about 30-40 mole% of at least one bile salt or at least one bile acid; about 5 to 15 mole% of at least one multivalent cationic lipid; about 5 to 15 mole% of at least one ionizable cationic lipid; about 35 to 45 mole% of at least one structural lipid; and about 0.5 to about 2.0 mole% of at least one conjugated lipid.
In some embodiments, the delivery vehicle comprises: about 33 mole% of at least one bile salt or at least one bile acid; about 12.5 mole% of at least one multivalent cationic lipid; about 12.5 mole% of at least one ionizable cationic lipid; about 41 mole% of at least one structural lipid; and about 1 mole% of at least one conjugated lipid.
In some embodiments, the delivery vehicle comprises any of the compositions disclosed in table 1B.
In some embodiments, at least one conjugated lipid is conjugated to at least one polypeptide. In some embodiments, the at least one polypeptide comprises at least one mucus penetrating polypeptide. In some embodiments, at least one mucus penetrating polypeptide comprises an amino acid sequence according to SEQ ID NO. 17.
In some embodiments, the delivery vehicle comprises a load (cargo). In some embodiments, the cargo comprises a nucleic acid, a protein, an antibody, a peptide, a small molecule, a biologic, a peptidomimetic, a ribozyme, a chemical agent, a viral particle, a growth factor, a cytokine, an immunomodulator, a fluorescent dye, and any combination thereof.
In some embodiments, the load comprises a nucleic acid. In some embodiments, the nucleic acid comprises DNA. In some embodiments, the DNA comprises plasmid DNA.
In some embodiments, the molar ratio of total nanoparticle cationic lipid to the total number of nucleotides comprised by the nucleic acid load is from about 2 to about 20. In some embodiments, the molar ratio of total nanoparticle cationic lipid to the total number of nucleotides comprised by the nucleic acid load is from about 14 to about 18.
In some embodiments, the nucleic acid comprises RNA. In some embodiments, the molar ratio of total nanoparticle cationic lipid to the total number of nucleotides comprised by the nucleic acid load is from about 2 to about 20. In some embodiments, the molar ratio of total nanoparticle cationic lipid to the total number of nucleotides comprised by the nucleic acid load is from about 2 to about 4. In some embodiments, the present disclosure provides a pharmaceutical composition comprising at least one delivery vehicle described herein and optionally a pharmaceutically acceptable excipient.
In some embodiments, pharmaceutically acceptable excipients include excipients, adjuvants, solutions, stabilizers, additives, surfactants, lyophilized ingredients, diluents, and any combination thereof.
In some embodiments, the pharmaceutical composition is formulated for enteral delivery.
In some embodiments, the present disclosure provides a method of delivering at least one load to a subject, the method comprising introducing at least one delivery vehicle described herein or at least one pharmaceutical composition described herein to the gastrointestinal tract of the subject. In some embodiments, at least one delivery vehicle or at least one pharmaceutical composition is introduced into the Gastrointestinal (GI) tract of a subject by at least one route of administration. In some embodiments, at least one route includes intravenous administration, intraperitoneal administration, intramuscular administration, transdermal administration, ocular administration, oral administration, intrarectal administration, direct injection into the gastrointestinal tract, and any combination thereof. In some embodiments, at least one delivery vehicle or at least one pharmaceutical composition targets at least one gastrointestinal cell. In some embodiments, the at least one gastrointestinal cell comprises at least one of an intestinal epithelial cell, a lamina propria cell, an intraepithelial lymphocyte, an intestinal muscle cell, an intestinal neuron, or any combination thereof.
In some embodiments, at least one load is delivered to the gastrointestinal cells. In some embodiments, at least one load is delivered to the intracellular space of the gastrointestinal cell. In some embodiments, the at least one cargo component, or the at least one expression product of the cargo is secreted from the gastrointestinal cells. In some embodiments, the secretion of the at least one load, the at least one load component, or the at least one expression product of the load comprises apical secretion (apical secretion) or basal secretion (basal secretion). In some embodiments, at least one load component, or at least one expression product of a load remains in a region proximal to the cell after secretion. In some embodiments, at least one cargo component, or at least one expression product of a cargo is secreted from the gastrointestinal cell foundation and into the circulation. In some embodiments, at least one load component, or at least one expression product of a load is systematically distributed after entering the cycle.
In some embodiments, the at least one load comprises at least one therapeutic agent. In some embodiments, the at least one therapeutic agent comprises one or more of a nucleic acid, a polypeptide, a protein, a biologic, an antibody, an enzyme, a hormone, a cytokine, an immunogen, and a gene or epigenetic editing system component. In some embodiments, the at least one therapeutic agent comprises at least one nucleic acid. In some embodiments, at least one nucleic acid encodes at least one polypeptide. In some embodiments, the at least one nucleic acid comprises DNA. In some embodiments, the at least one nucleic acid comprises plasmid DNA.
In some embodiments, the at least one nucleic acid comprises RNA. In some embodiments, the at least one nucleic acid comprises mRNA, circRNA, saRNA, and any combination thereof.
In some embodiments, the methods described herein comprise transfecting at least one gastrointestinal cell with at least one nucleic acid. In some embodiments, at least one gastrointestinal cell expresses at least one polypeptide encoded by at least one nucleic acid. In some embodiments, the polypeptide comprises granulocyte spleen stimulating factor (G-CSF), green Fluorescent Protein (GFP), and any combination thereof.
In some embodiments, the at least one nucleic acid comprises at least one non-coding RNA. In some embodiments, the at least one non-coding RNA includes one or more of interfering short RNAs (siRNA), micrornas (miRNA), long-chain non-coding RNAs, piwi-interacting RNAs (piRNA), nucleolar micrornas (snoRNA), cajal body-specific micrornas (scaRNA), transfer RNAs (tRNA), ribosomal RNAs (rRNA), and intranuclear micrornas (snRNA).
In some embodiments, the present disclosure provides a method for treating at least one therapeutic indication in a subject in need thereof, comprising delivering to the subject at least one delivery vehicle described herein or at least one pharmaceutical composition described herein by at least one method for delivering a load described herein. In some embodiments, at least one therapeutic indication comprises neurodegenerative diseases, ocular diseases, reproductive diseases, gastrointestinal diseases, brain diseases, skin diseases, skeletal diseases, musculoskeletal diseases, pulmonary diseases, thoracic diseases, cystic fibrosis, familial amaurosis dementia (tay-sachs), fragile X syndrome (fragile X), huntington's, neurofibromatosis, sickle cell disease, thalassemia, progressive pseudohypertrophic muscular dystrophy (Duchenne' smuscular dystrophy), familial Adenomatous Polyposis (FAP), attenuated FAP, microvilli inclusion body diseases (MVID), chronic inflammatory bowel disease, ileal Crohn's disease, juvenile polyposis, hereditary diffuse gastric cancer syndrome (HDGC), peutz-Jeghers syndrome, lynch syndrome, gastric proximal polyposis (gastric adenocarcinoma and proximal polyposis of the stomach), GAPPS), li-Fraomeni syndrome, familial gastric cancer, gilbert syndrome, telangiectasia, mucopolysaccharidosis (mucopolysaccharidosis), osler-Weber-Rendu syndrome, pancreatitis, keratoacanthoma, biliary tract occlusion, morquio syndrome, hurler's syndrome, hunter's syndrome, crigler-Najjar syndrome, rotor syndrome, peutz-Jeghers syndrome, dubin-Johnson syndrome, osteochondrosis dysplasia (Osteochodysplasas), polyposis, gastrointestinal infection, inflammatory Bowel Disease (IBD), ulcerative colitis, crohn's disease, hemophilia, short Bowel Syndrome (SBS), diabetes, non-alcoholic steatohepatitis (NASH), and at least one of hodgkin's lymphoma, non-hodgkin's lymphoma, acute lymphoblastic leukemia or Acute Myelogenous Leukemia (AML), neutropenia, or any combination thereof.
In some embodiments, the at least one therapeutic indication comprises at least one immune-related indication. In some embodiments, the at least one immune-related indication comprises at least one gastrointestinal indication. In some embodiments, the at least one therapeutic indication comprises at least one cancer-related indication.
Brief description of the drawings
The drawings are not necessarily to scale or in general, emphasis instead being placed upon illustrating the principles of various embodiments of the disclosure.
Fig. 1 shows the results of an exemplary assay to measure transfection efficiency of an exemplary delivery vehicle of the present disclosure carrying DNA as a load in HEK cells.
Fig. 2 shows the results of an exemplary assay for measuring the stability of an exemplary delivery vehicle of the present disclosure. "no treatment" means FRET results of the delivery vehicle in a zero bile salt environment. Results of exposure to delivery vehicles of specified bile salt concentrations were shown to be normalized to "no treatment" conditions.
Fig. 3 shows the results of an exemplary assay for measuring the stability of an exemplary delivery vehicle of the present disclosure. "no treatment" means FRET results of the delivery vehicle in a zero bile salt environment. Results of exposure to delivery vehicles of specified bile salt concentrations were shown to be normalized to "no treatment" conditions.
Fig. 4 shows the results of an exemplary assay for measuring the stability of an exemplary delivery vehicle of the present disclosure. "no treatment" means FRET results of the delivery vehicle in a zero bile salt environment. Results of exposure to delivery vehicles of specified bile salt concentrations were shown to be normalized to "no treatment" conditions.
Fig. 5 shows agarose gel electrophoresis using an exemplary delivery vehicle of the present disclosure (formulation No. 5 in table 2). Lanes from left are as follows: lane one shows the standard; lane 2 shows untreated delivery vehicle; lane three shows delivery vehicle treated with 7% triton-X100; lane four shows delivery vehicle treated with 7% triton-X plus heat (30 min at 70 ℃).
Fig. 6 shows a mouse colon section of a mouse dosed with 30 micrograms of DNA encapsulated in di and DiO labeled delivery vehicles. What is observed is the distribution of the carrier with 1% peg labeled with DiI and DiO (particle 5 of table 3) as shown by fluorescence imaging from DiI superimposed on bright field. For a description of particle 5 and other reference particles in the figures, see example 5, table 3.
Fig. 7 shows a mouse colon section of a mouse dosed with 30 micrograms of DNA encapsulated in di and DiO labeled delivery vehicles. What is observed is the distribution of the carrier with 2% peg labeled with DiI and DiO (particle 6 of table 3) as shown by fluorescence imaging from DiI superimposed on bright field.
Fig. 8 shows a mouse colon section of a mouse dosed with 30 micrograms of DNA encapsulated in di and DiO labeled delivery vehicle (particle 7 of table 3). What was observed is the distribution of the carrier containing 3% peg labeled with DiI and DiO as shown by fluorescence imaging from DiI superimposed on bright field.
Fig. 9 shows a mouse colon section of a mouse dosed with 30 micrograms of DNA encapsulated in di and DiO labeled delivery vehicles. What is observed is the distribution of the carrier with 5% peg labeled with DiI and DiO (particle 8 of table 3) as shown by fluorescence imaging from DiI superimposed on bright field.
Fig. 10 shows a mouse colon section of a mouse dosed with 30 micrograms of DNA encapsulated in di and DiO labeled delivery vehicles. What is observed is the distribution of the carrier with 10% peg labeled with DiI and DiO (particle 9 of table 3) as shown by fluorescence imaging from DiI superimposed on bright field.
Fig. 11A shows the distribution of delivery vehicles in representative colon sections of mice administered particles with a 0%/25% mvl5/DODMA mole percent ratio (particle 1 of table 3).
Fig. 11B shows the distribution of delivery vehicles in representative colon sections of mice administered particles with a 0%/25% mvl5/DODMA mole percent ratio (particle 1 of table 3).
Fig. 12A shows the distribution of delivery vehicles in representative colon sections of mice administered particles (particle 2 of table 3) with a 6.25%/18.75% (MVL 5/DODMA) mole percent ratio.
Fig. 12B shows the distribution of delivery vehicles in representative colon sections of mice administered particles (particle 2 of table 3) with a 6.25%/18.75% (MVL 5/DODMA) mole percent ratio.
Fig. 13A shows the distribution of delivery vehicles in representative colon sections of mice administered particles with a 12.5%/12.5% (MVL 5/DODMA) mole percent ratio (particle 3 of table 3).
Fig. 13B shows the distribution of delivery vehicles in representative colon sections of mice administered particles with a 12.5%/12.5% (MVL 5/DODMA) mole percent ratio (particle 3 of table 3).
Fig. 14A shows the distribution of delivery vehicles in representative colon sections of mice administered particles (particle 4 of table 3) with a 18.75%/6.25% (MVL 5/DODMA) molar% ratio.
Fig. 14B shows the distribution of delivery vehicles in representative colon sections of mice administered particles (particle 4 of table 3) with a 18.75%/6.25% (MVL 5/DODMA) molar% ratio.
Fig. 15A shows the distribution of delivery vehicles in representative colon sections of mice administered particles with a 25%/0% mvl5/DODMA mole% ratio (particles 10 of table 3).
Fig. 15B shows the distribution of delivery vehicles in representative colon sections of mice administered particles with a 25%/0% mvl5/DODMA mole% ratio (particles 10 of table 3).
Fig. 16A shows Swiss coil (Swiss roll) images of the colon of a section of a first mouse with DiI and DiO applied MVL 5/DODMA/DOPC/deoxycholate/DMG-PEG (particle 11 of table 3) obtained using BioTek rotation software. The figure shows the DiI channel.
Fig. 16B shows swiss coil images of the colon of a section of a first mouse with DiI and DiO applied MVL 5/DODMA/DOPC/deoxycholate/DMG-PEG (particle 11 of table 3) obtained using BioTek rotation software. The figure shows the DiI channel superimposed on the bright field.
Fig. 16C shows swiss coil images of the colon of a section of a second mouse with DiI and DiO applied MVL 5/DODMA/DOPC/deoxycholate/DMG-PEG (particle 11 of table 3) obtained using BioTek rotation software. The figure shows the DiI channel.
Fig. 16D shows swiss coil images of the colon of a section of a second mouse with DiI and DiO applied MVL 5/DODMA/DOPC/deoxycholate/DMG-PEG (particle 11 of table 3) obtained using BioTek rotation software. The figure shows the DiI channel superimposed on the bright field.
Fig. 17A shows swiss coil images of the colon of a section of a first mouse with DiI and DiO applied MVL 5/DODMA/GMO/deoxycholate/DMG-PEG (particle 12 of table 3) obtained using BioTek rotation software. The figure shows the DiI channel.
Fig. 17B shows swiss coil images of the colon of a section of a first mouse with DiI and DiO applied MVL 5/DODMA/GMO/deoxycholate/DMG-PEG (particle 12 of table 3) obtained using BioTek rotation software. The figure shows the DiI channel superimposed on the bright field.
Fig. 17C shows swiss coil images of the colon of a section of a second mouse with DiI and DiO applied MVL 5/DODMA/GMO/deoxycholate/DMG-PEG (particle 12 of table 3) obtained using BioTek rotation software. The figure shows the DiI channel.
Fig. 17D shows swiss coil images of the colon of a section of a second mouse with DiI and DiO applied MVL 5/DODMA/GMO/deoxycholate/DMG-PEG (particle 12 of table 3) obtained using BioTek rotation software. The figure shows the DiI channel superimposed on the bright field.
Fig. 18A shows swiss coil images of the colon of a section of a first mouse with DiI and DiO applied MVL 5/DODMA/DSPC/deoxycholate/DMG-PEG (particle 5 of table 3) obtained using BioTek rotation software. The figure shows the DiI channel.
Fig. 18B shows swiss coil images of the colon of a section of a first mouse with DiI and DiO applied MVL 5/DODMA/DSPC/deoxycholate/DMG-PEG (particle 5 of table 3) obtained using BioTek rotation software. The figure shows the DiI channel superimposed on the bright field.
Fig. 18C shows swiss coil images of the colon of a section of a second mouse with DiI and DiO applied MVL 5/DODMA/DSPC/deoxycholate/DMG-PEG (particle 5 of table 3) obtained using BioTek rotation software. The figure shows the DiI channel.
Fig. 18D shows swiss coil images of the colon of a section of a second mouse with DiI and DiO applied MVL 5/DODMA/DSPC/deoxycholate/DMG-PEG (particle 5 of table 3) obtained using BioTek rotation software. The figure shows the DiI channel superimposed on the bright field.
Fig. 19A shows swiss coil images of the colon of a section of a first mouse with di and DiO applied PBS obtained using BioTek rotation software. The figure shows the DiI channel.
Fig. 19B shows swiss coil images of the colon of a section of a first mouse with di and DiO applied PBS obtained using BioTek rotation software. The figure shows the DiI channel superimposed on the bright field.
Fig. 19C shows swiss coil images of the colon of a section of a second mouse with di and DiO-administered PBS obtained using BioTek rotation software. The figure shows the DiI channel.
Fig. 19D shows swiss coil images of the colon of a section of a second mouse with di and DiO-administered PBS obtained using BioTek rotation software. The figure shows the DiI channel superimposed on the bright field.
FIG. 20 shows a bar graph comparing the stability of lipid structures incorporating different bile salts in 10g/L bile salts (cholate: deoxycholate mixture) by measuring perturbations in lipid structure using FRET between DiI and DiO. FRET values were normalized for no treatment.
Detailed Description
Delivering agents such as therapeutic agents to epithelial tissues and cells such as in the Gastrointestinal (GI) tract, vagina, and lungs presents certain challenges. In these tissues, the epithelial cells are covered by a mucosal layer, so the therapeutic agent must penetrate and migrate through the mucus to reach the epithelial cells. Furthermore, once within or through the mucus layer, the therapeutic agent must access the intended target cell, and in some embodiments, interact with the cell membrane and/or enter the cell. Thus, the use of a delivery vehicle that not only penetrates and passes through the mucus layer but also into the range of intended epithelial cell targets improves the delivery of the agent (also referred to herein as "payload"). Furthermore, in the case of the GI tract and other tissues, the harsh environment (e.g., bile acids naturally present in the GI) may present challenges to the stability of delivery and successful delivery of the load to the intended target cells.
Provided herein are delivery vehicles for delivering a load to a desired target in a subject. Also disclosed herein are delivery vehicles having improved stability in high bile salt environments, such as in the gastrointestinal tract. In some embodiments, the delivery vehicles disclosed herein may provide stability in the harsh environment of the GI tract and may be further suitable for use in the mucilage environment. In some embodiments, the delivery vehicles herein can provide increased rates of transport through or across mucosal layers in or around a target tissue or cell. In some embodiments, the delivery vehicles herein provide for penetration through mucus to reduce or prevent entrapment of the delivery vehicle in epithelial mucus, as well as epithelial arrival functionality that brings the delivery vehicle into proximity to epithelial cells, e.g., within a distance of 20 microns or less. Thus, the delivery vehicle may be suitable for delivering a cargo (e.g., a nucleic acid) to a mucosal epithelial cell, such as an intestinal epithelial cell, a lung epithelial cell, a cervical epithelial cell, a rectal epithelial cell, an endometrial cell, or the like. Furthermore, the delivery vehicle may also be suitable for delivery to an organ, such as skin. In some embodiments, the delivery vectors herein carry a therapeutic load (e.g., nucleic acid, protein, or drug) and are useful for treating diseases affecting the GI tract such as familial polyposis (FAP), attenuated FAP, colorectal cancer, chronic inflammatory bowel disease, ileal crohn's disease, microvilli inclusion body disease, and congenital diarrhea.
In some embodiments, the delivery vehicles provided herein comprise various lipid components and have a nanoparticle structure, such as a Lipid Nanoparticle (LNP). In some embodiments, the lipid component of the delivery vehicle may be manufactured in a manner that forms liposomes, micelles, or other lipid structures. In some embodiments, the delivery vehicles described herein comprise at least one bile salt or bile acid, at least one cationic lipid, at least one structural lipid, and at least one conjugated lipid. In some embodiments, the delivery vehicle herein comprises at least one bile salt or bile acid, at least two (2) cationic lipids, at least one structural lipid, and at least one conjugated lipid. In some embodiments, the disclosed delivery vehicle comprises at least one bile salt or bile acid, at least one multivalent cationic lipid, at least one non-multivalent ionizable cationic lipid, at least one structural lipid, and at least one conjugated lipid. In some embodiments, the delivery vehicle lacks one, some, or all but one of a bile salt, bile acid, cationic lipid (multivalent or ionizable), structural lipid, or conjugated lipid. In some embodiments, the delivery vehicle is free of cholesterol.
In some embodiments, the delivery vehicles provided herein (also referred to herein as "charge-separated" delivery vehicles) include those that separate positive and negative charges into separate sites within the vehicle, such that positively charged molecules and negatively charged molecules are separated from each other, rather than being interspersed.
In some embodiments, the delivery vehicles provided herein may include additional mucus-penetrating features that may aid in the penetration and movement of the delivery vehicle through mucus surrounding epithelial cells. These additional features include, but are not limited to, the incorporation of polymers such as polyethylene glycol (PEG), polymers with methyl groupsAzolinesThe Polymer (PMOZ), the poly ≡oxazoline Polymer (PEOZ) with ethyl groups are incorporated into the delivery vehicle surface and/or by including a Mucus Penetrating Peptide (MPP) attached to the delivery vehicle surface. In some embodiments, the delivery vehicle does not comprise a PEG coating or a low density PEG coating (or a low density coating of another polymer).
Also provided herein are pharmaceutical compositions (also referred to as medicaments) formulated from the delivery vehicles disclosed herein and pharmaceutically acceptable excipients for administration to a subject. The pharmaceutical compositions described herein may be formulated for any route of administration including, but not limited to, oral, injectable, parenteral, topical, transdermal, ocular, otic, pulmonary, intranasal, nasal, buccal, rectal or vaginal.
Also provided herein are methods of delivering a load to a subject using the delivery vehicles disclosed herein, as well as methods of treating a therapeutic indication in a subject in need thereof.
I. Delivery vehicle
Provided herein are delivery vehicles that may optionally include at least one load. In some embodiments, the delivery vehicle may be or include a liposome, micelle, exosome, viral particle, polymeric delivery agent, or nanoparticle, such as a Lipid Nanoparticle (LNP) and a non-lipid nanoparticle. In some embodiments, the delivery vehicle may be or include a lipid structure. In some embodiments, the delivery vehicle may be or include at least one Lipid Nanoparticle (LNP).
Delivery vehicle class
Nanoparticles
In some embodiments, the delivery vehicle may be or comprise nanoparticles. The term "nanoparticle" as used herein refers to any particle having a size in the range of 10-1000 nm. In some embodiments, the nanoparticle may have any size, including, but not limited to, about 10-900, about 10-800, about 10-700, about 10-600, about 10-500, about 10-400, about 10-300, about 10-200, about 10-100, about 100-1000, about 100-900, about 100-800, about 100-700, about 100-600, about 100-500, about 100-400, about 100-300, about 100-200, about 200-1000, about 200-900, about 200-800, about 200-700, about 200-600, about 200-500, about 200-400, about 300-300, about 300-1000, about 300-900, about 300-800, about 300-700, about 300-600, about 300-500, about 300-400, about 400-1000, about 400-900, about 400-700, about 400-600, about 400-500, about 500-1000, about 500-800, about 500-500, about 600-600, about 600-700, about 700-700, about 1000, or about 900-900. In some embodiments, the size of the nanoparticle may be between about 50nm and 150 nm.
In some embodiments of the present invention, in some embodiments, the nanoparticle may be 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 275, 280, 285, 290, 295, 300, 305, 310, 315, 320, 325, 330, 335, 340, 345, 350, 355, 360, 365, 370, 380, 385, 390, 395, 400, 405, 410, 415, 420, 425, 430, 435, 440, 445, 450, 455, 460, 465, 470, 475, 480, 485, 495, 500, 505 510, 515, 520, 525, 530, 535, 540, 545, 550, 555, 560, 565, 570, 575, 580, 585, 590, 595, 600, 605, 610, 615, 620, 625, 630, 635, 640, 645, 650, 655, 660, 665, 670, 675, 680, 685, 690, 695, 700, 705, 710, 715, 720, 725, 730, 735, 740, 745, 750, 755, 760, 765, 770, 775, 780, 785, 790, 795, 800, 805, 810, 815, 820, 825, 830, 835, 840, 845, 850, 855, 860, 865, 870, 875, 880, 885, 890, 895, 900, 905, 910, 915, 920, 925, 930, 935, 940, 945, 950, 955, 960, 965, 970, 975, 980, 985, 990, 995 or 1000nm.
In some embodiments, the delivery vehicle nanoparticle may have a defined shape. In some embodiments, the shape of the nanoparticle may be, but is not limited to, spherical, oval, disc-shaped, rod-shaped, conical, geodesic, or any combination thereof.
Lipid nanoparticles
In some embodiments, the delivery vehicle may be or comprise a nanoparticle, which may be a Lipid Nanoparticle (LNP). As known in the art, LNPs can be characterized as small solid or semi-solid particles having an outer lipid layer with a hydrophilic outer surface exposed to a non-LNP environment; an interior space, which may be aqueous (vesicle-like) or non-aqueous (micelle-like); and at least one hydrophobic membrane-to-membrane space. The membrane of the LNP may be lamellar or non-lamellar. Furthermore, the membrane of the LNP may consist of 1, 2, 3, 4, 5 or more layers. In some embodiments, the LNP may comprise a load into its interior space, into the inter-membrane space, onto its exterior surface, or any combination thereof.
Non-lipid nanoparticles
In some embodiments, the delivery vehicle may be or comprise nanoparticles, which may be non-lipid based nanoparticles. Non-lipid based nanoparticles include, but are not limited to, carbon-based nanoparticles, polypeptide-based nanoparticles, silicon-based nanoparticles (i.e., porous silicon nanoparticles), nucleotide-based nanoparticles, and gold nanoparticles.
Liposome
In some embodiments, the delivery vehicle may be or comprise at least one liposome. As used herein, "liposome" may refer to a vesicle comprising at least one lipid bilayer membrane surrounding an aqueous internal nanoparticle space. Typically, the liposomes are not derived from progenitor cells or host cells. Liposomes comprise (large) multilamellar vesicles (MLVs), which may be hundreds of nanometers in diameter, and comprise a series of concentric bilayers separated by narrow aqueous spaces. Liposomes also include small single cell vesicles (SUVs), which may be less than 50nm in diameter. Furthermore, liposomes may comprise Large Unilamellar Vesicles (LUVs), which may be between 50 and 500nm in diameter. In some embodiments, liposomes differ from LNPs primarily in their method of manufacture and may comprise any or all of the same components and the same amounts of components as the lipid nanoparticle.
Micelle
In some embodiments, the delivery vehicle may be or comprise at least one micelle. As used herein, "micelle" refers to a small particle that does not have an aqueous intra-particle space. Without wishing to be bound by theory, the intra-particle space of the micelle is occupied by the hydrophobic tail of the lipid comprising the micelle membrane and possibly the associated loading, rather than any additional lipid head groups. In some embodiments, micelles differ from LNPs primarily in their method of manufacture, and micelles may comprise any or all of the same components as lipid nanoparticles.
Exosome
In some embodiments, the delivery vehicle may be or comprise at least one exosome. As used herein, "exosomes" refer to small membrane-bound vesicles of endocytic origin. Without wishing to be bound by theory, exosomes are typically released from the host/progenitor cells into the extracellular environment after the multivesicular body fuses with the cytoplasmic membrane. Thus, exosomes often include components of the progenitor cell membrane in addition to the designed components and loads. Exosome membranes are typically lamellar, comprising bilayer lipids, with aqueous inter-nanoparticle spaces.
Virus particles
In some embodiments, the delivery vehicle may be or comprise at least one virus-like particle. As used herein, "virus-like particle" refers to a vesicle composed primarily of a protein capsid, sheath, shell or envelope (all of which are used interchangeably herein) derived from a virus that can be loaded with a payload portion. In general, virus-like particles are non-infectious and can be synthesized using cellular machinery to express viral capsid protein sequences, which then self-assemble and incorporate the relevant payload portions, although virus-like particles can be formed by providing the capsid and payload components (without expressing the relevant cellular machinery) and allowing them to self-assemble.
In some embodiments, the virus-like particle may be derived from at least one viral species, such as, but not limited to, parvoviridae (Parvoviridae), retroviridae (Retroviridae), flaviviridae (flavviridae), paramyxoviridae (Paramyxoviridae), and phage. In some embodiments, the virus-like particle may be derived from adeno-associated virus, HIV, hepatitis c virus, HPV, or any combination thereof.
Polymer delivery technology
In some embodiments, the delivery vehicle may be or comprise at least one polymeric delivery agent. As used herein, "polymer delivery agent" refers to a non-aggregating delivery agent comprising a soluble polymer conjugated to a loading moiety through various linking groups.
Lipid structure
In some embodiments, the delivery vehicle may be or comprise at least one lipid structure. In some embodiments, the at least one lipid structure may be or include a lipid particle, a lipid nanoparticle, a vesicle, a liposome, a micelle, or any combination thereof. In general, vesicles refer to lipid structures in which an aqueous volume is encapsulated by amphiphilic lipid bilayers (e.g., monolayer; monolayer or multilamellar; multilamellar). In some embodiments, lipid structure refers to an arrangement in which the lipid at least partially coats the interior comprising the therapeutic product. In some embodiments, lipid structure refers to a lipid aggregate in which lipid encapsulated therapeutic products are contained in a relatively disordered lipid mixture.
In some embodiments, the lipid structure may be a cationic liposome. In some embodiments, the liposome may be a cationic liposome for carrying negatively charged polynucleic acids, such as DNA. The presence of positively charged amines may facilitate binding to anions such as those found in DNA. The liposomes so formed may be the result of energy contributions from van der Waals forces and electrostatic binding to DNA loading (which may contribute in part to the shape of the liposome).
Biocompatibility, biodegradability and functional lifetime
In some embodiments, the delivery vehicles described herein may be biocompatible and biodegradable. In some embodiments, the delivery vehicle is biodegradable upon introduction into a subject. In some embodiments, biodegradation may begin immediately after introduction. In some embodiments, biodegradation can occur within the mucosal tract of a subject who has received administration of the delivery vehicle. In some embodiments, biodegradation may result in release of the load. In some embodiments, biodegradation may include decomposition of components of the nanoparticle structure, such as polymers.
In some embodiments, biodegradation can occur under standard body conditions, such as about 97.6°f to about 99°f. In some embodiments, biodegradation may occur at a temperature of about 95°f to about 106°f. In some embodiments, biodegradation may occur at about 95°f, 96°f, 97°f, 98°f, 99°f, 100°f, 101°f, 102°f, 103°f, 104°f, 105°f, or up to 106°f. In some embodiments, biodegradation may occur at about 50°f to about 150°f.
In some embodiments, biodegradation may not occur.
In some embodiments, when biodegradation occurs, it may take about 1 minute to about 100 years after the nanoparticle or structure is administered to the subject. In some embodiments, biodegradation may take about 1 minute, 5 minutes, 30 minutes, 1 hour, 3 hours, 7 hours, 10 hours, 15 hours, 20 hours, 25 hours, 2 days, 4 days, 8 days, 12 days, 20 days, 30 days, 1.5 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 1.5 years, 3 years, 5 years, 8 years, 10 years, 15 years, 20 years, 30 years, 40 years, 50 years, 60 years, 70 years, 80 years, 90 years, or at least about 100 years.
In some embodiments, the delivery vehicle may function at least or at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 6, 27, 28, 29, 30, 40, 50, 60, 70, 80, 90, or 100 days after introduction to a subject in need thereof. In some embodiments, the delivery vehicle may function at least or at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months after introduction to the subject. In some embodiments, the delivery vehicle provided herein can function for at least or at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, or 30 years after introduction to a subject. In some embodiments, the delivery vehicle may function over a lifetime as long as the recipient. In some embodiments, the delivery vehicle may function at 100% of its normal intended operation. In some embodiments, the delivery vehicle may also function at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% of its normal intended operation. In some embodiments, the function of the delivery vehicle may refer to delivery efficiency, persistence of the lipid nanoparticle, stability of the lipid nanoparticle, or any combination thereof.
In some embodiments, the delivery vectors provided herein can deliver a load, such as a nucleic acid, to a target cell (e.g., RNA, DNA (e.g., microloop DNA)). In some embodiments, the function may include the percentage of cells that receive nucleic acid from the delivery vehicle composition. In some embodiments, function may refer to the frequency or efficiency of protein production from a nucleic acid. In some embodiments, the delivery vector composition may deliver nucleic acid to cells encoding at least a portion of a gene, such as an APC, and the frequency or efficiency may describe the functionally complete gene recovered or produced by delivery of the load.
Delivery vehicle component
The components of the delivery vehicle may be selected according to the desired target, load, size, etc. As a non-limiting example, the delivery vehicle component may be selected to increase the stability of the delivery vehicle in a high bile salt environment (e.g., the gastrointestinal tract of a subject); allowing efficient penetration and transport through the mucus layer, increasing the uptake rate of the target cells, or any combination thereof.
It is to be understood that any singular reference to a component as used herein may include reference to one and only one, one or more, or at least one such component. Similarly, any plural reference to components used herein may include reference to one and only one, one or more, or at least one such component unless otherwise indicated.
Lipid
The delivery vehicles herein may include one or more lipids that may be selected to provide different advantageous properties. For example, in the disclosed delivery vehicle can be used in such as amine pK a Cationic lipids that differ in nature, such as chemical stability, half-life in the circulatory system, half-life in the tissue, net accumulation in the tissue, or toxicity.
In some embodiments, the delivery vehicle may comprise at least one lipid. In some embodiments, the delivery vehicle may comprise at least one bile salt or bile acid. In some embodiments, the delivery vehicle may comprise at least one bile salt, at least one bile acid, at least one cationic lipid, at least one structural lipid, at least one conjugated lipid, and any combination thereof. In some embodiments, cationic (and neutral) lipids may be used for gene delivery.
Bile salts and bile acids
In some embodiments, the delivery vehicle may comprise at least one bile salt or bile acid. Without wishing to be bound by theory, it is believed that inclusion of these lipids increases the stability of the delivery vehicle in a high bile salt environment. Without wishing to be bound by theory, the presence of bile salts in the delivery vehicle may prevent the delivery vehicle film from containing more bile salts from the intestinal environment, thereby preventing the breakdown of absorbed additional bile salts.
Bile acid
The delivery vehicles disclosed herein may include at least one bile acid. Typically, bile acids are steroid acids, examples of which naturally occurring are synthesized in the liver (i.e., primary bile acid) and colon (i.e., secondary bile acid) of animals. The term "bile acid" as used herein may include any member of the family of steroid acids found in the bile of animals (e.g. humans). Any reference to bile acids as used herein may include reference to the same compounds, either naturally or synthetically prepared.
Any reference to a bile acid as used herein may include reference to a bile acid, one and only one bile acid, one or more bile acids, or at least one bile acid. In addition, pharmaceutically acceptable bile acid esters may be used as "bile acids" as described herein, for example bile acids conjugated with amino acids (e.g., glycine or taurine). Other bile acid esters may include, for example, substituted or unsubstituted alkyl esters, substituted or unsubstituted heteroalkyl esters, substituted or unsubstituted aryl esters, substituted or unsubstituted heteroaryl esters, and the like.
In some embodiments, the delivery vehicle may comprise a bile acid, such as, but not limited to, 3β,5α,6β -trihydroxy cholanic acid, 12-ketochenodeoxycholic acid, 12-ketodeoxycholic acid, 12-ketolithocholic acid, 3-oxo chenodeoxycholic acid, 3-oxo deoxycholic acid, 3α,6β,7α,12α -tetrahydroxy bile acid, 3α,6α,7α,12 alpha-tetrahydroxy bile acid, 4-bromobenzoic acid, 6, 7-diketo-lithocholic acid, 7-ketodeoxycholic acid, 7-ketolithocholic acid, allocholic acid, allo-iso-lithocholic acid, orthocholic acid (delta 14 isomer), arachidyl amido cholanic acid, chenodeoxycholic acid-D4, cholic acid, dehydrocholic acid, dehydrolithocholic acid, deoxycholic acid, dioxo-cholic acid, glyco-12-oxo Dan Danwan acid, glycochenodeoxycholic acid, glycocholic acid hydrate, glycodehydrocholic acid, glycodeoxycholic acid, glycohyodeoxycholic acid, glycolithocholic acid, glycoursodeoxycholic acid, glyco-gamma-murine cholic acid, hyodeoxycholic acid, obeticholic acid, pentadecanoic acid, bear deoxycholic acid, alpha-murine deoxycholic acid, beta-murine cholic acid, omega-murine cholic acid, or any combination thereof.
In some embodiments, the delivery vehicle may comprise cholic acid. In some embodiments, the delivery vehicle may comprise chenodeoxycholic acid, lithocholic acid, taurodeoxycholic acid, or a combination thereof.
In some embodiments, the delivery vehicle may comprise Xiong Erchun, 5β -cholanic acid, 3-oxo-cholanic acid, and any combination thereof.
Bile salts
The delivery vehicles disclosed herein may include at least one bile salt. Typically, bile salts are bile acids that have been conjugated to an amino acid such as glycine or taurine. The term "bile salt" as used herein may include any member of a large family of molecules comprising salts of steroid acids found in bile of animals (e.g. humans). Typically, the bile salt may be a conjugated bile acid. In some embodiments, the bile salt may be any bile acid conjugate. In some embodiments, the bile salt may be a bile acid conjugated with taurine or glycine. In some embodiments, the bile salt may be any salt of any bile acid. In some embodiments, the bile salt may be any bile acid conjugate anion.
Any reference to bile salts as used herein may include reference to the same compounds, either naturally or synthetically prepared.
Any reference to a bile salt as used herein may include reference to a bile salt, one and only one bile salt, one or more bile salts, or at least one bile salt.
In some embodiments, the delivery vehicle may comprise bile salts such as, but not limited to, sulfobromophthalein disodium salt hydrate, taurine-3 beta, 5 alpha, 6 beta-Trihydroxycholanic acid, tauchenodeoxycholic acid sodium salt, taurocholate sodium salt hydrate, taurocholate sodium salt, taurodeoxycholic acid sodium salt, taurocholate deoxycholate, taurocholate sodium salt, taurocholate 3-sulfuric acid disodium salt, taurocholate sodium salt, tauro-beta-mous acid sodium salt, tauroursodeoxycholate sodium salt, tauro-alpha-mous acid sodium salt, tauro-gamma-mous acid sodium salt, tauro-omega-mous acid sodium salt, beta-estradiol 17- (beta-D-glucuronide) sodium salt, lithocholic acid 3-sulfate (disodium salt), chenodeoxycholic acid 3-sulfate (disodium salt) chenodeoxycholic acid 7-sulfate (disodium salt), cholic acid 3-sulfate (disodium salt), cholic acid 7-sulfate (disodium salt), cholic acid sodium salt, deoxycholic acid 3-sulfate (disodium salt), deoxycholic acid disulfate (trisodium salt), phenoxymethyl penicillin potassium salt, chenodeoxycholic acid disulfate (trisodium salt) sodium chenodeoxycholate, cholate, methylcholate, sodium taurocholate hydrate, 1-naphthyl isothiocyanate, deoxycholate, pig deoxycholate, glycocholate, sodium glycochenodeoxycholate, sodium cholate hydrate, taurocholate, taurodeoxycholate, taurochenodeoxycholate, sodium deoxycholate, sodium cholate, sodium silicate, chenodeoxycholate, lithocholic acid salt, isophthalate, allopsocholate, deoxycholate sodium monohydrate, dehydrolithocholate, glycodeoxycholate sodium, glycocholate sodium hydrate, taurodeoxycholate sodium hydrate, chenodeoxycholate sodium, glycocholate sulfate, glycocholate, taurocholate sodium hydrate, taurocholate sodium, glycodeoxycholate sodium, and any combination thereof.
In some embodiments, the delivery vehicle may comprise cholate, deoxycholate, conjugates and derivatives thereof, or a combination thereof.
In some embodiments, the delivery vehicle may comprise cholate, deoxycholate, chenodeoxycholate, lithocholate, and any combination thereof.
In some embodiments, the delivery vehicle may comprise deoxycholate.
Amount or concentration of bile salts or bile acids
In some embodiments, the concentration of bile salts or bile acids in the delivery vehicle may comprise from about 80 mole% to about 10 mole%, such as from about 80 mole% to about 70 mole%, from about 65 mole% to about 55 mole%, from about 60 mole% to about 50%, from about 55 mole% to about 45 mole%, from about 50 mole% to about 40 mole%, from about 45 mole% to about 35 mole%, from about 40 mole% to about 30 mole%, from about 35 mole% to about 25 mole%, from about 30 mole% to about 20 mole%, from about 25 mole% to about 15 mole%, from about 20 mole% to about 10 mole%, from about 15 mole% to about 10 mole%, from about 60 mole% to about 20 mole%, from about 25.9 mole%, from about 30.4 mole%, from about 34.9 mole%, from about 39.4 mole%, from about 37.1 mole%, from about 43.9 mole%, or about 45 mole%. In some embodiments, the concentration of bile salt or bile acid in the delivery vehicle may comprise about 5 mole%, 10 mole%, 15 mole%, 20 mole%, 25 mole%, 30 mole%, 35 mole%, 40 mole%, 45 mole%, 50 mole%, 55 mole%, 60 mole%, 65 mole%, 70 mole%, 75 mole%, 80 mole%, or 85 mole%.
In some embodiments, the amount of bile salt or bile acid in the delivery vehicle may be from about 5 to about 85 mole% of the total amount of lipids in the delivery vehicle. For example, the amount of bile salt or bile acid in the delivery vehicle may be about 5-85 mole%, about 15-85 mole%, about 25-85 mole%, about 35-85 mole%, about 45-85 mole%, about 55-85 mole%, about 65-85 mole%, about 75-85 mole%, about 5-75 mole%, about 15-75 mole%, about 25-75 mole%, about 35-75 mole%, about 45-75 mole%, about 55-75 mole%, about 65-75 mole%, about 5-65 mole%, about 15-65 mole%, about 25-65 mole%, about 35-65 mole%, about 45-65 mole%, about 55-65 mole%, about 5-55 mole%, about 15-55 mole%, about 25-55 mole%, about 35-55 mole%, about 45-55 mole%, about 5-45 mole%, about 15-45 mole%, about 25-45 mole%, about 35-45 mole%, about 5-35 mole%, about 15-35 mole%, about 25-25%, about 15% or about 15-25% of the total lipid in the delivery vehicle. In some embodiments, the amount of bile salt or bile acid in the delivery vehicle may be about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, or 85 mole% of the total amount of lipid in the delivery vehicle.
In some embodiments, the amount of bile salt or bile acid in the delivery vehicle may be from about 5 to about 40 mole% of the total amount of lipids in the delivery vehicle. In some embodiments, the amount of bile salt or bile acid in the delivery vehicle may be from about 20 to about 40 mole% of the total amount of lipids in the delivery vehicle. In some embodiments, the amount of bile salt or bile acid in the delivery vehicle may be from about 30 to about 40 mole% of the total amount of lipids in the delivery vehicle. In some embodiments, the amount of bile salt or bile acid in the delivery vehicle may be about 35 mole% of the total amount of lipids in the delivery vehicle.
Bile salts or bile acids may be included in the nanoparticle at a level of about 5 to about 40 mole percent of the total nanoparticle lipid (e.g., about 20 to about 40 or about 33 to about 37 mole percent of the total nanoparticle lipid).
Multiple bile acid or bile salt delivery vehicles
In some embodiments, the delivery vehicle may comprise more than one bile salt or bile acid. In some embodiments, the delivery vehicle may comprise at least two bile salts or bile acids. In some embodiments, the delivery vehicle may comprise at least one bile acid and at least one bile salt.
In some embodiments, the delivery vehicle may comprise cholic acid and deoxycholate.
In some embodiments, when more than one bile salt or bile acid is present in the delivery vehicle, each bile salt or bile acid is present in a different amount.
In some embodiments, the amount of any one of the bile salts or bile acids in the delivery vehicle may be from about 5 to about 85 mole% of the total amount of lipids in the delivery vehicle. For example, the amount of any one bile salt or bile acid in the delivery vehicle may be about 5-85 mole%, about 15-85 mole%, about 25-85 mole%, about 35-85 mole%, about 45-85 mole%, about 55-85 mole%, about 65-85 mole%, about 75-85 mole%, about 5-75 mole%, about 15-75 mole%, about 25-75 mole%, about 35-75 mole%, about 45-75 mole%, about 55-75 mole%, about 65-75 mole%, about 5-65 mole%, about 15-65 mole%, about 25-65 mole%, about 35-65 mole%, about 45-65 mole%, about 55-55 mole%, about 15-55 mole%, about 25-55 mole%, about 35-55 mole%, about 45-55 mole%, about 5-45 mole%, about 15-45 mole%, about 25-45 mole%, about 35-45 mole%, about 5-35 mole%, about 15-35%, about 25-25% or about 25% of the total lipid in the delivery vehicle. In some embodiments, the amount of any one of the bile salts or bile acids in the delivery vehicle may be about 5 mole%, 10 mole%, 15 mole%, 20 mole%, 25 mole%, 30 mole%, 35 mole%, 40 mole%, 45 mole%, 50 mole%, 55 mole%, 60 mole%, 65 mole%, 70 mole%, 75 mole%, 80 mole%, or 85 mole% of the total amount of lipids in the delivery vehicle.
In some embodiments, when more than one bile salt or bile acid is present in the delivery vehicle, each bile salt or bile acid is present in about the same amount.
In some embodiments, the total amount of all bile salts or bile acids in the delivery vehicle may be from about 5 to about 85 mole% of the total amount of lipids in the delivery vehicle. For example, the total amount of all bile salts or bile acids in the delivery vehicle may comprise about 5-85 mole%, about 15-85 mole%, about 25-85 mole%, about 35-85 mole%, about 45-85 mole%, about 55-85 mole%, about 65-85 mole%, about 75-85 mole%, about 5-75 mole%, about 15-75 mole%, about 25-75 mole%, about 35-75 mole%, about 45-75 mole%, about 55-75 mole%, about 65-75 mole%, about 5-65 mole%, about 15-65 mole%, about 25-65 mole%, about 35-65 mole%, about 45-65 mole%, about 55-65 mole%, about 5-55 mole%, about 15-55 mole%, about 25-55 mole%, about 35-55 mole%, about 45-55 mole%, about 5-45 mole%, about 15-45 mole%, about 25-45 mole%, about 35-45 mole%, about 5-35 mole%, about 15-35 mole%, about 25-35%, about 25-25%, about 25% or about 15-25% of the total amount of lipid in the delivery vehicle. In some embodiments, the total amount of all bile salts or bile acids in the delivery vehicle may comprise about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, or 85 mole% of the total amount of lipids in the delivery vehicle.
In some embodiments, the nanoparticle bile salts may include deoxycholate and/or lithocholate. The nanoparticle may comprise two bile salts. The nanoparticle may include deoxycholate at a level of about 20 to about 30 mole% of the total nanoparticle lipid and lithocholate at a level of about 5 to about 10 mole% of the total nanoparticle lipid.
Bile acid and bile salt derivatives
In some embodiments, the delivery vehicle may comprise a bile acid-like or bile salt-like component. The terms "bile acid-like" and "bile salt-like" as used herein refer to molecules that, although not known to be found in animal bile, would otherwise be recognized by those skilled in the art as potential members of those respective families. As one non-limiting example, bile acid-like lipids may include stereoisomers of a fixer-like acid having longer or shorter carbon chains, more or fewer hydroxyl groups, or varying numbers of carbon rings than naturally occurring bile acids. As one non-limiting example, bile-salt-like lipids can include conjugates of bile acid-like molecules or bile salts conjugated to amino acids that differ from those found in animal bile.
Cationic lipids
In some embodiments, the delivery vehicle of the present disclosure may comprise a cationic lipid. In some embodiments, the cationic lipid may acquire a positive charge through one or more amines present in the polar head group. As one non-limiting example, the cationic lipid may include a multivalent cationic lipid, an ionizable cationic lipid, or any combination thereof.
In some embodiments, the cationic lipids may be selected such that the properties of a delivery vehicle comprising a plurality of different cationic lipids (i.e., the lipid structures of a mixed lipid) are more desirable than the properties of a delivery vehicle comprising a single cationic lipid (i.e., the single lipid structure of an individual lipid). In some embodiments, the net tissue accumulation and long-term toxicity (if any) of the cationic lipids may be modulated in an advantageous manner by selecting a mixture of cationic lipids rather than selecting a single cationic lipid in a given formulation. In some embodiments, such mixtures may also provide better loading (e.g., nucleic acid) encapsulation and/or release. In some embodiments, the combination of cationic lipids may also affect systemic stability as compared to the single cationic lipid in the formulation.
Multivalent cationic lipids
In some embodiments, the delivery vehicle may comprise at least one multivalent cationic lipid. In general, a multivalent cationic lipid is understood to be a cationic lipid whose head group has more than one positive charge. For example, the multivalent cationic lipid can have 3, 4, 5, or more positive charges. In some embodiments, the multivalent cationic lipid can include divalent, trivalent, tetravalent, pentavalent, hexavalent, heptavalent, octavalent, and the like amino head groups.
Non-limiting examples of multivalent cationic lipids that can be included in the delivery vehicle can include N1- [2- ((1S) -1- [ (3-aminopropyl) amino ] -4- [ bis (3-amino-propyl) amino ] butylcarboxamido) ethyl ] -3, 4-bis [ oleyloxy ] -benzamide (MVL 5), N4-cholesteryl-spermine HCl (GL 67), salts thereof, and any combination thereof.
In some embodiments, the delivery vectors provided herein can be generated using MVL 5. In some embodiments, the lipid nanoparticle of the delivery vehicle may comprise a multivalent cationic lipid, including, but not limited to (MVL 5), salts thereof, and any combination thereof.
Ionizable cationic lipids
In some embodiments, the delivery vehicle may include at least one ionizable cationic lipid. In some embodiments, the delivery vehicle may
In some embodiments, ionizable cationic lipids for use in the delivery vehicles herein (e.g., in the lipid nanoparticles for the disclosed delivery vehicles) can include, but are not limited to, 1, 2-dioleyloxy-3-dimethylaminopropane (DODMA), N- [1- (2, 3-dioleyloxy) propyl ] -N, N, N-trimethylammonium chloride (DOTMA), [1, 2-bis (oleoyloxy) -3- (trimethylammonio) propane ] (DOTAP), dimethyl Dioctadecyl Ammonium (DDA), 3 beta [ N- (N ', N' -dimethylaminoethane) -carbamoyl ] cholesterol (DC-Chol), and dioctadecyl amidoglycinamide (DOGS), 1, 2-dialkyl-sn-glycero-3-ethylcholine, 1, 2-dialkyl-3-dimethylammonium-propane, 1, 2-dialkyl-3-trimethylammonio-propane, 1, 2-di-O-alkylammonium-3-propane, 1, 2-di-alkoxy-3-methylammonium-propane, N, N-di-alkylaminoglycinamide, N-2-di- (N ', N' -dimethylaminopropyl) -carbamide (DOGS), 1, 2-dialkyl-sn-3-ethylammonium-ethyl phosphorylcholine, 1, 2-dialkyl-3-dimethylammonium-propane, N- (N, 2-dialkyl-3-dimethylammonium-dicarboxyl) -2-methyl-3-alkoxy-N- (N-dialkyl) amine 1, 2-dialkyl-sn-glycero-3- [ (N- (5-amino-1-carboxypentyl) iminodiacetic acid) succinyl ], N1- [2- ((1S) -1- [ (3-aminopropyl) amino ] -4- [ di (3-amino-propyl) amino ] butylcarboxamido) ethyl ] -3, 4-di [ alkyl ] -benzamide, 1, 2-dialkoxy-N, N-dimethylaminopropane, 4- (2, 2-dioctyl-9, 12-dienyl- [1,3] dioxolan-4-ylmethyl) -dimethylamine, O-alkylethylphosphocholine, (6Z, 9Z,28Z, 31Z) -heptadec-6,9,28,31-tetraen-19-yl 4- (dimethylamino) butyrate (MC 3), (6Z, 9Z,28Z, 31Z) -heptadec-6,9,28,31-tetraen-19-yl 3- (dimethylamino) propionate (MC 2), MC4, 3 beta- [ N- (N ', N' -dimethylamino) -amino-ethane ] amino ] -N-4-dimethylcholesterol, 2-dimethy-l-2-N-aminopropane, 2-3-dimethy-N-glycin-3-ethyl-3-glycinyl-N, 2-dimethy-3-glycin-3-ethyl-N-yl-1, 2-dimethy lamino-N-ethyl-2-N-3-yl-glycinate, 1, 2-di-O-alkyl-3-trimethylammonium propane, 1, 2-dialkoxy-3-dimethylaminopropane, N-dialkyl-N, N-dimethylammonium, N- (4-carboxybenzyl) -N, N-dimethyl-2, 3-bis (alkoxy) propane-1-ammonium, 1, 2-dialkyl-sn-glycero-3- [ (N- (5-amino-1-carboxypentyl) iminodiacetic acid) succinyl ], N1- [2- ((1S) -1- [ (3-aminopropyl) amino ] -4- [ bis (3-amino-propyl) amino ] butylcarboxamido) ethyl ] -3, 4-di [ alkyl ] -benzamide, 7- (4- (dimethylamino) butyl) -7-hydroxytridec-1, 13-diyldioleate (CL 1H 6) 7- (4- (diisopropylamino) butyl) -7-hydroxytridecane-1, 13-diyldioleate (CL 4H 6), CL1A6, CL3A6, CL4A6, CL5A6, CL6A6, CL7A6, CL8A6, CL9A6, CL10A6, CL11A6, CL12A6, CL13A6, CL14A6, CL15A6, YSK12-C4 (e.g.US 20200129431A1 and Sato Y et al understeer holding structure-activity relationships of pH-sensitive cationic lipids facilitates the rational identification of promising lipid nanoparticles for delivering siRNAs in vivo J Control release.2019;295 in the description of the embodiments in the claims 140-152, both of which are incorporated herein by reference for the disclosure of ionizable cationic lipids), and any combination thereof.
In some embodiments, the ionizable cation may include, but is not limited to, any one of MC2, CL1H6, CL4H6, DODMA, or any combination thereof.
Biscationic lipid delivery vehicles
In some embodiments, the delivery vehicle comprises at least 2 cationic lipids. In some embodiments, the delivery vehicle comprises at least two ionizable cationic lipids. In some embodiments, the delivery vehicle comprises at least two multivalent cationic lipids. In some embodiments, the delivery vehicle comprises at least one multivalent cationic lipid and at least one ionizable cationic lipid. In some embodiments, the delivery vehicle comprises a multivalent cationic lipid and an ionizable cationic lipid.
In some embodiments, the delivery vehicle comprises: (a) MVL5, GL67, or any combination thereof; and (b) MC2, CL1H6, CL4H6, DODMA, or any combination thereof. In some embodiments, the delivery vehicle comprises MVL5 and MC2; MVL5 and CL1H6, MVL5 and CL4H6, MVL5 and DODMA, or any combination thereof.
In some embodiments, the cationic lipid is present in the delivery vehicle in varying amounts. In some embodiments, the cationic lipid is present in the delivery vehicle in the same amount.
Amount of cationic lipid in delivery vehicle
Total amount of cationic lipid
In some embodiments, the total amount of cationic lipid in the delivery vehicle may be about 5-90 mole% of all delivery vehicle lipids. For example, the delivery vehicle may include about 5-90 mole%, about 5-80 mole%, about 5-70 mole%, about 5-60 mole%, about 5-50 mole%, about 5-40 mole%, about 5-30 mole%, about 5-20 mole%, about 5-10 mole%, about 10-90 mole%, about 10-80 mole%, about 10-70 mole%, about 10-60 mole%, about 10-50 mole%, about 10-40 mole%, about 10-30 mole%, about 10-20 mole%, about 20-90 mole%, about 20-80 mole%, about 20-70 mole%, about 20-60 mole%, about 20-50 mole%, about 20-40 mole%, about 30-90 mole%, about 30-80 mole%, about 30-70 mole%, about 30-60 mole%, about 30-50 mole%, about 30-40 mole%, about 40-90 mole%, about 40-80 mole%, about 40-70%, about 40-60%, about 60-60%, about 50-60%, about 60% or about 50-60% of the lipid.
In some embodiments, the delivery vehicle may include from about 5 to 60 mole% cationic lipid. In some embodiments, the delivery vehicle may include from about 10 to 60 mole% cationic lipid. In some embodiments, the delivery vehicle may include from about 10 to 50 mole% cationic lipid. In some embodiments, the delivery vehicle may include from about 10 to about 30 mole% cationic lipid. In some embodiments, the delivery vehicle may include about 25 mole% cationic lipid.
Amount of cationic lipid in biscationic delivery vehicle
In some embodiments, more than one cationic lipid is present in the delivery vehicle, any one of which may be present in an amount of about 5-90 mole% of the total amount of delivery vehicle lipids. For example, any of the cationic lipids can be present in an amount of about 5 to 90 mole%, about 5 to 80 mole%, about 5 to 70 mole%, about 5 to 60 mole%, about 5 to 50 mole%, about 5 to 40 mole%, about 5 to 30 mole%, about 5 to 20 mole%, about 5 to 10 mole%, about 10 to 90 mole%, about 10 to 80 mole%, about 10 to 70 mole%, about 10 to 60 mole%, about 10 to 50 mole%, about 10 to 40 mole%, about 10 to 30 mole%, about 10 to 20 mole%, about 20 to 90 mole%, about 20 to 80 mole%, about 20 to 70 mole%, about 20 to 60 mole%, about 20 to 50 mole%, about 20 to 30 mole%, about 30 to 90 mole%, about 30 to 70 mole%, about 30 to 60 mole%, about 30 to 50 mole%, about 30 to 40 mole%, about 40 to 90 mole%, about 40 to 60 to about 60%, about 50 to about 80 mole%, about 50 to about 60%, about 60 to about 60 mole%, or about 50 to about 80% of the total amount of the delivery vehicle lipid.
In some embodiments, more than one cationic lipid is present in the delivery vehicle, any one of which may be present in an amount of about 5-60 mole% of the total amount of delivery vehicle lipids. In some embodiments, more than one cationic lipid is present in the delivery vehicle, any one of which may be present in an amount of about 5-30 mole% of the total amount of delivery vehicle lipids. In some embodiments, more than one cationic lipid is present in the delivery vehicle, any one of which may be present in an amount of about 5-15 mole% of the total amount of delivery vehicle lipids. In some embodiments, more than one cationic lipid is present in the delivery vehicle, any of which may be present in an amount of about 12.5 mole% of the total amount of delivery vehicle lipids.
In some embodiments, more than one cationic lipid is present in the delivery vehicle, any one of which may be present in an amount of about 5-75 mole% of the total amount of cationic lipids in the delivery vehicle. For example, any of the cationic lipids can be present in an amount of about 5-15 mole%, about 5-25 mole%, about 5-35 mole%, about 5-45 mole%, about 5-55 mole%, about 5-65 mole%, about 5-75 mole%, about 10-70 mole%, about 10-60 mole%, about 10-50 mole%, about 10-40 mole%, about 10-30 mole%, about 10-20 mole%, about 20-70 mole%, about 20-60 mole%, about 20-50 mole%, about 20-40 mole%, about 20-30 mole%, about 30-70 mole%, about 30-60 mole%, about 30-50 mole%, about 30-40 mole%, about 30-70 mole%, about 30-60 mole%, about 30-50 mole%, about 40-70 mole%, about 40-60 mole%, about 40-50 mole%, about 50-70 mole%, about 50-60 mole%, or about 60-70 mole% of the total amount of cationic lipids in the delivery vehicle.
In some embodiments, more than one cationic lipid is present in the delivery vehicle, any one of which may be present in an amount of about 40-60 mole% of the total amount of cationic lipids in the delivery vehicle. In some embodiments, more than one cationic lipid is present in the delivery vehicle, any one of which may be present in an amount of about 50 mole% of the total amount of cationic lipids in the delivery vehicle.
In some embodiments, the delivery vehicle may include any multivalent cationic lipid provided herein in an amount of less than about 50 mole%, 48 mole%, 46 mole%, 44 mole%, 42 mole%, 40 mole%, 38 mole%, 36 mole%, 34 mole%, 32 mole%, 30 mole%, 28 mole%, 26 mole%, 24 mole%, 22 mole%, 20 mole%, 18 mole%, 16 mole%, 14 mole%, 12 mole%, 10 mole%, 8 mole%, 6 mole%, 4 mole%, 2 mole%, or 0 mole% of the total amount of delivery vehicle lipids. In some embodiments, the delivery vehicle may include any multivalent cationic lipid provided herein in an amount of about 50 mole%, 48 mole%, 46 mole%, 44 mole%, 42 mole%, 40 mole%, 38 mole%, 36 mole%, 34 mole%, 32 mole%, 30 mole%, 28 mole%, 26 mole%, 24 mole%, 22 mole%, 20 mole%, 18 mole%, 16 mole%, 14 mole%, 12 mole%, 10 mole%, 8 mole%, 6 mole%, 4 mole%, 2 mole%, or 0 mole% of the total amount of delivery vehicle lipids. In some embodiments, the delivery vehicle may include any of the multivalent cationic lipids provided herein at a concentration of 5-50 mole%, 5-40 mole%, 5-30 mole%, 5-25 mole%, 5-20 mole%, 5-15 mole%, 10-50 mole%, 10-40 mole%, 10-30 mole%, 10-25 mole%, 15-50 mole%, 15-40 mole%, 15-30 mole%, and 15-25 mole% of the total amount of delivery vehicle lipid.
In some embodiments, the delivery vehicle may include any of the ionizable cationic lipids provided herein in an amount that is less than about 50, 48, 46, 44, 42, 40, 38, 36, 34, 32, 30, 28, 26, 24, 22, 20, 18, 16, 14, 12, 10, 8, 6, 4, 2, or 0 mole% of the total amount of delivery vehicle lipids. In some embodiments, the delivery vehicle may include any of the ionizable cationic lipids provided herein in an amount of about 50 mole%, 48 mole%, 46 mole%, 44 mole%, 42 mole%, 40 mole%, 38 mole%, 36 mole%, 34 mole%, 32 mole%, 30 mole%, 28 mole%, 26 mole%, 24 mole%, 22 mole%, 20 mole%, 18 mole%, 16 mole%, 14 mole%, 12 mole%, 10 mole%, 8 mole%, 6 mole%, 4 mole%, 2 mole%, or 0 mole% of the total amount of delivery vehicle lipids. In some embodiments, the delivery vehicle may include any of the ionizable cationic lipids provided herein at a concentration of 5-50 mole%, 5-40 mole%, 5-30 mole%, 5-25 mole%, 5-20 mole%, 5-15 mole%, 10-50 mole%, 10-40 mole%, 10-30 mole%, 10-25 mole%, 15-50 mole%, 15-40 mole%, 15-30 mole%, and 15-25 mole% of the total amount of delivery vehicle lipid.
In some embodiments, the nanoparticle cationic lipid can include MVL5. In some embodiments, MVL5 may be present at a level of about 5 to about 20 mole% of the total nanoparticle lipid.
In some embodiments, the nanoparticle cationic lipid may include one or more of MC2, CL1H6, and CL4H6, each of which may be present at a level of about 5 to about 20 mole% of the total nanoparticle lipid.
Structural lipids
In some embodiments, the delivery vehicle may comprise at least one structural lipid. In some embodiments, the at least one structural lipid component may be any lipid or lipid-soluble molecule that increases cellular uptake of the nanoparticle, increases the rate or efficiency of transfection, increases stability of the nanoparticle during formation, aids in nanoparticle formation, may be used to modulate the overall charge of the nanoparticle, increases stability of the nucleic acid load in the gastrointestinal tract, or any combination thereof, but is not limited thereto.
In some embodiments, the structural lipid component may be, but is not limited to, at least one of a neutral lipid, an anionic lipid, a phospholipid, and any combination thereof.
In some embodiments, the at least one structural lipid component may be selected from, but is not limited to, at least one of 1, 2-distearoyl-sn-glycero-3-phosphorylcholine (DSPC), 1, 2-dimyristoyl-sn-glycero-3-phosphorylcholine (DMPC) dioleoyl phosphatidylethanolamine (DOPE), glycerol Monooleate (GMO), and any combination thereof.
Phospholipid
In some embodiments, the delivery vehicle may comprise phosphatidylcholine. Exemplary phosphatidylcholines include, but are not limited to, dilauroyl phosphatidylcholine, dimyristoyl phosphatidylcholine, dipalmitoyl phosphatidylcholine, distearoyl phosphatidylcholine, ditolyl phosphatidylcholine, dioleoyl phosphatidylcholine, ditolyl phosphatidylcholine, palmitoyl-oleoyl-phosphatidylcholine, lecithin phosphatidylcholine, myristoyl-palmitoyl phosphatidylcholine, palmitoyl-myristoyl-phosphatidylcholine, myristoyl-stearoyl phosphatidylcholine, palmitoyl-stearoyl-phosphatidylcholine, stearoyl-palmitoyl phosphatidylcholine, stearoyl-oleoyl-phosphatidylcholine, stearoyl-linoleoyl phosphatidylcholine, and palmitoyl-linoleoyl-phosphatidylcholine.
In some embodiments, the structural lipids may include short-chain bis-N-heptadecanylphosphatidylcholine (DHPC), di (hexadecanoyl) phosphoethanolamine (DHPE), 1, 2-dioleoyl-sn-glycero-3-phosphocholine (DPPC), dimyristoyl phosphoethanolamine (DPPE), dimyristoyl phosphatidylglycerol (DMPG), dioleoyl phosphatidylcholine (DOPC), dioleoyl-phosphatidylethanolamine 4- (N-maleimidomethyl) -cyclohexane-1-carboxylate (DOPE-mal), dioleoyl phosphatidylglycerol (DOPG), 1, 2-dioleoyl-sn-glycero-3- (phosphol-serine) (DOPS), cell-free fused phospholipid (DPPE), dipalmitoyl phosphatidylcholine (DPPC), dipalmitoyl phosphatidylethanolamine (DPPE), dipalmitoyl phosphatidylglycerol (DPPG), dipalmitoyl phosphatidylcholine (DPPC), distearoyl phosphatidylethanolamine (DSPC), distearoyl phosphatidylethanolamine (DSPE), stearoyl phosphatidylcholine (DSPE), stearoyl-cholesterol (DSPE), 1, 2-dioleoyl-glycero-3- (phospho-L-serine) (DPPE), cell-fusine (DPPE), dipalmitoyl-phosphatidyl (DPPE), dipalmitoyl, dipe (DPPE) Mannosylated dipalmitoyl phosphatidylethanolamine (ManDOG), 1, 2-dioleoyl-sn-glycero-3-phosphoethanolamine-N- [4- (p-maleimidomethyl) cyclohexane-carboxamide ] (MCC-PE), 1, 2-dimentyl-sn-glycero-3-phosphoethanolamine (ME 16.0 PE), 1-myristoyl-2-hydroxy-sn-glycero-phosphocholine (MHPC), 1-oleoyl-2-cholestenyl hemisuccinyl-sn-glycero-3-phosphocholine (OChemsPC), phosphatidic Acid (PA), phosphatidylethanolamine lipid (PE), phosphatidylglycerol (PG), partially Hydrogenated Soybean Phosphatidylcholine (PHSPC), phosphatidylinositol (PI), phosphatidylinositol-4-phosphate (PIP), palmitoyl phosphatidylcholine (POPC), phosphatidylethanolamine (POPE), palmitoyl Phosphatidylglycerol (PG), phosphatidylserine (PS), 18-1-trans-stearoyl-2-cholesteryl-3-phosphocholine (OCheme), phosphatidylcholine (SPC), soybean phosphatidylethanolamine-2-phosphotidyline (SPC), soybean phosphatidylethanolamine-4-phosphate (PIP), palmitoyl phosphatidylinositol (PIP), palmitoyl phosphatidylcholine (POPC), palmitoyl phosphatidylethanolamine (POPE), 1, 2-di-arachidonyl-sn-glycero-3-phosphoethanolamine, 1, 2-di (docosahexaenoic acid) -sn-glycero-3-phosphocholine, 1, 2-di (docosahexaenoic acid) -sn-glycero-3-phosphoethanolamine, 1, 2-di-linolenoyl-sn-glycero-3-phosphoethanolamine, 1, 2-di-oleoyl-sn-glycero-3-phosphoethanolamine, 1, 2-dioleyl-sn-glycero-3-phosphoethanolamine, 1, 2-distearoyl-sn-glycero-3-phosphoethanolamine, and any combination thereof.
In some embodiments, the delivery vehicle may include asymmetric phosphatidylcholine. Asymmetric phosphatidylcholine may be referred to as 1-acyl, 2-acyl-sn-glycero-3-phosphorylcholine, wherein the acyl groups are different from each other.
In some embodiments, the delivery vehicle may include symmetrical phosphatidylcholine. Symmetrical phosphatidylcholine may be referred to as 1, 2-diacyl-sn-glycero-3-phosphorylcholine.
The abbreviation "PC" as used herein refers to phosphatidylcholine. Phosphatidylcholine 1, 2-dimyristoyl-sn-glycero-3-phosphorylcholine may be abbreviated herein as "DMPC". Phosphatidylcholine 1, 2-dioleoyl-sn-glycero-3-phosphorylcholine may be abbreviated herein as "DOPC". Phosphatidylcholine 1, 2-dipalmitoyl-sn-glycero-3-phosphorylcholine may be abbreviated herein as "DPPC". In general, saturated acyl groups found in various lipids include groups named propionyl, butyryl, pentanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl, lauroyl, tridecanoyl, myristoyl, pentadecanoyl, palmitoyl, phytanoyl, heptadecanoyl, stearoyl, nonadecanoyl, arachidoyl, heneicosanoyl, behenyl, tricosanoyl and tetracosanoyl. The corresponding IUPAC names for saturated acyl groups are tricarbonic, tetracarboxylic, pentacarbonic, hexacarbonic, heptacarbonic, octacarbonic, nonacarbonic, decacarbonic, undecanecarbonic, dodecacarbonic, tridecanc, tetradecanecarbonic, pentadecanocarbonic, hexadecanecarbonic, 3,7,11, 15-tetramethylhexadecanecarbonic, heptadecanocarbonic, octadecanc, nonadecanocarbonic, eicosanoic, heneicosanoic, behenic, tricosanoic and tetracosanoic. Unsaturated acyl groups found in symmetrical and unsymmetrical phosphatidylcholines include myristoyl, palmitoyl, oleoyl, elaitoyl, linoleoyl, linolenoyl, eicosenoyl and arachidonoyl. The corresponding IUPAC names of unsaturated acyl groups are 9-cis-tetradecanedioic acid, 9-cis-hexadecanedioic acid, 9-cis-octadecanedioic acid, 9-trans-octadecanedioic acid, 9-cis-12-cis-octadecadienoic acid, 9-cis-12-cis-15-cis-octadecatrienoic acid, 11-cis-eicosenoic acid and 5-cis-8-cis-11-cis-14-cis-eicosetetracenic acid.
Exemplary phosphatidylethanolamine include dimyristoyl-phosphatidylethanolamine, dipalmitoyl-phosphatidylethanolamine, distearoyl-phosphatidylethanolamine, dioleoyl-phosphatidylethanolamine, and phosphatidylethanolamine. Phosphatidylethanolamine may also be referred to as 1, 2-diacyl-sn-glycero-3-phosphoethanolamine or 1-acyl-2-acyl-sn-glycero-3-phosphoethanolamine under IUPAC naming system, depending on whether they are symmetrical or asymmetrical lipids. Exemplary phosphatidic acids include dimyristoyl phosphatidic acid, dipalmitoyl phosphatidic acid, and dioleoyl phosphatidic acid. Phosphatidic acids may also be referred to as 1, 2-diacyl-sn-glycero-3-phosphate or 1-acyl-2-acyl-sn-glycero-3-phosphate under the IUPAC naming system, depending on whether they are symmetrical or asymmetrical lipids.
Exemplary phosphatidylserine include dimyristoyl phosphatidylserine, dipalmitoyl phosphatidylserine, dioleoyl phosphatidylserine, distearoyl phosphatidylserine, palmitoyl-oleyl phosphatidylserine, and cephalin phosphatidylserine. Phosphatidylserine can also be referred to as 1, 2-diacyl-sn-glycero-3- [ phospho-L-serine ] or 1-acyl-2-acyl-sn-glycero-3- [ phospho-L-serine ] under IUPAC naming system, depending on whether they are symmetrical or asymmetrical lipids. The abbreviation "PS" as used herein refers to phosphatidylserine.
Exemplary phosphatidylglycerols include dilauroyl phosphatidylglycerol, dipalmitoyl phosphatidylglycerol, distearyl phosphatidylglycerol, dioleoyl phosphatidylglycerol, dimyristoyl phosphatidylglycerol, palmitoyl-oleoyl-phosphatidylglycerol, and lecithroyl glycerol. Phosphatidylglycerols can also be referred to under the IUPAC naming system as 1, 2-diacyl-sn-glycero-3- [ phospho-rac- (1-glycerol) ] or 1-acyl-2-acyl-sn-glycero-3- [ phospho-rac- (1-glycerol) ], depending on whether they are symmetrical or asymmetrical lipids. Phosphatidylglycerol 1, 2-dimyristoyl-sn-glycero-3- [ phosphoric acid-rac- (1-glycerol) ] is abbreviated herein as "DMPG". Phosphatidylglycerol 1, 2-dipalmitoyl-sn-glycero-3- (phosphoric acid-rac-1-glycerol) (sodium salt) is abbreviated herein as "DPPG".
Suitable sphingomyelins may include cephalin, lecithins, dipalmitoyl sphingomyelin and distearyl sphingomyelin.
Other suitable lipids include glycolipids, sphingolipids, etherlipids, glycolipids such as cerebrosides and gangliosides, and sterols such as cholesterol or ergosterol.
In some embodiments, dioleoyl phosphatidylethanolamine (DOPE), polyethylenimine (PEI), neutral lipids can often be used in combination with cationic lipids because it has membrane destabilization at low pH, which aids in endolysosomal escape.
Anionic lipids
In some embodiments, the lipid nanoparticles of the delivery vehicles provided herein may further comprise an anionic lipid. Generally, the anionic lipid may comprise any of a variety of fatty acid chains in the hydrophobic region. The specific fatty acids incorporated determine the fluid properties of the lipid structure in terms of phase behaviour and elasticity.
In some embodiments, divalent cations may be incorporated into the anionic lipid structure to enable nucleic acids to condense (condensation) prior to encapsulation by the anionic lipid. Several divalent cations can be used in the anionic lipid complex, e.g. Ca 2+ 、Mg 2+ 、Mn 2+ And Ba (beta) 2+ 。
In some embodiments, ca 2+ Can be used in anionic lipid structures.
In some embodiments, suitable anionic lipids include, but are not limited to: phosphatidylglycerol, cardiolipin, diacylglyceridephosphatidylserine, diacylglyceridephosphatidic acid, N-dodecanoylphospholipid ethanolamine, N-succinylphospholipid ethanolamine, N-glutaryl phosphatidylethanolamine, lysyl phosphatidylglycerol, palmitoyl-based oil acylphosphatidylglycerol (POPG), or any combination thereof.
In some embodiments, the anionic lipids in the lipid nanoparticle include at least one of the following: phosphatidylglycerol, cardiolipin, dialkylphosphatidylserine, dialkylphosphatidic acid, N-lauroyl phosphatidylethanolamine, N-succinyl phosphatidylethanolamine, N-glutaryl phosphatidylethanolamine, lysyl phosphatidylglycerol, palmitoyl phosphatidylglycerol (POPG), glycerophosphoinositol monophosphate, glycerophosphoinositol diphosphate, glycerophosphate triphosphate, glycerophosphate, cytidine-5' -diphosphate-glycerol, glycosylglycerophospholipid, glycerophosphate-inositol glycan, 1, 2-dialkyl-sn-glycero-3-phosphate methanol, 1, 2-dialkyl-sn-glycero-3-phosphate ethanol, 1, 2-dialkyl-sn-glycero-3-phosphate propanol and/or 1, 2-dialkyl-sn-glycero-3-phosphate butanol.
In some embodiments, when the anionic lipid is conjugated to an alkyl group and the anionic lipid is present in the liquid phase, the alkyl group is a conjugated derivative of at least one of: oleic acid, elaidic acid, giant whale acid, erucic acid, nervonic acid, mildic acid, eicosenoic acid (palulinic acid), isooleic acid, palmitoleic acid, docosatetraenoic acid, arachidonic acid, dihomo-gamma-linolenic acid, elaidic acid, linoleic acid, docosahexaenoic acid, eicosapentaenoic acid, stearidonic acid, alpha-linolenic acid, or salts thereof, or any combination thereof. In other cases, the alkyl group is a conjugated derivative of at least one of the following: myristic acid, pentadecanoic acid, palmitic acid, heptadecanoic acid, stearic acid, lauric acid, tridecanoic acid, nonadecanoic acid, arachic acid, heneicosanoic acid, behenic acid, tricosanoic acid, cerotic acid, and/or salts thereof, or any combination thereof. Above, an alkyl group is considered to be in the gel phase if it has a phase transition temperature of >37 ℃, otherwise it is present in the liquid phase.
In some embodiments, the anionic lipid may be a saturated lipid having a phase transition temperature above 37 ℃, such a lipid may be used in a solid phase and the cationic lipid in a liquid phase. In some embodiments, when the anionic lipid is unsaturated or a short chain lipid having a transition temperature below 37 ℃, then it may be used in the liquid phase, while the cationic lipid may be used in the gel or solid phase.
In some embodiments, bile salts may be used as the anionic component in the delivery vehicle. In some embodiments, non-bile salts may be used as the anionic component.
In some embodiments, the anionic liposomes can be used to deliver other (non-nucleic acid) therapeutic agents.
Sterols and sterol-containing mixtures
In some embodiments, the lipid structure may comprise cholesterol or a derivative thereof, a phospholipid, a mixture of phospholipids and cholesterol or a derivative thereof, or a combination. Examples of cholesterol derivatives include, but are not limited to, cholestanol, cholestanone, cholestenone, fecal sterols, cholestenyl-2 '-hydroxyethyl ether, cholestenyl-4' -hydroxybutyl ether, and mixtures thereof.
In some embodiments, the structural lipid component is not a sterol. In some embodiments, the at least one structural lipid is not cholesterol. In some embodiments, the delivery vehicle contains less than 10 mole%, less than 5 mole%, less than 1 mole%, less than 0.1 mole%, less than 0.01 mole%, less than 0.001 mole%, less than 0.0001 mole% cholesterol or cholesterol derivatives. In some embodiments, the delivery vehicle is formed in the absence of any cholesterol in the formulation mixture. In some embodiments, the delivery vehicle is substantially free of cholesterol.
Saturated non-cationic lipids
In some embodiments, the delivery vehicle (i.e., lipid delivery vehicle) may comprise (or further comprise) a saturated non-cationic lipid. In some embodiments, the phase transition temperature of the saturated non-cationic lipid may be at least about 20 ℃, 22 ℃, 24 ℃, 26 ℃, 28 ℃, 30 ℃, 32 ℃, 34 ℃, 36 ℃, 38 ℃, 40 ℃, 42 ℃, 44 ℃, 46 ℃, 48 ℃, 50 ℃, 52 ℃, 54 ℃, 56 ℃, 58 ℃, and/or up to about 60 ℃. For example, the phase transition temperature of the saturated non-cationic lipid may be about 30 ℃ to 60 ℃, 35 ℃ to 60 ℃, 37 ℃ to 55 ℃, 37 ℃ to 50 ℃, 37 ℃ to 45 ℃, or 37 ℃ to 40 ℃.
Amount of structured lipids in delivery vehicle
Total amount of structural lipids
In some embodiments, the structural lipids may comprise about 5-75 mole% of the total delivery vehicle lipids. For example, the structured lipid may comprise about 5-15 mole%, about 5-25 mole%, about 5-35 mole%, about 5-45 mole%, about 5-55 mole%, about 5-65 mole%, about 5-75 mole%, about 15-25 mole%, about 15-35 mole%, about 15-45 mole%, about 15-55 mole%, about 15-65 mole%, about 15-75 mole%, about 25-35 mole%, about 25-45 mole%, about 25-55 mole%, about 25-65 mole%, about 25-75 mole%, about 35-45 mole%, about 35-55 mole%, about 35-65 mole%, about 35-75 mole%, about 45-55 mole%, about 45-65 mole%, about 45-75 mole%, about 55-65 mole%, about 55-75 mole%, or about 65-75 mole% of the total delivery vehicle lipid.
In some embodiments, the structural lipids may comprise about 30-50 mole% of the delivery vehicle lipid. In some embodiments, the structural lipid may comprise about 35-45 mole% of the delivery vehicle lipid. In some embodiments, the structural lipid component may comprise about 40 mole% of the delivery vehicle lipid.
In some embodiments, the nanoparticle structured lipid may include one or more of DSPC and DMPC and may be present at a level of about 35 to about 45 mole% of the total nanoparticle lipid.
Amount of phospholipid cholesterol mixture
In some embodiments, when the lipid structure comprises a mixture of phospholipids and cholesterol or cholesterol derivatives, the lipid structure may comprise up to about 40, 50, or 60 mole% of the total lipids present in the lipid structure. The one or more phospholipids and/or cholesterol may comprise from about 10 mol% to about 60 mol%, from about 15 mol% to about 60 mol%, from about 20 mol% to about 60 mol%, from about 25 mol% to about 60 mol%, from about 30 mol% to about 60 mol%, from about 10 mol% to about 55 mol%, from about 15 mol% to about 55 mol%, from about 20 mol% to about 55 mol%, from about 25 mol% to about 55 mol%, from about 30 mol% to about 55 mol%, from about 13 mol% to about 50 mol%, from about 15 mol% to about 50 mol%, or from about 20 mol% to about 50 mol% of the total lipid present in the lipid structure.
Amount of phospholipid cholesterol mixture
In some embodiments, the concentration of the at least one unsaturated non-cationic lipid in the lipid nanoparticle may be less than 50 mole%, 45 mole%, 40 mole%, 35 mole%, 30 mole%, 25 mole%, 20 mole%, 15 mole%, 10 mole%, 5 mole%, or 2 mole% of the total lipid concentration of the lipid nanoparticle. In some embodiments, the concentration of the at least one unsaturated non-cationic lipid in the lipid nanoparticle may be about 50 mole%, 45 mole%, 40 mole%, 35 mole%, 30 mole%, 25 mole%, 20 mole%, 15 mole%, 10 mole%, 5 mole%, or 2 mole% of the total lipid concentration of the lipid nanoparticle. In some embodiments, the concentration of the at least one unsaturated non-cationic lipid in the lipid nanoparticle may be 5-50 mole%, 5-40 mole%, 5-30 mole%, 5-25 mole%, 5-20 mole%, 5-15 mole%, 10-50 mole%, 10-40 mole%, 10-30 mole%, 10-25 mole%, 15-50 mole%, 15-40 mole%, 15-30 mole%, and 15-25 mole%.
Conjugated lipids
In some embodiments, the delivery vehicle may comprise at least one conjugated lipid. In some embodiments, the at least one conjugated lipid may comprise at least one conjugated lipid and at least one hydrophilic polymer.
In some embodiments, the conjugated lipid may comprise at least one lipid selected from, but not limited to, phospholipids, neutral lipids, glycerides, diglycerides, or any combination thereof.
In some embodiments, conjugated lipids may include, but are not limited to, any one of 1, 2-dimyristoyl-rac-glycerol (DMG), 1, 2-dimyristoyl-sn-glycero-3-phosphoethanolamine (DMPE), 1, 2-distearoyl-rac-glycerol (DSG), 1, 2-dipalmitoyl-rac-glycerol (DPG), 1, 2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE), diacylglycerol (DAG), 1, 2-dipalmitoyl-sn-glycero-3-phosphoethanolamine (DPPE), or any combination thereof.
In some embodiments, the hydrophilic polymer may include polyethylene glycol, poly (2-alkyl-2- ≡oxazoline), polyvinyl alcohol, or any combination thereof. In some embodiments, the hydrophilic polymer may have a molecular weight of at least about 500Da to about 500 kDa.
In some embodiments, the hydrophilic polymer (e.g., PEG) may have an average molecular weight of 500 to 20,000 daltons. In some embodiments of the present invention, in some embodiments, the hydrophilic polymer may have a molecular weight of about 500 to 20,000, 1,000 to 20,000, 1,500 to 20,000, 2,000 to 20,000, 2,500 to 20,000, 3,000 to 20,000, 3,500 to 20,000, 4,000 to 20,000, 4,500 to 20,000, 5,000 to 20,000, 5,500 to 20,000, 6,000 to 20,000, 6,500 to 20,000, 7,000 to 20,000, 7,500 to 20,000, 8,000 to 20,000, 8,500 to 20,000, 9,000 to 20,000, 9,500 to 20,000, 10,000 to 20,000, 10,500 to 20,000, 11,000 to 20,000, 11,500 to 20,000, 12,000 to 20,000, 12,500 to 20,000, 13,000 to 20,000, 13,500 to 20,000, 14,000 to 20,000, 15,000 and 15,000. 15,500 to 20,000, 16,000 to 20,000, 16,500 to 20,000, 17,000 to 20,000, 17,500 to 20,000, 18,000 to 20,000, 18,500 to 20,000, 19,000 to 20,000, 19,500 to 20,000, 500 to 19,500, 1,000 to 19,500, 1,500 to 19,500, 2,000 to 19,500, 2,500 to 19,500, 3,000 to 19,500, 3,500 to 19,500, 4,000 to 19,500, 4,500 to 19,500, 5,000 to 19,500, 5,500 to 19,500, 6,000 to 19,500, 7,000 to 19,500, 7,500 to 19,500, 8,000 to 19,500, 8,500 to 19,500, 9,000 to 19,500, 9,500 to 19,500, 10,000 to 19,500, 10,500 to 19,500, 11,500, 11,000 to 19,500. 15,500 to 20,000, 16,000 to 20,000, 16,500 to 20,000, 17,000 to 20,000, 17,500 to 20,000, 18,000 to 20,000, 18,500 to 20,000, 19,000 to 20,000, 19,500 to 20,000, 500 to 19,500, 1,000 to 19,500, 1,500 to 19,500, 2,000 to 19,500, 2,500 to 19,500, 3,000 to 19,500, 3,500 to 19,500, and 4,000 to 19,500, 4,500 to 19,500, 5,000 to 19,500, 5,500 to 19,500, 6,000 to 19,500, 6,500 to 19,500, 7,000 to 19,500, 7,500 to 19,500, 8,000 to 19,500, 8,500 to 19,500, 9,000 to 19,500, 9,500 to 19,500, 10,000 to 19,500, 10,500 to 19,500, 11,000 to 19,500, 7,000 to 18,500, 7,500 to 18,500, 8,000 to 18,500, 8,500 to 18,500, 9,000 to 18,500, 9,500 to 18,500, 10,000 to 18,500, 10,500 to 18,500, 11,500 to 18,500, 12,000 to 18,500, 12,500 to 18,500, 13,000 to 18,500, 13,500 to 18,500, 14,000 to 18,500, 14,500 to 18,500, 15,000 to 18,500, 15,500 to 18,500, 16,000 to 18,500, 16,500 to 18,500, 17,000 to 18,500, 18,000 to 18,500, 1,500 to 18,000, 2,000 to 18,000, 3,000 to 18,000, 3,500 to 18,000, 4,000 to 18,000, 5,000 to 18,500, and 6,000 to 18,500. 6,500 to 18,000, 7,000 to 18,000, 7,500 to 18,000, 8,000 to 18,000, 8,500 to 18,000, 9,000 to 18,000, 9,500 to 18,000, 10,000 to 18,000, 10,500 to 18,000, 11,000 to 18,000, 11,500 to 18,000, 12,000 to 18,000, 12,500 to 18,000, 13,000 to 18,000, 13,500 to 18,000, 14,000 to 18,000, 14,500 to 18,000, 15,000 to 18,000, 15,500 to 18,000, 16,000 to 18,000, 16,500 to 18,000, 17,000 to 18,000, 17,500 to 18,000, 1,500 to 17,500, 2,500 to 17,500, 3,000 to 17,500, 3,500 to 17,500, 4,000 to 17,17, 4,500 to 17,500, 5,500 to 500, 5,500, and 5,500 to 500,500. 6,000 to 17,500, 6,500 to 17,500, 7,000 to 17,500, 7,500 to 17,500, 8,000 to 17,500, 8,500 to 17,500, 9,000 to 17,500, 9,500 to 17,500, 10,000 to 17,500, 10,500 to 17,500, 11,000 to 17,500, 11,500 to 17,500, 12,000 to 17,500, 12,500 to 17,500, 13,000 to 17,500, 13,500 to 17,500, 14,000 to 17,500, 14,500 to 17,500, 15,000 to 17,500, 15,500 to 17,500, 16,000 to 17,500, 17,000 to 17,500, 1,500 to 17,000, 2,000 to 17,000, 3,000 to 17,000, 3,500 to 17,000, 4,000 to 17,000, 5,500 to 17,500, 5,500, and 5,500 to 17,500. 6,000 to 17,000, 6,500 to 17,000, 7,000 to 17,000, 7,500 to 17,000, 8,000 to 17,000, 8,500 to 17,000, 9,000 to 17,000, 9,500 to 17,000, 10,000 to 17,000, 10,500 to 17,000, 11,000 to 17,000, 11,500 to 17,000, 12,000 to 17,000, 12,500 to 17,000, 13,000 to 17,000, 13,500 to 17,000, 14,000 to 17,000, 14,500 to 17,000, 15,000 to 17,000, 15,500 to 17,000, 16,000 to 17,000, 1,500 to 16,500, 2,500 to 16,500, 3,000 to 16,500, 3,500 to 16,500, 4,000 to 16,500, 4,500 to 16,500, 5,500, 16,500 to 16,500, 5,500 and 5,500 to 500,500, 500, 500,500, and so forth, 6,500 to 16,500, 7,000 to 16,500, 7,500 to 16,500, 8,000 to 16,500, 8,500 to 16,500, 9,000 to 16,500, 9,500 to 16,500, 10,000 to 16,500, 11,000 to 16,500, 11,500 to 16,500, 12,000 to 16,500, 12,500 to 16,500, 13,000 to 16,500, 13,500 to 16,500, 14,000 to 16,500, 14,500 to 16,500, 15,000 to 16,500, 15,500 to 16,500, 16,000 to 16,500, 1,500 to 16,000, 2,000 to 16,000, 3,000 to 16,000, 4,000 to 16,000, 4,500 to 16,000, 5,000 to 16,000, 6,000 to 16,000, 7,000 to 16,500, 7,500, 7,000 and 7,500. 8,000 to 16,000, 8,500 to 16,000, 9,000 to 16,000, 9,500 to 16,000, 10,000 to 16,000, 10,500 to 16,000, 11,000 to 16,000, 11,500 to 16,000, 12,000 to 16,000, 12,500 to 16,000, 13,000 to 16,000, 13,500 to 16,000, 14,000 to 16,000, 14,500 to 16,000, 15,000 to 16,000, 15,500 to 16,000, 1,500 to 15,500, 2,000 to 15,500, 2,500 to 15,500, 3,000 to 15,500, 4,000 to 15,500, 5,000 to 15,500, 5,500 to 15,500, 6,000 to 15,500, 7,000 to 15,500, 7,500, 500 to 15,500, 8,000 to 15,500, 8,500 and 9 to 15,500, 9,500, and 9,500. 9,500 to 15,500, 10,000 to 15,500, 10,500 to 15,500, 11,000 to 15,500, 11,500 to 15,500, 12,000 to 15,500, 12,500 to 15,500, 13,000 to 15,500, 13,500 to 15,500, 14,000 to 15,500, 14,500 to 15,500, 15,000 to 15,500, 1,500 to 15,000, 2,000 to 15,000, 2,500 to 15,000, 3,000 to 15,000, 3,500 to 15,000, 4,000 to 15,000, 4,500 to 15,000, 5,000 to 15,000, 6,000 to 15,000, 7,000 to 15,000, 7,500 to 15,000, 8,000 to 15,000, 8,500 to 15,000, 9,000 to 15,000, 9,500 to 15,000, 9,000 to 15,000, 10,000 to 15,000, 11,000 to 15,000, 15,11,000 and 15,11,000. 11,500 to 15,000, 12,000 to 15,000, 12,500 to 15,000, 13,000 to 15,000, 13,500 to 15,000, 14,000 to 15,000, 14,500 to 15,000, 1,500 to 14,500, 2,000 to 14,500, 2,500 to 14,500, 3,000 to 14,500, 3,500 to 14,500, 4,000 to 14,500, 4,500 to 14,500, 5,000 to 14,500, 5,500 to 14,500, 6,000 to 14,500, 6,500 to 14,500, 7,000 to 14,500, 7,500 to 14,500, 8,000 to 14,500, 8,500 to 14,500, 9,000 to 14,500, 10,000 to 14,500, 10,500 to 14,500, 11,000 to 14,500, 11,500 to 14,500, 12,500, 12,000 to 14,500, 12,500 to 14,500, 13,500 to 13,500, and 13,500 14,000 to 14,500, 1,500 to 14,000, 2,000 to 14,000, 2,500 to 14,000, 3,000 to 14,000, 3,500 to 14,000, 4,000 to 14,000, 4,500 to 14,000, 5,000 to 14,000, 5,500 to 14,000, 6,000 to 14,000, 6,500 to 14,000, 7,000 to 14,000, 7,500 to 14,000, 8,000 to 14,000, 8,500 to 14,000, 9,000 to 14,000, 9,500 to 14,000, 10,000 to 14,000, 10,500 to 14,000, 11,000 to 14,000, 11,500 to 14,000, 12,000 to 14,000, 12,500 to 14,000, 13,500 to 14,000, 1,500 to 13,500, 2,000 to 13,500, 2,500 to 13,500, 3,500 to 13,000, 3,500 to 13,500, 4,500 to 13,500, and 13,500 to 500, 13,500, and 13,500 to 13,500, and so long-called 5,000 to 13,500, 5,500 to 13,500, 6,500 to 13,500, 7,000 to 13,500, 7,500 to 13,500, 8,000 to 13,500, 8,500 to 13,500, 9,000 to 13,500, 9,500 to 13,500, 10,000 to 13,500, 10,500 to 13,500, 11,000 to 13,500, 11,500 to 13,500, 12,000 to 13,500, 12,500 to 13,500, 13,000 to 13,500, 1,500 to 13,000, 2,000 to 13,000, 2,500 to 13,000, 3,000 to 13,000, 3,500 to 13,000, 4,000 to 13,000, 4,500 to 13,000, 5,000 to 13,000, 6,000 to 13,000, 6,500 to 13,000, 7,000 to 13,000, 7,500 to 13,000, 8,000 to 13,000, 8,500, and 8,500 to 13,000. 9,000 to 13,000, 9,500 to 13,000, 10,000 to 13,000, 10,500 to 13,000, 11,000 to 13,000, 11,500 to 13,000, 12,000 to 13,000, 12,500 to 13,000, 1,500 to 12,500, 2,000 to 12,500, 2,500 to 12,500, 3,000 to 12,500, 3,500 to 12,500, 4,000 to 12,500, 4,500 to 12,500, 5,000 to 12,500, 5,500 to 12,500, 6,000 to 12,500, 6,500 to 12,500, 7,000 to 12,500, 7,500 to 12,500, 8,000 to 12,500, 9,000 to 12,500, 10,000 to 12,500, 10,500 to 12,500, 11,000 to 12,500, 11,500, 12,500 to 12,500, 12,500 to 12,500, 1,500, 2,000 to 12,500, and 2,000 to 12,000,500. 2,500 to 12,000, 3,000 to 12,000, 3,500 to 12,000, 4,000 to 12,000, 4,500 to 12,000, 5,000 to 12,000, 5,500 to 12,000, 6,000 to 12,000, 6,500 to 12,000, 7,000 to 12,000, 7,500 to 12,000, 8,000 to 12,000, 8,500 to 12,000, 9,000 to 12,000, 9,500 to 12,000, 10,000 to 12,000, 10,500 to 12,000, 11,000 to 12,000, 11,500 to 12,000, 1,500 to 11,500, 2,000 to 11,500, 2,500 to 11,500, 3,000 to 11,500, 3,500 to 11,500, 4,500 to 11,500, 5,000 to 11,500, 5,500 to 11,500, 6,500 to 11,500, 7,500, and 7,500 to 11,500 8,000 to 11,500, 8,500 to 11,500, 9,000 to 11,500, 9,500 to 11,500, 10,000 to 11,500, 10,500 to 11,500, 11,000 to 11,500, 1,500 to 11,000, 2,000 to 11,000, 2,500 to 11,000, 3,000 to 11,000, 3,500 to 11,000, 4,000 to 11,000, 4,500 to 11,000, 5,000 to 11,000, 5,500 to 11,000, 6,000 to 11,000, 6,500 to 11,000, 7,000 to 11,000, 7,500 to 11,000, 8,000 to 11,000, 8,500 to 11,000, 9,000 to 11,000, 9,500 to 11,000, 10,000 to 11,000, 10,500 to 11,000, 1,500 to 10,500, 2,000 to 10,500, 2,500 to 10,500, 2,500, 3,500 to 10,000, 3,500, 10,500, 3,500 to 10,500, and 4,500 to 10,500, and 10,500. 4,500 to 10,500, 5,000 to 10,500, 5,500 to 10,500, 6,000 to 10,500, 6,500 to 10,500, 7,000 to 10,500, 7,500 to 10,500, 8,000 to 10,500, 8,500 to 10,500, 9,000 to 10,500, 9,500 to 10,500, 10,000 to 10,500, 1,500 to 10,000, 2,000 to 10,000, 2,500 to 10,000, 3,000 to 10,000, 3,500 to 10,000, 4,000 to 10,000, 4,500 to 10,000, 5,000 to 10,000, 6,000 to 10,000, 6,500 to 10,000, 7,000 to 10,000, 7,500 to 10,000, 8,000 to 10,000, 8,500 to 10,000, 9,000 to 10,000, 9,500 to 10,000, 1, 9,500 to 9,500, and 9,500 to 9,500. 2,500 to 9,500, 3,000 to 9,500, 4,000 to 9,500, 4,500 to 9,500, 5,000 to 9,500, 5,500 to 9,500, 6,000 to 9,500, 6,500 to 9,500, 7,000 to 9,500, 7,500 to 9,500, 8,000 to 9,500, 8,500 to 9,500, 9,000 to 9,500, 1,500 to 9,000, 2,000 to 9,000, 2,500 to 9,000, 3,000 to 9,000, 3,500 to 9,000, 4,000 to 9,000, 4,500 to 9,000, 5,000 to 9,000, 5,500 to 9,000, 6,000 to 9,000, 7,000 to 9,000, 7,500 to 9,000, 8,000 to 9,000, 8,9,000 to 9,000, 8,500 to 9,000, 1,500, 2,500 to 9,000, 2,500, 8,500 to 8,500, 3,500, and 3,500 to 500. 3,500 to 8,500, 4,000 to 8,500, 4,500 to 8,500, 5,000 to 8,500, 5,500 to 8,500, 6,000 to 8,500, 6,500 to 8,500, 7,000 to 8,500, 7,500 to 8,500, 8,000 to 8,500, 1,500 to 8,000, 2,000 to 8,000, 2,500 to 8,000, 3,000 to 8,000, 3,500 to 8,000, 4,000 to 8,000, 4,500 to 8,000, 5,000 to 8,000, 5,500 to 8,000, 6,000 to 8,000, 6,500 to 8,000, 7,000 to 8,000, 7,500 to 8,000, 1,500 to 7,500, 2,000 to 7,500, 3,000 to 7,500, 3,500 to 7,500, 4,000 to 7,500, 4,500 to 7,500, 7,500 to 7,500, 5,500 to 500, 7,500, and 7,500 to 500,500, 500, 500,500, and so forth, 6,500 to 7,500, 7,000 to 7,500, 1,500 to 7,000, 2,000 to 7,000, 2,500 to 7,000, 3,000 to 7,000, 3,500 to 7,000, 4,000 to 7,000, 4,500 to 7,000, 5,000 to 7,000, 5,500 to 7,000, 6,000 to 7,000, 6,500 to 7,000, 1,500 to 6,500, 2,000 to 6,500, 2,500 to 6,500, 3,000 to 6,500, and 3,500 to 6,500, 4,000 to 6,500, 4,500 to 6,500, 5,000 to 6,500, 5,500 to 6,500, 6,000 to 6,500, 1,500 to 6,000, 2,000 to 6,000, 2,500 to 6,000, 3,000 to 6,000, 3,500 to 6,000, 4,000 to 6,000, 4,500 to 6,000, 5,000 to 6,000, 5,500 to 6,000, 1,500 to 5,500, 2,000 to 5,500, and 2,500 to 5,500, 3,000 to 5,500, 3,500 to 5,500, 4,000 to 5,500, 4,500 to 5,500, 5,000 to 5,500, 1,500 to 5,000, 2,000 to 5,000, 2,500 to 5,000, 3,000 to 5,000, 3,500 to 5,000, 4,000 to 5,000, 4,500 to 5,000, 1,500 to 4,500, 2,000 to 4,500, 2,500 to 4,500, 3,000 to 4,500, 3,500 to 4,500, 4,000 to 4,500, 1,500 to 4,000, 2,500 to 4,000, 3,000 to 4,000, 3,500 to 4,000, 1,500 to 4,000, 2,000 to 3,500, 2,500 to 3,500, 3,000 to 3,500, 1,500 to 3,000, 2,000 to 3,000, 2,500 to 500, 2,500 and 2,500 daltons.
In some embodiments, the at least one hydrophilic polymer may comprise polyethylene glycol (PEG). In some embodiments, the hydrophilic polymer may comprise polyethylene glycol (PEG), and the conjugated lipid may be a pegylated lipid. In some embodiments, the pegylated lipid may comprise 1, 2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE) -PEG, 1, 2-distearoyl-rac-glycerol (DSG) -PEG, 1, 2-dipalmitoyl-rac-glycerol (dpp) -PEG, diacylglycerol (DAG) -PEG, 1, 2-dimyristoyl-rac-glycerol (DMG) -PEG, 1, 2-dipalmitoyl-sn-glycero-3-phosphoethanolamine (DPPE) -PEG, 1, 2-dimyristoyl-sn-glycero-3-phosphoethanolamine (DMPE) -PEG, or any combination thereof.
In some embodiments of the present invention, in some embodiments, conjugated lipids may include Siglec-1L-PEG-DSPE, PEG-S-DSG, PEG-S-DMG, PEG-PE, PEG-PAA, PEG-OH DSPE C18, PEG-DSPE, PEG-DSG, PEG-DPG, PEG-DOMG, PEG-DMPE Na, PEG-DMPE, PEG-DMG2000, PEG-DMG C14, PEG-DMG2000, PEG-DMG, PEG-DMA, PEG-ceramide C16, PEG-C-DOMG, PEG-C-DMG, PEG-C-DMA, PEG-cDMA, PEGA, PEG-C-DMA, PEG400, PEG2K-DMG, PEG2K-C11, PEG2000-PE, PEG2000P, PEG-DSPE, PEG2000-DOMG, PEG2000-DMG, PEG2000-C-DMA, PEG2000, PEG200, PEG (2K) -DMG, PEG-DSPE C18' PEG DMPE C14, PEG DLPE C12, mPEG-PLA, MPEG-DSPE, mPEG3000-DMPE, MPEG-2000-DSPE, MPEG2000-DSPE, mPEG2000-DPPE, mPEG2000-DMPE, mPEG2000-DMG, mPPE-PEG 2000, HPEG-2K-LIPD, folic acid PEG-DSPE, DSPE-PEGMA 500, DSPE-PEGMA, DSPE-PEG6000, DSPE-PEG5000, DSPE-PEG2K-NAG, DSPE-PEG2K, DSPE-PEG2000 maleimide, DSPE-PEG2000, DSPE-PEG, DSG-PEGMA, DSG-PEG5000, DPPE-PEG-2K, DPPE-PEG, DPPE-mPEG2000, DPPE-mPEG, DPG-PEGMA, DOPE-PEG2000, DMPE-PEGMA, DMPE-PEG2000, DMPE-mPEG2000, DSPE-mPEG, DMG-PEGMA, DMG-PEG2000, DMG-PEG, cl8PEG750, CI8PEG5000, CI8PEG3000, CI8PEG2000, CI6PEG2000, CI4PEG2000, C18-PEG5000, C18PEG, C16PEG, C14-PEG-DSPE200, C14-PEG2000, C14-PEG, C14PEG, (PEG) -C-DOMG, PEG-C-DMA, and any combination thereof.
In some embodiments, the conjugated lipid component may comprise DMG-PEG. In some embodiments, the conjugated lipid component may comprise DMPE-PEG.
Without wishing to be bound by theory, it is believed that conjugation of the hydrophilic polymer may reduce aggregation of the lipid component, and is therefore sometimes referred to as a stability or stabilizing component.
Amount of conjugated lipid in delivery vehicle
In some embodiments, the conjugated lipid may comprise about 0.5-2.0 mole% of the delivery vehicle lipid. For example, the number of the cells to be processed, the conjugated lipid component may comprise about 0.1 to 2 mole%, about 0.1 to 1.8 mole%, about 0.1 to 1.6 mole%, about 0.1 to 1.5 mole%, about 0.1 to 1.4 mole%, about 0.1 to 1.2 mole%, about 0.1 to 1 mole%, about 0.1 to 0.8 mole%, about 0.1 to 0.6 mole%, about 0.1 to 0.4 mole%, about 0.1 to 0.3 mole%, about 0.1 to 0.2 mole%, about 0.2 to 2 mole%, about 0.2 to 1.8 mole%, about 0.2 to 1.6 mole%, about 0.2 to 1.5 mole%, about 0.2 to 1.4 mole%, about 0.2 to 1.2 mole%, about 0.2 to 1 mole%, about 0.2 to 0.8 mole%, about 0.2 to 0.6 mole%, about 0.1 to 0.4 mole%, about 0.2 to 1.3 mole%, about 0.2 to 1.8 mole%, about 0.2 to 1.2 mole%, about 0.3 mole% of the delivery vehicle lipid about 0.3 to 1.8 mol%, about 0.3 to 1.6 mol%, about 0.3 to 1.5 mol%, about 0.3 to 1.4 mol%, about 0.3 to 1.2 mol%, about 0.3 to 1.6 mol%, about 0.3 to 0.8 mol%, about 0.3 to 0.6 mol%, about 0.3 to 0.4 mol%, about 0.4 to 2 mol%, about 0.4 to 1.8 mol%, about 0.4 to 1.6 mol%, about 0.4 to 1.5 mol%, about 0.4 to 1.4 mol%, about 0.4 to 1.2 mol%, about 0.4 to 1.8 mol%, about 0.4 to 0.6 mol%, about 0.6 to 2 mol%, about 0.6 to 1.8 mol%, about 0.6 to 1.6 mol%, about 0.6 to 1.5 mol%, about 0.4 to 1.8 mol%, about 0.4 to 1.6 mol%, about 0.4 to 1.2 mol%, about 0.4 to 1.4 mol%, about 0.2 to 1.8 mol%, about 0.4 to 1.2 mol%, about 0.4 to 1.8 mol%, about 0.4 to 1.2 mol%, about 0.3 to 1.8 mol% and about 0.3 to 1.2 mol% of the, about 0.8 to 2 mol%, about 0.8 to 1.8 mol%, about 0.8 to 1.6 mol%, about 0.8 to 1.5 mol%, about 0.8 to 1.4 mol%, about 0.8 to 1.2 mol%, about 0.8 to 1.8 mol%, about 1 to 2 mol%, about 1 to 1.8 mol%, about 1 to 1.6 mol%, about 1 to 1.5 mol%, about 1 to 1.4 mol%, about 1 to 1.2 mol%, about 1.2 to 2 mol%, about 1.2 to 1.8 mol%, about 1.2 to 1.6 mol%, about 1.2 to 1.5 mol%, about 1.2 to 1.4 mol%, about 1.4 to 2 mol%, about 1.4 to 1.8 mol%, about 1.4 to 1.6 mol%, about 1.4 to 1.5 mol%, about 1.5 to 2 mol%, about 1.5 to 1.5 mol%, about 1.2 to 1.8 mol%, about 1.6.8 to 1.6 mol%, or about 1.8 to 1.6 mol%. In some embodiments, the conjugated lipid may comprise about 1 mole% of the delivery vehicle lipid.
In some embodiments, the concentration of conjugated lipid may be greater than about 0 mole%, 0.5 mole%, 1 mole%, 1.5 mole%, 2 mole%, 2.5 mole%, 3 mole%, 3.5 mole%, 4 mole%, 4.5 mole%, 5 mole%, 5.5 mole%, 6 mole%, 6.5 mole%, 7 mole%, 7.5 mole%, 8 mole%, 8.5 mole%, 9 mole%, 9.5 mole%, 10 mole%, 10.5 mole%, 11 mole%, 11.5 mole%, 12 mole%, 12.5 mole%, 13 mole%, 13.5 mole%, 14 mole%, 14.5 mole%, 15 mole%, 15.5 mole%, 16 mole%, 16.5 mole%, 17 mole%, 17.5 mole%, 18 mole%, 18.5 mole%, 19 mole%, 19.5 mole%, 20 mole%, 20.5 mole%, 21 mole%, 21.5 mole%, 22 mole%, 22.5 mole%, 23 mole%, 23.5 mole%, 24 mole%, 24.5 mole%, 26 mole%, 28.25 mole%, 28.5 mole%, 28 mole%, 28.5 mole%, 30 mole%. In some embodiments, the concentration of conjugated lipid is from about 0.5 mol% to about 20 mol%, from 0.5 mol% to about 5 mol%, from 0.5 mol% to about 10 mol%, from 5 mol% to about 10 mol%, or from 10 mol% to about 20 mol%.
In some embodiments, the concentration of conjugated lipid may be less than about 0.5 mole%, 1 mole%, 1.5 mole%, 2 mole%, 2.5 mole%, 3 mole%, 3.5 mole%, 4 mole%, 4.5 mole%, 5 mole%, 5.5 mole%, 6 mole%, 6.5 mole%, 7 mole%, 7.5 mole%, 8 mole%, 8.5 mole%, 9 mole%, 9.5 mole%, 10 mole%, 10.5 mole%, 11 mole%, 11.5 mole%, 12 mole%, 12.5 mole%, 13 mole%, 13.5 mole%, 14 mole%, 14.5 mole%, 15 mole%, 15.5 mole%, 16 mole%, 16.5 mole%, 17 mole%, 17.5 mole%, 18 mole%, 18.5 mole%, 19 mole%, 19.5 mole%, 20 mole%, 20.5 mole%, 21 mole%, 21.5 mole%, 22 mole%, 22.5 mole%, 23 mole%, 23.5 mole%, 24 mole%, 24.5 mole%, 25.26 mole%, 28.5%, 28 mole%, 28.5 mole%, 28.30 mole%, 28 mole%. In some embodiments, the concentration of conjugated lipid is from about 0.5 mol% to about 20 mol%, from 0.5 mol% to about 5 mol%, from 0.5 mol% to about 10 mol%, from 5 mol% to about 10 mol%, or from 10 mol% to about 20 mol%.
Additional delivery vehicle component
In some embodiments, a delivery vehicle herein, such as the lipid structures described herein for such purposes, further comprises additional components, such as, but not limited to, a Mucus Penetrating Peptide (MPP), a Cell Penetrating Peptide (CPP), a ligand, a mucus penetrating polymer, a targeting agent, or any combination thereof. In some embodiments, the delivery vehicle may comprise additional components conjugated to the lipid or lipid modification of the delivery vehicle. In some embodiments, the delivery vehicle may comprise additional components conjugated to at least one conjugated lipid of the delivery vehicle.
In some embodiments, the nanoparticle conjugated lipid can be conjugated to a hydrophilic polymer. The hydrophilic polymer may comprise PEG. The conjugated lipid may comprise one or more of DMG-PEG and DMPE-PEG and may be present at a level of about 0.5 to about 2.0 mole% of the total nanoparticle lipid. Alternative lipid (Alternative Lipid)
In some embodiments, the delivery vehicle may comprise an alternative lipid family or class.
In some embodiments, the delivery vehicles herein may include additional components. For example, the lipid structure for the delivery vehicle may comprise a lipid bilayer. In some cases, the lipid bilayer may be generated from one or more compositions selected from the group consisting of: phospholipids, phosphatidyl-choline, phosphatidyl-serine, phosphatidyl-diethanolamine, phosphatidylinositol, sphingolipids and ethoxylated sterols, or mixtures thereof. In an illustrative example of such an embodiment, the phospholipid may be lecithin; phosphatidylinositol may be derived from soybean, canola, cottonseed, egg, and mixtures thereof; sphingolipids can be ceramides, cerebrosides, sphingosine, and sphingomyelin, and mixtures thereof; the ethoxylated sterols may be phytosterols, PEG- (polyethylene glycol) -5 campesterol. In certain embodiments, the phytosterols comprise a mixture of at least two of the following compositions: sitosterol (sitosterol), campesterol (camposterol), and stigmasterol. In other embodiments, the lipid layer may comprise one or more phosphatidyl groups selected from the group consisting of: phosphatidylcholine, phosphatidyl-ethanolamine, phosphatidyl-serine, phosphatidyl-inositol, lyso-phosphatidyl-choline, lyso-phosphatidyl-ethanolamine, lyso-phosphatidyl-inositol, or lyso-phosphatidyl-inositol.
In some embodiments, the lipid bilayer may comprise a phospholipid selected from monoacyl or diacylglycerol phosphate. In other cases, the lipid bilayer may comprise one or more phosphoinositides selected from the group consisting of: phosphatidylinositol-3-phosphate (PI-3-P), phosphatidylinositol-4-phosphate (PI-4-P), phosphatidylinositol-5-phosphate (PI-5-P), phosphatidylinositol-3, 4-diphosphate (PI-3, 4-P2), phosphatidylinositol-3, 5-diphosphate (PI-3, 5-P2), phosphatidylinositol-4, 5-diphosphate (PI-4, 5-P2), phosphatidylinositol-3, 4, 5-triphosphate (PI-3, 4, 5-P3), lysophosphatidylinositol-3-phosphate (LPI-3-P), lysophosphatidylinositol-4-phosphate (LPI-4-P), lysophosphatidylinositol-5-phosphate (LPI-5-P), lysophosphatidylinositol-3, 4-diphosphate (LPI-3, 4-P2), lysophosphatidylinositol-3, 5-diphosphate (LPI-3, 5-P2), lysophosphatidylinositol-3, 4-triphosphate (LPI-3, 4-P2), lysophosphatidylinositol-3-phosphate (LPI-4-P) and lysophosphatidylinositol-4-phosphate (LPI-P2), phosphatidyl-inositol (PI) or lysophosphatidyl-inositol (LPI).
In some embodiments, the lipid structure, e.g., a liposome lipid, may be or include fatty acids, glycerolipids, glycerophospholipids, sphingolipids, glycolipids, polyketides (derived from condensation of ketoacyl subunits); sterol lipid pregnenolone lipid (derived from condensation of isoprene subunits) or any combination thereof.
Saturated cationic lipids
In some embodiments, the delivery vehicle may comprise at least one saturated cationic lipid. The term "saturated" as used herein to describe lipids is used in its broadest sense to mean lipids containing the largest possible number of hydrogen atoms, i.e., no carbon-carbon double or triple bonds.
In some embodiments, the saturated cationic lipid can have a phase transition temperature of at least about 20 ℃.
In some embodiments, the saturated cationic lipid may comprise a saturated cationic lipid having a phase transition temperature of at least about 37 ℃.
In some embodiments, saturated cationic lipids can be used in the delivery vehicles provided herein. Saturated cationic lipids can be positively charged at pH 4 or at a pH greater than pH 4. In examples where the saturated cationic lipid comprises an alkyl group, the alkyl group may be a conjugated derivative of at least one of: myristoyl, pentadecanoyl, palmitoyl, heptadecanoyl, stearoyl, lauroyl, tridecanoyl, nonadecanoyl, arachidoyl, heneicosanoyl, behenoyl, tricosanoyl, tetracosanoyl, or any combination thereof.
In some embodiments, the delivery vehicle of the present disclosure may comprise at least one saturated cationic lipid and at least one bile salt, wherein the at least one saturated cationic lipid may have a phase transition temperature of at least about 37 ℃. In some embodiments, the saturated cationic lipid has a phase transition temperature of at least about 20 ℃, 22 ℃, 24 ℃, 26 ℃, 28 ℃, 30 ℃, 32 ℃, 34 ℃, 36 ℃, 38 ℃, 40 ℃, 42 ℃, 44 ℃, 46 ℃, 48 ℃, 50 ℃, 52 ℃, 54 ℃, 56 ℃, 58 ℃, and/or up to about 60 ℃. For example, the phase transition temperature of the saturated cationic lipid may be 30 ℃ to 60 ℃, 35 ℃ to 60 ℃, 37 ℃ to 55 ℃, 37 ℃ to 50 ℃, 37 ℃ to 45 ℃, or 37 ℃ to 40 ℃. In some embodiments, the delivery vehicle of the present disclosure may comprise at least one saturated cationic lipid, wherein the phase transition temperature of the at least one saturated cationic lipid may be at least about 37 ℃. In some embodiments, the cationic lipid may be in the gel phase of the lipid structure and the anionic lipid may be in the liquid phase.
In some embodiments, the saturated cationic lipid may include at least one of the following: 1, 2-stearoyl-3-trimethylammonium-propane (DSTAP), 1, 2-dipalmitoyl-3-trimethylammonium-propane (DPTAP), 1, 2-distearoyl-3-dimethylammonium-propane (DSDAP), or any combination thereof. In some embodiments, the saturated cationic lipid may include at least one of the following: 1, 2-dialkyl-sn-glycero-3-ethylphosphocholine, 1, 2-dialkyl-3-dimethylammonium-propane, 1, 2-dialkyl-3-trimethylammonium-propane, 1, 2-di-O-alkyl-3-trimethylammonium propane, 1, 2-dialkoxy-3-dimethylaminopropane, N-dialkyl-N, N-dimethylammonium, N- (4-carboxybenzyl) -N, N-dimethyl-2, 3-bis (alkoxy) propan-1-ammonium, 1, 2-dialkyl-sn-glycero-3- [ (N- (5-amino-1-carboxypentyl) iminodiacetic acid) succinyl ], N1- [2- ((1S) -1- [ (3-aminopropyl) amino ] -4- [ bis (3-amino-propyl) amino ] butylcarboxamido) ethyl ] -3, 4-bis [ alkyl ] -benzamide, or any combination thereof.
Unsaturated cationic lipids
In some embodiments, the delivery vehicle may comprise at least one unsaturated cationic lipid. The term "unsaturated" as used herein in describing lipids, is used in its broadest sense to refer to lipids containing less than the largest possible number of hydrogen atoms, i.e., containing at least one carbon-carbon double or triple bond.
In some embodiments, the unsaturated cationic lipid may have a positive charge at about pH 4 or at a pH greater than about pH 4 and less than about pH 8. In examples where the unsaturated cationic lipid comprises an alkyl group, the alkyl group may be a conjugated derivative of at least one of: oleic acid, elaidic acid, giant whale acid, erucic acid, nervonic acid, medetoic acid, eicosenoic acid, isooleic acid, palmitoleic acid, docosatetraenoic acid, arachidonic acid, dihomo-gamma-linolenic acid, elaidic acid, linoleic acid, docosahexaenoic acid, eicosapentaenoic acid, stearidonic acid, alpha-linolenic acid, or any combination thereof. In some embodiments, the cationic lipid may be in the liquid phase of the lipid structure and the anionic lipid may be in the gel phase or solid phase of the lipid structure.
In some embodiments, the unsaturated cationic lipid may comprise at least one of the following: 1, 2-dialkyl-sn-glycero-3-ethylphosphocholine, 1, 2-dialkyl-3-dimethylammonium-propane, 1, 2-dialkyl-3-trimethylammonium-propane, 1, 2-di-O-alkyl-3-trimethylammonium-propane, 1, 2-dialkoxy-3-dimethylaminopropane, N-dialkyl-N, N-dimethylammonium, N- (4-carboxybenzyl) -N, N-dimethyl-2, 3-bis (alkoxy) propan-1-ammonium, 1, 2-dialkyl-sn-glycero-3- [ (N- (5-amino-1-carboxypentyl) iminodiacetic acid) succinyl ], N1- [2- ((1S) -1- [ (3-aminopropyl) amino ] -4- [ bis (3-amino-propyl) amino ] butylcarboxamido) ethyl ] -3, 4-di [ alkyl ] -benzamide, 1, 2-dialkoxy-N, N-dimethylaminopropane, 4- (2, 2-dioctyl-9, 12-dienyl- [1,3] dioxolan-4-ylmethyl) -dimethylamine, O-alkylethylcholine, (6Z, 9Z,28Z, 31Z) -heptadec-6,9,28,31-tetraen-19-yl 4- (dimethylamino) butyrate (MC 3), MC2, MC4, 3 beta- [ N- (N ', N' -dimethylaminoethane) -carbamoyl ] cholesterol, N4-cholestenyl-spermine, or salts thereof, or any combination thereof. In some embodiments, the cationic lipid may comprise or may be 7- (4- (dimethylamino) butyl) -7-hydroxytridecane-1, 13-diyldioleate (CL 1H 6), CL1A6, CL3A6, CL4A6, CL5A6, CL6A6, CL7A6, CL8A6, CL9A6, CL10A6, CL11A6, CL12A6, CL13A6, CL14A6, CL15A6, YSK12-C4, such as US20200129431A1 and Sato Y et al underscore structure-activity relationships of pH-sensitive cationic lipids facilitates the rational identification of promising lipid nanoparticles for delivering siRNAs in vivo.j Control release.2019;295:140-152, both of which are incorporated herein by reference in relation to unsaturated cationic lipids.
In some embodiments, the concentration of the at least one unsaturated cationic lipid in the lipid nanoparticle may be less than 50 mole%, 45 mole%, 40 mole%, 35 mole%, 30 mole%, 25 mole%, 20 mole%, 15 mole%, 10 mole%, 5 mole%, or 2 mole% of the total lipid concentration of the lipid nanoparticle. In some embodiments, the concentration of the at least one unsaturated cationic lipid in the lipid nanoparticle may be about 50 mole%, 45 mole%, 40 mole%, 35 mole%, 30 mole%, 25 mole%, 20 mole%, 15 mole%, 10 mole%, 5 mole%, or 2 mole% of the total lipid concentration of the lipid nanoparticle. In some embodiments, the concentration of the at least one unsaturated cationic lipid nanoparticle may be 5-50 mole%, 5-40 mole%, 5-30 mole%, 5-25 mole%, 5-20 mole%, 5-15 mole%, 10-50 mole%, 10-40 mole%, 10-30 mole%, 10-25 mole%, 15-50 mole%, 15-40 mole%, 15-30 mole%, and 15-25 mole%.
Lipid modification
In some embodiments, the lipid structure used as a delivery vehicle may be modified. In some embodiments, the modification may be a surface modification. In some embodiments, the surface modification may increase the average rate of movement of the lipid structure in mucus compared to a similar lipid structure.
In some embodiments, the similar lipid structures may not be surface modified, or the similar lipid structures may be modified with polyethylene glycol (PEG) polymers. In some embodiments, the modification may facilitate preventing degradation in vivo. In some embodiments, the modification may also facilitate transport of the lipid structure. For example, due to pH-sensitive modifications, the modifications may allow transport of lipid structures within the Gastrointestinal (GI) tract having an acidic pH value. In some embodiments, the surface modification may also increase the average rate of movement of the lipid structure in the mucus. For example, the modification can increase the rate by 1X, 2X, 3X, 4X, 5X, 6X, 7X, 8X, 9X, 10X, 20X, 30X, 40X, 50X, 60X, 70X, 80X, 90X, 100X, 300X, 500X, 700X, 900X, or up to about 1000X as compared to an unmodified lipid-like structure or a lipid structure having a modification comprising PEG.
In some embodiments, modification of the lipid structure occurs via a bond. In some embodiments, the bond may be a covalent bond, a non-covalent bond, a polar bond, an ionic bond, a hydrogen bond, or any combination thereof. In some embodiments, a bond may be considered an association of two groups or portions of groups. For example, the lipid structure may be bonded to PEG through a linker comprising a covalent bond. In some embodiments, the bond may occur between two adjacent groups. The keys may be dynamic. Dynamic bonds may occur when one group is temporarily associated with a second group. For example, polynucleic acids suspended in liposomes can bind to portions of the lipid bilayer during their suspension.
In some embodiments, the modification may be polyethylene glycol (PEG) addition. The method of modifying the surface of the lipid structure with PEG may include physical adsorption thereof on the surface of the lipid structure, covalent attachment thereof on the lipid structure, coating thereof on the lipid structure, or any combination thereof.
In some embodiments, PEG may be covalently attached to the lipid particle prior to formation of the lipid structure. PEG of various molecular weights can be used. The PEG may have about 10 to about 100 units of an ethylene PEG component that may be conjugated to a phospholipid via an amine group, comprising or containing about 1% to about 20%, preferably about 5% to about 15%, about 10% by weight of the lipids included in the lipid structure.
Targeting agents
In some embodiments, the delivery vehicle may comprise at least one targeting agent. In some embodiments, the term targeting agent may refer to a moiety, compound, antibody, etc., that specifically binds to a particular type or class of cells and/or other particular type of compound (e.g., a moiety that targets a particular cell or cell type).
In some embodiments, the targeting agent may be specific (e.g., have affinity) for the surface of certain target cells, target cell surface antigens, target cell receptors, or combinations thereof.
In some embodiments, a targeting agent may refer to an agent that has a specific effect (e.g., lysis) when exposed to a specific type or class of substance and/or cell, and that effect may drive the delivery vehicle to target a specific type or class of cell. In some embodiments, the term targeting agent may refer to an agent that may be part of and act in a targeting agent of a delivery vehicle, although the agent itself may or may not be specific for a particular type or class of cells themselves.
In some embodiments, by incorporating a targeting agent into a delivery vehicle of the invention, the efficiency of cellular uptake of the polynucleic acid delivered by the delivery vehicle can be enhanced and/or made more specific.
In some embodiments, the delivery vehicles described herein can comprise one or more small molecule targeting agents (e.g., carbohydrate moieties). In some embodiments, suitable targeting agents may also include antibodies, antibody-like molecules or peptides, such as integrin binding peptides, e.g., RGD-containing peptides, or small molecules, such as vitamins such as folic acid, carbohydrates, e.g., lactose and galactose, or other small molecules, as non-limiting examples.
In some embodiments, the cell surface antigen that can be targeted by the targeting agent can include a cell surface molecule such as a protein, a sugar, a lipid, or other antigen on the cell surface. In some embodiments, the cell surface antigen undergoes internalization. Examples of cell surface antigens include, but are not limited to, type 1 and type 2 transferrin receptor, EGF receptor, HER2/Neu, VEGF receptor, integrin, NGF, CD2, CD3, CD4, CDs, CDI9, CD20, CD22, CD33, CD43, CD56, CD69, and leucine rich repeat G protein coupled receptor 5 (LGR 5).
In some embodiments, the targeting agent may further comprise an artificial affinity molecule, such as a peptide mimetic or aptamer. In some embodiments, a peptidomimetic can refer to a compound in which at least a portion of a peptide, such as a therapeutic peptide, is modified and the three-dimensional structure of the peptidomimetic remains substantially the same as the three-dimensional structure of the peptide. In some embodiments, the peptidomimetics (peptide and non-peptide analogs) can have improved properties (e.g., reduced proteolysis, increased retention, or increased bioavailability). In some embodiments, the peptidomimetics generally have improved oral availability, which makes them particularly suitable for treating human or animal disorders. In some embodiments, the peptidomimetics may or may not have a similar two-dimensional chemical structure, but have common three-dimensional structural features and geometry.
In some embodiments, the targeting agent may be a protein targeting agent (e.g., peptides and antibodies, antibody fragments). In some embodiments, the delivery vehicle may comprise a plurality of different targeting agents. In embodiments, the lipid structure modification may provide biocompatibility and may be modified to have a targeting substance, including, for example, a targeting peptide, including antibodies, aptamers, polyethylene, or combinations thereof. In some embodiments, the targeting agent is a receptor. In some embodiments, a T Cell Receptor (TCR), a B Cell Receptor (BCR), a single chain variable fragment (scFv), a Chimeric Antigen Receptor (CAR), or a combination thereof may be used as a targeting agent.
In some embodiments, one or more targeting agents may be coupled to the polymer forming the delivery vehicle. In some embodiments, the targeting agent may be bound to a polymer coating the delivery vehicle. In some embodiments, the targeting agent may be covalently coupled to the polymer. In some embodiments, the targeting agent may be bound to the polymer such that the targeting agent may be substantially at or near the surface of the resulting delivery vehicle. In some embodiments, monomers comprising a targeting agent residue (e.g., a polymerizable derivative of a targeting agent, such as a (alkyl) acrylic acid derivative of a peptide) can be copolymerized to form a copolymer that forms the delivery vehicle provided herein.
In some embodiments, one or more targeting agents may be coupled to the polymer of the delivery vehicle of the present invention through a linking moiety. In some embodiments, the linking moiety that couples the targeting agent to the membrane destabilizing polymer may be a cleavable linking moiety (e.g., comprise a cleavable bond). In some embodiments, the linking moiety may be cleavable and/or comprise a bond cleavable under endosomal conditions. In some embodiments, the linking moiety may be cleavable and/or comprise a bond cleavable by a particular enzyme (e.g., phosphatase or protease). In some embodiments, the linking moiety may be cleavable and/or comprise a bond that can be cleaved upon a change in an intracellular parameter (e.g., pH, redox potential). In some embodiments, the linking moiety can be cleavable and/or comprise a bond that can be cleaved upon exposure to a Matrix Metalloproteinase (MMP) (e.g., a linking moiety of an MMP cleavable peptide).
In some embodiments, the targeting agent of the delivery vehicle may rely on cleavage of the cleavable segment in the polymer. For example, the polymers of the present invention may comprise cleavable segments that, upon cleavage, expose the delivery vehicle and/or the core of the delivery vehicle. In some embodiments, the cleavable segment may be at either or both ends of the polymers of the present invention. In some embodiments, the cleavable segments are positioned along the length of the polymer and optionally can be located between blocks of the polymer. For example, in certain embodiments, the cleavable segment may be located between the first and second blocks of the polymer, and the first block may be cleaved from the second block when the delivery vehicle may be exposed to a particular cleavage species. In some embodiments, the cleavable segment can be an MMP cleavable peptide that can be cleaved upon exposure to MMP.
In some embodiments, attachment of a targeting agent, such as an antibody or peptide, to a polymer or lipid may be accomplished in any suitable manner, for example, by any of a variety of conjugation chemistry methods, including, but not limited to, amine-carboxy linkages, amine-thiol linkages, amine-carbohydrate linkages, amine-hydroxy linkages, amine-amine linkages, carboxy-thiol linkages, carboxy-carbohydrate linkages, carboxy-hydroxy linkages, carboxy-carboxy linkages, thiol-carbohydrate linkages, thiol-hydroxy linkages, thiol-thiol linkages, carbohydrate-hydroxy linkages, carbohydrate-carbohydrate linkages, and hydroxy-hydroxy linkages. In some embodiments, "click" chemistry may be used to attach the targeting agent to the polymer of the delivery vehicle provided herein. In some embodiments, multiple conjugation chemistries are optionally used. In some embodiments, the targeting agent can be attached to a monomer, and the resulting compound can then be used to polymerize to synthesize at least one polymer (e.g., copolymer) used in the delivery vehicles described herein. In some embodiments, the targeting agent may be linked to the sense or antisense strand of the siRNA bound to the polymer of the delivery vehicle. In some embodiments, the targeting agent may be attached to the 5 'or 3' end of the sense strand or the antisense strand.
Mucus and cell penetrating agent
Delivery vehicles herein, such as the lipid structures described herein for such purposes, may also comprise a Mucus Penetrating Peptide (MPP), a Cell Penetrating Peptide (CPP), or both.
Mucus penetrating component
In some embodiments, the delivery vehicle may comprise at least one Mucus Penetrating Peptide (MPP), such as those disclosed in PCT/US 2019/032584, the contents of which are incorporated herein by reference in their entirety, with respect to MPP and MPP sequences (e.g., any of those listed in table 3 therein). In some embodiments, the MPP may have cell penetrating properties in addition to enhanced penetration through mucus layers such as those naturally found in the colon, lungs, eyes, and cervix.
In some embodiments, the MPP may target the delivery vehicle to an intracellular component of the cell. In some embodiments, the MPP may be designed to specifically target certain cell types.
In some embodiments, the MPP may be conjugated to a delivery vehicle to allow the delivery vehicle to have enhanced performance when compared to a similar delivery vehicle lacking MPPs. Such enhanced properties may include, but are not limited to, increased penetration of particles through the mucus layer, increased penetration into the cell, increased specificity of the penetrated cell (i.e., targeting of the cell), or any combination thereof.
In some embodiments, a lipid structure with MPP may internalize into a cell with an efficacy of at least about 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or up to about 100% compared to a similar particle without MPP.
In some embodiments, the MPP may be conjugated to a lipid structure. In some embodiments, the MPP may be conjugated to at least one delivery vehicle such that the MPP may be in full or partial contact with the mucus layer, mucus-containing tissue, organ, or cell outer surface.
In some embodiments, the MPP may be conjugated to a surface modification of the nanoparticle comprising the delivery vehicle such that the MPP may be in full or partial contact with the mucus layer, mucus-containing tissue, organ, or cell outer surface.
In some embodiments, the MPP may be conjugated to a load comprising a delivery vehicle such that the MPP may be in full or partial contact with the mucus layer, mucus-containing tissue, organ, or cell outer surface.
In some embodiments, the presence of MPP may impart improved penetration (diffusion and/or movement through) of the delivery vehicle through the mucus. In some embodiments, penetration may be increased by a factor of 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 50, 100 or more as compared to delivery of delivery vehicles and/or loads without MPP.
In some embodiments, the MPP may have an amino acid sequence comprising about 3 to 100 amino acids, including but not limited to about 3 to 5, 5 to 10, 10 to 20, 20 to 40, 30 to 60, or 80 to 100 amino acids. In some embodiments, the MPP may have about 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, or up to about 100 amino acids.
In some embodiments, the MPP may have the ability to penetrate a mucus layer that covers or surrounds a target cell or tissue. In some embodiments, the MPP may be used to penetrate the mucus layer of a target tissue (e.g., intestinal epithelium, colon, lung, eye, or cervix of a mammal).
In some embodiments, the MPP may be conjugated to a delivery vehicle, including nanoparticles, to allow the delivery vehicle to penetrate through the mucus layer and also for interaction with cells resulting in increased cell penetration or targeting. In some embodiments, the particles having MPP penetrate the mucus layer with an efficacy of at least about 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or up to about 100% as compared to similar particles not containing MPP.
Various methods of determining the penetration of a mucus layer are known in the art and can be used to assess penetration of MPP or MPP conjugated directly or indirectly to a delivery vehicle.
Cell penetrating component
In some embodiments, the delivery vehicle herein is designed to internalize in an epithelial cell (e.g., an epithelial cell within the gastrointestinal tract). In some embodiments, the delivery vehicle herein comprises a component for internalization of a cell. In some embodiments, the component is a peptide, a carbohydrate, or a ligand. In some embodiments, the delivery vehicle includes peptides, particularly Cell Penetrating Peptides (CPPs) and cell penetrating peptides with mucus penetrating functions, for internalization into cells of a subject.
In some embodiments, the Cell Penetrating Peptide (CPP) may be a short polypeptide, which may allow for increased delivery vehicle and/or load uptake into the cell. The Cell Penetrating Peptide (CPP) may be a peptide sequence that facilitates efficient penetration through the cytoplasmic membrane. Exemplary CPPs include those disclosed in PCT/US17/61111, which is incorporated herein by reference in its entirety with respect to CPPs.
Connector (linker)
In some embodiments, methods for attaching compounds to nucleotides can include, but are not limited to, proteins, labels, and other chemical entities. In some embodiments, crosslinking agents such as n-maleimidobutyryl oxy-succinimide ester (GMBS) and sulfo-GMBS have reduced immunogenicity. In some embodiments, substituents have been chemically attached to the 5' end of the pre-constructed oligonucleotide using amidite or H-phosphonate. In some embodiments, substituents may also be attached to the 3' end of the oligomer. This last method uses 2,2 '-dithioethanol attached to a solid support to displace diisopropylamine from the 3' phosphonate with the acridine moiety and then be deleted after phosphorus oxidation.
In some embodiments, an oligonucleotide may include one or more modified nucleotides having a group attached to a base via a linker arm. For example, biotin linkage to the C-5 position of dUTP via an allylamine linkage arm can be utilized. In some embodiments, the attachment of biotin and other groups to the 5-position of the pyrimidine via a linker arm may also be performed.
In some embodiments, chemical crosslinking may include the use of spacer arms, i.e., linkers or tethers. In some embodiments, the spacer arm provides intramolecular flexibility or adjusts the intramolecular distance between the conjugate moieties, which can help maintain biological activity. In some embodiments, the spacer arm may be in the form of a peptide moiety comprising a spacer amino acid. In some embodiments, the spacer may be part of a crosslinker, such as in "long chain SPDP.
In some embodiments, various coupling or crosslinking agents such as protein A, carbodiimide, bismaleimide, dithiobisnitrobenzoic acid (DTNB), N-succinimidyl-5-acetyl-thioacetate (SATA) and N-succinimidyl-3- (2-pyridyldithio) propionate (SPDP), 6-Hydrazinonicotinamide (HYNIC), N 3 S and N 2 S 2 Can be used in well known procedures to synthesize targeted constructs. For example, biotin can be conjugated to an oligonucleotide by DTPA using the bicyclic anhydride method. In some embodiments, sulfosuccinimidyl 6- (biotinylamino) hexanoate (NHS-LC-biotin, available from Pierce Chemical co. Rockford, ill.), a lysine conjugate of biotin, is useful in the preparation of biotin compounds. Due to the availability of primary amines, the corresponding biotin acid chloride or acid precursor can be coupled to the amino derivative of the therapeutic agent by known methods.
In some embodiments, by coupling the biotin moiety to the surface of the particle, another moiety can be coupled to avidin, and then coupled to the particle by a strong avidin-biotin affinity, or vice versa. In some embodiments where the polymer particles comprise PEG moieties on the particle surface, the free hydroxyl groups of the PEG may be used to link or link (e.g., covalently link) additional molecules or moieties to the particles.
In some embodiments, it may be desirable to release the moiety once the drug, such as a polynucleic acid, has entered the cell. In some embodiments, the moiety may be utilized to identify a number of cells that have received the polynucleic acid. In some embodiments, for example, the moiety may be an antibody, dye, scFv, peptide, glycoprotein, carbohydrate, ligand, polymer. In some embodiments, the moiety may be in contact with the linker.
In some embodiments, the linker may be non-cleavable.
In some embodiments, the linker may be a cleavable linker that can allow release of the moiety from the lipid structure upon contact with the target cell. In some embodiments, the moiety may have better ability to be absorbed by intracellular components of the cell (e.g., intestinal crypt cells or intestinal crypt stem cells) when separated from the lipid structure. In some embodiments, the linking group may comprise a disulfide bond, an acylhydrazone, a vinyl ether, an orthoester, or N-PO3.
In some embodiments, it may be necessary or desirable to separate portions from the lipid structure so that portions may enter intracellular compartments. In some embodiments, cleavage of the linker of the release moiety may be due to a change in intracellular conditions as compared to extracellular, e.g., due to a change in intracellular pH. In some embodiments, cleavage of the linker may occur due to the presence of an intracellular enzyme that cleaves the linker once a drug, such as a polynucleic acid, enters the cell. In some embodiments, cleavage of the linker may occur in response to energy or a chemical substance applied to the cell. In some embodiments, examples of the types of energy that can be used to effect cleavage of the linker include, but are not limited to, light, ultrasound, microwave, and radio frequency energy.
In some embodiments, the linker may be a photolabile linker. In some embodiments, the linker for linking the complex may also be an acid labile linker, such as, but not limited to, a linker formed by using cis-aconitic acid, cis-carboxylic acid chain triene (cis-carboxylic alkatriene), polymaleic anhydride, and other acid labile linkers.
Delivery vehicle with charge separation
In some embodiments, the delivery vehicle may comprise particles (e.g., nanoparticles) that exhibit charge separation as described herein. In some embodiments, the delivery vehicles provided herein can be used to deliver any type of load to a target, such as a target cell. The delivery vehicles provided herein with charge separation and epithelial arrival functions can be used to deliver any type of load to a target, such as a target cell.
In some embodiments, the delivery vehicles provided herein contain a positive charge and a negative charge separated into different sites within the particle, wherein each site contains a different polymer (imparting a charge to the site). In some embodiments, the delivery vehicles provided herein contain positively and negatively charged lipids, wherein the sites separate by phase, e.g., into a liquid phase and a gel phase. In some cases, the delivery vehicle may comprise a positively charged liquid phase and a negatively charged gel phase; or a positively charged gel phase and a negatively charged liquid phase.
In some embodiments, the delivery vehicles (e.g., lipid nanoparticles, liposomes, and micelle-like structures) herein can have at least two sites and comprise positive and negative charges that are not dispersed but are located in separate sites. For example, negative and positive charges may be present at opposite sites of the lipid structures provided herein at a pH of about 5.5 to 8.0, such as at a pH of about 7.4.
In some embodiments, the positive and negative charges are in two separate sites, where each site is a different phase of the lipid structure, such as a liquid phase or a solid phase (gel phase). In some embodiments, the positive charge may be on the liquid phase and the negative charge may be on a solid phase, such as a gel phase, or vice versa. Charge separation may allow for both attractive and repulsive forces.
In some embodiments, the positive lipid may be attracted to the target cell due to its high negative potential. In some embodiments, the repulsive force on the negative surface may prevent the positive surface from being dynamically trapped in mucus. In some embodiments, the cationic charge, for example on a lipid on the delivery vehicle, may be attracted to the mucus en route to the target cell and may be kinetically trapped in the mucus thereby trapping the delivery vehicle. The mucus eventually breaks off, thereby clearing the delivery vehicle.
In some embodiments, the anionic delivery vehicle may be repulsed by and may not pass through the mucus. Zwitterionic particles may act like neutral particles without net force. The zwitterionic particles may follow the flow of water similar to the pegylated system, may not be trapped in mucus, but may not reach epithelial cells.
In some embodiments of the delivery vehicle, the first site comprises an unsaturated or short tail lipid. In some embodiments, the unsaturated lipid comprises a cationic or ionizable cationic lipid. In some embodiments, the cationic lipid comprises a multivalent cationic lipid or a monovalent cationic lipid.
In some embodiments, charge separation can result in excellent and/or unexpected performance of the subject delivery vehicle. For example, the use of PEG is believed to increase trafficking to target cells (e.g., intestinal epithelial cells as provided in Maisel K et al Effect of surface chemistry on nanoparticle interaction with gastrointestinal mucus and distribution in the gastrointestinal tract following oral and rectal administration in the mouse.j Control Release, incorporated herein by reference). In some embodiments, increasing pegylation results in a reduced distribution within or at the intestinal tissue as compared to conventional carriers, thereby providing support for using a reduced pegylation delivery vehicle. One mechanism by which reduced pegylation may improve transport and/or distribution to and near target cells is by increasing exposure of positive charges at the surface of the subject carrier by reducing the shielding properties of the pegylation.
In some embodiments, the delivery vehicles provided herein comprising charge separation can have improved transport, transfection of target cells, epithelial arrival, or a combination thereof, as compared to a similar delivery vehicle lacking charge separation. In some embodiments, the improvement is about 1-fold, 50-fold, 99-fold, 148-fold, 197-fold, 246-fold, 295-fold, 344-fold, 393-fold, 442-fold, 491-fold, 540-fold, 589-fold, 638-fold, 687-fold, 736-fold, 785-fold, 834-fold, 883-fold, 932-fold, 981-fold, or up to about 1000-fold as compared to a similar delivery vehicle lacking the charge separation.
In some embodiments, the delivery vehicle has a first site that is positively charged at a pH between about 5.5 and 8.0 and a second site that is negatively charged at a pH between about 5.5 and 8.0, wherein the first and second sites are separated such that the positive and negative charges are not interspersed, and wherein one or both sites contain lipids.
In some embodiments, the first site comprises an unsaturated or short tail lipid, such as a cationic or ionizable cationic lipid, such as a multivalent cationic lipid or a monovalent cationic lipid.
In some embodiments, the ratio of cationic charge in the first site to anionic charge in the second site at pH 7.4 is about 0.25, 0.45, 0.65, 0.85, 1.05, 1.25, 1.45, 1.65, 1.85, 2.05, 2.25, 2.45, 2.65, or 2.85. In some embodiments, the ratio of cationic charge in the first site to anionic charge in the second site is about 0.25 to about 1.05, 0.75 to about 1.25, 1.05 to about 1.45, or 0.85 to about 1.85 at pH 7.4. In some embodiments, the ratio of multivalent lipids to ionizable cationic lipids in the delivery vehicle is about (6%, 6.25%, 6.5%, 6.75%, 7%, 7.25%, 7.5%, 7.75%, or 8%) to (8%, 8.25%, 8.5%, 8.75%, 9%, 9.25%, 9.5%, 9.75%, 10%), (12%, 12.25%, 12.5%, 12.75%, or 13%) to (12%, 12.25%, 12.5%, 12.75%, or 13%) or (18%, 18.25%, 18.5%, 18.75%, 19%, 19.25%, 19.5%, 19.75%, 20%) to (6%, 6.25%, 6.5%, 6.75%, 7%, 7.25%, 7.5%, 7.75%, or 8%). In some aspects, the concentration of bile salts is about 10 mole%, 15 mole%, 20 mole%, 25 mole%, 30 mole%, 35 mole%, 40 mole%, 45 mole%, 50 mole%, 55 mole%, 60 mole%, 65 mole%, 70 mole%, 75 mole%, or about 80 mole%. In some embodiments, the bile salt is about 10 to 30 mole%, 20 to 50 mole%, 30 to 60 mole%, or 40 to 80 mole%. Suitable alternative formulations may comprise multivalent lipids, ionizable cationic lipids, bile salts, structural lipids, and/or lipid-PEG in a molar ratio that is about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% higher or lower than those provided herein.
In some embodiments, the delivery vehicle may comprise a high temperature phase-change lipid, for example a high temperature phase-change neutral lipid such as DSPC, and a bile salt such as deoxycholate, cholic acid, or a conjugate thereof. Deoxycholate may be used as a solid phase (gel phase), wherein deoxycholate provides a negative charge. On the same delivery vehicle, the cationic lipid may be present as an unsaturated or short tail lipid and may be present in the liquid phase. Multivalent cationic lipids, such as MVL5, can be used to create sufficient positive-to-negative charge ratios to provide attractive and repulsive balances to the system, thereby creating a delivery vehicle comprising charge separation.
In some embodiments, the delivery vehicles herein, including those with charge separation, are useful in treating diseases and conditions affecting and/or originating from mucosal tissue, such as gastrointestinal mucosal tissue. Non-limiting examples include Familial Adenomatous Polyposis (FAP), attenuated FAP, colorectal cancer, chronic inflammatory bowel disease, microvilli inclusion body disease, and congenital diarrhea disease. In some embodiments, delivery vehicles with charge separation can be used to provide therapeutic agents and/or nucleic acids for expression of the therapeutic agents in mucosal tissues, and such agents can remain in targeted epithelial cells and/or be delivered to other disease-affected cells and tissues in the subject.
Cryoprotectants and preservatives
In some embodiments, the pharmaceutical compositions or delivery vehicles disclosed herein may be frozen, for example, for storage or transport.
In some embodiments, to maintain size and uniformity (as measured by polydispersity index (PDI)), the delivery vehicle may include a pharmaceutical composition in some embodiments or the delivery vehicle may be combined with a cryoprotectant. In some embodiments, the cryoprotectant may be, but is not limited to, glycerol, phosphate buffer, tris-sucrose buffer, or any combination thereof.
In some embodiments, a suitable phosphate buffer may comprise 0.001-0.1mg potassium dihydrogen phosphate, 0.01-0.1mg disodium hydrogen phosphate dihydrate, 0.001-0.1mg potassium chloride, 0.1-0.5mg sodium chloride, and 1-10mg sucrose.
In some embodiments, a suitable phosphate buffer may comprise 0.01mg potassium dihydrogen phosphate, 0.07mg disodium hydrogen phosphate dihydrate, 0.01mg potassium chloride, 0.36mg sodium chloride, and 6mg sucrose.
In some embodiments, a suitable Tris-sucrose buffer may comprise 10-30mM Tris (hydroxymethyl) aminomethane (Tris) and 5-15% w/v sucrose.
In some embodiments, a suitable Tris-sucrose buffer may comprise 20mM Tris (hydroxymethyl) aminomethane (Tris) and 10% w/v sucrose.
Exemplary delivery vehicles
Exemplary lipid combinations
In some embodiments, the delivery vehicle herein may include any of at least one bile salt or bile acid, at least one cationic lipid, at least one structural lipid, at least one conjugated lipid, and any combination thereof. In some embodiments, the delivery vehicle herein may include at least one bile salt or bile acid, at least one cationic lipid, at least one structural lipid, and at least one conjugated lipid. In some embodiments, the delivery vehicle herein may include at least one bile salt or bile acid, at least two cationic lipids, at least one structural lipid, and at least one conjugated lipid. In some embodiments, the delivery vehicle herein may include at least one bile salt or bile acid, at least one multivalent cationic lipid, at least one ionizable cationic lipid, at least one structural lipid, and at least one conjugated lipid.
In some embodiments, the delivery vehicle comprises at least one saturated lipid, at least one unsaturated cationic lipid, or an unsaturated non-cationic lipid, and a bile salt. In some embodiments, the lipid nanoparticle comprises a bile salt and a saturated cationic lipid having a phase transition temperature of at least about 37 ℃ and a non-cationic lipid. In some embodiments, the lipid nanoparticle comprises a bile salt and a multivalent cationic lipid and a non-cationic lipid, wherein the multivalent cationic lipid, the non-cationic lipid, or the multivalent cationic lipid and the non-cationic lipid have a phase transition temperature of at least about 37 ℃. In some embodiments, the lipid nanoparticle comprises at least one saturated lipid, wherein the saturated lipid comprises a saturated cationic lipid having a phase transition temperature of at least about 37 ℃ or a saturated non-cationic lipid having a phase transition temperature of at least about 37 ℃. In some aspects, the lipid nanoparticle further comprises at least one of: a non-cationic lipid, a multivalent cationic lipid, a permanently charged cationic lipid, or any combination thereof.
In some embodiments, the lipid nanoparticle comprises a bile salt and a saturated cationic lipid, an unsaturated cationic lipid, and a non-cationic lipid, wherein the phase transition temperature of the unsaturated cationic lipid, the non-cationic lipid, or the unsaturated cationic lipid and the non-cationic lipid is at least about 37 ℃.
In some embodiments, the lipid structure may include one or more of an anionic or cationic lipid, a neutral lipid, a sterol, and a lipid selected to reduce aggregation of the lipid particles during formation. Aggregation may be caused by steric stabilization of the lipid structure, which may prevent charge-induced aggregation during formation. The lipid structure may include two or more cationic lipids. In one aspect, the cationic lipid may be on a first phase and the anionic lipid on a second phase such that the lipid structure contains two phases of lipids with different charges.
In some embodiments, the delivery vehicle may comprise any one of the following: n1- [2- ((1S) -1- [ (3-aminopropyl) amino ] -4- [ bis (3-amino-propyl) amino ] butylcarboxamido) ethyl ] -3, 4-bis [ oleyloxy ] -benzamide (MVL 5)/(6Z, 9Z,28Z, 31Z) -heptadeca-6,9,28,31-tetraen-19-yl 3- (dimethylamino) propionate (MC 2)/1, 2-distearoyl-sn-glycero-3-phosphorylcholine (DSPC)/deoxycholate/1, 2-dimyristoyl-rac-glycero-3-methoxypolyethylene glycol (DMG-PEG); MVL5/MC 2/DSPC/deoxycholate/1, 2-dimyristoyl-sn-glycero-3-phosphoethanolamine (DMPE) -PEG; MVL5/7- (4- (dimethylamino) butyl) -7-hydroxytridecane-1, 13-diyldioleate (CL 1H 6)/DSPC/deoxycholate/DMG-PEG; MVL5/7- (4- (diisopropylamino) butyl) -7-hydroxytridecane-1, 13-diyldioleate (CL 4H 6)/DSPC/deoxycholate/DMG-PEG; MVL5/MC 2/DSPC/goose deoxycholate/DMG-PEG; MVL5/MC2/1, 2-dimyristoyl-sn-glycero-3-phosphorylcholine (DMPC)/deoxycholate/DMG-PEG; MVL5/MC 2/DMPC/deoxycholate/DMPE-PEG; MVL5/CL1H 6/DMPC/deoxycholate/DMG-PEG; MVL5/MC 2/DSPC/deoxycholate/lithocholate/DMG-PEG; MVL5/CL1H 6/DSPC/deoxycholate/lithocholate/DMG-PEG; MVL5/MC 2/DSPC/allophanate/DMG-PEG; or MVL5/MC 2/DSPC/dehydrolithocholic acid salt/DMG-PEG.
Exemplary composition of delivery vehicle
In some embodiments, the delivery vehicles provided herein may comprise at least one of a multivalent lipid, a cationic lipid, a structural lipid, a bile salt, a bile acid, or a conjugated lipid (i.e., lipid-PEG). Any or all of the lipids provided herein may be formulated at any mole%, including, for example, but not limited to: 0 mol%, 0.5 mol%, 1 mol%, 1.5 mol%, 2 mol%, 2.5 mol%, 3 mol%, 3.5 mol%, 4 mol%, 4.5 mol%, 5 mol%, 5.5 mol%, 6 mol%, 6.5 mol%, 7 mol%, 7.5 mol%, 8 mol%, 8.5 mol%, 9 mol%, 9.5 mol%, 10 mol%, 10.5 mol%, 11 mol%, 11.5 mol%, 12 mol%, 12.5 mol%, 13 mol%, and 13.5 mol%, 14 mol%, 14.5 mol%, 15 mol%, 15.5 mol%, 16 mol%, 16.5 mol%, 17 mol%, 17.5 mol%, 18 mol%, 18.5 mol%, 19 mol%, 19.5 mol%, 20 mol%, 20.5 mol%, 21 mol%, 21.5 mol%, 22 mol%, 22.5 mol%, 23 mol%, 23.5 mol%, 24 mol%, 24.5 mol%, 25 mol%, 25.5 mol%, 26 mol%, 26.5 mol%, 27 mol%, 27.5 mol%, 28 mol%, 28.5 mol%, 29 mol%, 29.5 mol%, 30 mol%, 30.5 mol%, 31 mol%, 31.5 mol%, 32 mol%, 32.5 mol%, 33 mol%, 33.5 mol%, 34 mol%, 34.5 mol%, 35 mol%, 35.5 mol%, 36 mol%, 36.5 mol%, 37 mol%, 37.5 mol%, 38 mol%, 38.5 mol%, 39 mol%, 39.5 mol%, 40 mol%, 40.5 mol%, 41 mol%, 41.5 mol%, 42 mol%, 42.5 mol%, 43 mol%, 43.5 mol%, 44 mol%, 44.5 mol%, 45 mol%, 45.5 mol%, 46 mol%, 46.5 mol%, 47 mol%, 47.5 mol%, 48 mol%, 48.5 mol%, 49 mol%, 49.5 mol%, 50 mol%, 50.5 mol%, 51 mol%, and 51 mol% > 51.5 mol%, 52 mol%, 52.5 mol%, 53 mol%, 53.5 mol%, 54 mol%, 54.5 mol%, 55 mol%, 55.5 mol%, 56 mol%, 56.5 mol%, 57 mol%, 57.5 mol%, 58 mol%, 58.5 mol%, 59 mol%, 59.5 mol%, 60 mol%, 60.5 mol%, 61 mol%, 61.5 mol%, 62 mol%, 62.5 mol%, 63 mol%, 63.5 mol%, 64 mol%, 64.5 mol%, 65 mol%, 65.5 mol%, 66 mol%, 66.5 mol%, 67 mol%, 67.5 mol%, 68 mol%, 68.5 mol%, 69.5 mol%, 70 mol%, 70.5 mol%, 71 mol%, 71.5 mol%, 72 mol%, 72.5 mol%, 73 mol%, 73.5 mol%, 74 mol%, 74.5 mol%, 75 mol%, 75.5 mol%, 76 mol%, 76.5 mol%, 77 mol%, 78 mol%, 79.80 mol%, or 80 mol%.
In some embodiments, the delivery vehicle may comprise 5 to 40 mole% of at least one bile salt or bile acid; 5-90 mole% of at least one cationic lipid; 5-75 mole% of at least one structural lipid; and 0.5-2 mole% of at least one conjugated lipid.
In some embodiments, the delivery vehicle may comprise about 5-40 mole% of at least one bile salt or bile acid; about 5 to 60 mole% of a cationic lipid; about 5 to 60 mole% of a second cationic lipid; about 5-75 mole% of at least one structural lipid; and about 0.5 to about 2.0 mole% of at least one conjugated lipid.
In some embodiments, the delivery vehicle may comprise about 20-40 mole% of at least one bile salt or bile acid; about 5 to 30 mole% of a cationic lipid; about 5 to 30 mole% of a second cationic lipid; about 30-50 mole% of at least one structural lipid; and about 0.5 to about 2.0 mole% of at least one conjugated lipid.
In some embodiments, the delivery vehicle may comprise about 30-40 mole% of at least one bile salt or bile acid; about 5-15 mole% of a cationic lipid; about 5-15 mole% of a second cationic lipid; about 35 to 45 mole% of at least one structural lipid; and about 0.5 to about 2.0 mole% of at least one conjugated lipid.
In some embodiments, the delivery vehicle may comprise about 33 mole% of at least one bile salt; about 12.5 mole% of a cationic lipid; about 12.5 mole% of a second cationic lipid; about 41 mole% of at least one structural lipid; and about 1 mole% of at least one conjugated lipid.
In some embodiments, the delivery vehicle may comprise any of the formulations disclosed in table 1B or any combination thereof.
A variety of molar ratios can be used to create the delivery vehicle. In some embodiments, a delivery vehicle (e.g., a delivery vehicle for a pharmaceutical formulation) comprises MVL5, MC2, deoxycholate, DSPC, and DMG-PEG in a molar ratio of about 0.96:0.96:2.592:3.168:0.0768:0.0384:0.0384.
In some embodiments, the composition nanoparticle comprises at least one bile salt, each of the at least one cationic lipid, about 0.5 to about 3, about 2 to about 10 of the at least one structural lipid, and about 0.02 to about 0.10 of the at least one conjugated lipid in a molar ratio between the components of about 1 to about 5.
In some embodiments, the delivery vehicle (e.g., nanoparticle) bile salts may include one or more of deoxycholate, xiong Erchun, lithocholate, isophthalate, allophanate, dehydrolithocholate, and 5 β -cholanic acid. In some embodiments, the delivery vehicle cationic lipid may comprise MVL5. In some embodiments, the delivery vehicle cationic lipid may comprise MC2. In some embodiments, the delivery vehicle structure lipid may comprise DSPC. In some embodiments, the delivery vehicle conjugated lipid may comprise DMG-PEG. In some embodiments, the molar ratio of bile salt to MVL5 to MC2 to DSPC to DMG-PEG in the delivery vehicle may be about 2.592:0.96:0.96:3.168:0.768. In some embodiments, the delivery vehicle bile salt may comprise deoxycholate.
In some embodiments, the composition of the delivery vehicle (e.g., nanoparticle) may include MVL5, MC2, DSPC, deoxycholate, and DMPE-PEG in a molar ratio of 2.4:2.4:7.9:6.48:0.192.
In some embodiments, the delivery vehicle may include MVL5, CL1H6, DSPC, deoxycholate, and DMG-PEG in molar ratios of about 2.4, 7.9, 6.48, and 0.192.
In some embodiments, the delivery vehicle may include MVL5, CL4H6, DSPC, deoxycholate, and DMG-PEG in molar ratios of about 2.4, 7.9, 6.48, and 0.192.
In some embodiments, the delivery vehicle may include MVL5, MC2, DSPC, chenodeoxycholate, and DMG-PEG in molar ratios of about 2.4, 7.9, 6.48, and 0.192.
In some embodiments, the delivery vehicle may include MVL5, MC2, DMPC, deoxycholate, and DMG-PEG in molar ratios of about 2.4, 7.9, 6.48, and 0.192.
In some embodiments, the delivery vehicle may include MVL5, MC2, DMPC, deoxycholate, and DMPE-PEG in molar ratios of about 2.4, 7.9, 6.48, and 0.192.
In some embodiments, the delivery vehicle may include MVL5, CL1H6, DMPC, deoxycholate, and DMG-PEG in molar ratios of about 2.4, 7.9, 6.48, and 0.192.
In some embodiments, the delivery vehicle may include MVL5, MC2, DSPC, deoxycholate, lithocholate, and DMG-PEG in molar ratios of about 2.4, 7.9, 5.2, 1.3, and 0.192.
In some embodiments, the delivery vehicle may include MVL5, CL1H6, DSPC, deoxycholate, lithocholate, and DMG-PEG in molar ratios of about 2.4, 7.9, 5.2, 1.3, and 0.192.
In some embodiments, the delivery vehicle may include MVL5, MC2, DSPC, allo-isophthalate, and DMG-PEG in molar ratios of about 2.4, 7.92, 6.48, and 0.192.
In some embodiments, the delivery vehicle may include MVL5, MC2, DSPC, dehydrolithocholate, and DMG-PEG in molar ratios of about 2.4, 7.92, 6.48, and 0.192.
In some embodiments, the composition of the delivery vehicle may include 12.4 mole% MVL5, 12.4 mole% MC2, 40.8 mole% DSPC, 33.4 mole% of at least one bile salt, and 1 mole% of at least one conjugated lipid. In some embodiments, the at least one conjugated lipid may comprise DMG-PEG or DMPE-PEG. In some embodiments, the at least one bile salt comprises one or more of taurodeoxycholate, taurochenodeoxycholate, glycocholate, 3-oxo-cholanic acid, and deoxycholate.
Exemplary delivery vehicles are described herein and provided, for example, in table 1A, table 1B, table 2, table 3, table 4, and table 8. Any of the delivery vehicles illustrated may be further modified. For example, additional lipids and loads can be produced, and modifications, additions, and reductions can be made. In some embodiments, any of the delivery vehicles in table 1 may further comprise lipid-PEG.
Table 1A: exemplary design of delivery vehicle
Table 1B: exemplary delivery vehicle compositions
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Exemplary delivery vehicle embodiments
In some embodiments, a delivery vehicle is provided that comprises a load in a lipid structure, such as a lipid nanoparticle, and wherein the lipid nanoparticle comprises a bile salt and at least one of: (a) Saturated cationic lipids having a phase transition temperature of at least about 37 ℃, and non-cationic lipids; (b) A saturated cationic lipid, an unsaturated cationic lipid, a non-cationic lipid, wherein the phase transition temperature of the unsaturated cationic lipid, the non-cationic lipid, or the unsaturated cationic lipid and the non-cationic lipid is at least about 37 ℃; or (c) a multivalent cationic lipid, a non-cationic lipid, wherein the multivalent cationic lipid, the non-cationic lipid, or the phase transition temperature of the multivalent cationic lipid and the non-cationic lipid is at least about 37 ℃, wherein the lipid nanoparticle comprising bile salts and at least one of (a), (b), or (c) is absent from (i); (ii) A lipid nanoparticle comprising at least one of (a), (b) or (c) but no bile salts; or (iii) a delivery vehicle that comprises bile salts but does not comprise at least one of (a), (b) or (c) but is otherwise the same, is stable in a high bile salt environment.
In some embodiments, a delivery vehicle is provided comprising a cargo and a lipid structure, such as a lipid nanoparticle, wherein the lipid nanoparticle comprises a bile salt and at least one of: (a) Saturated cationic lipids having a phase transition temperature of at least about 37 ℃; (b) Saturated cationic lipids, unsaturated cationic lipids, and non-cationic lipids, wherein the phase transition temperature of the unsaturated cationic lipids, non-cationic lipids, or unsaturated cationic lipids and non-cationic lipids is at least about 37 ℃; or (c) a multivalent cationic lipid and a non-cationic lipid, wherein the multivalent cationic lipid, the non-cationic lipid, or the multivalent cationic lipid and the non-cationic lipid have a phase transition temperature of at least about 37 ℃, wherein the lipid nanoparticle comprising bile salts and at least one of (a), (b), or (c) is absent from (i); (ii) A lipid nanoparticle comprising at least one of (a), (b) or (c) but no bile salts; or (iii) a delivery vehicle comprising a bile salt but not at least one of (a), (b) or (c) but otherwise identical, exhibits increased stability in a solution comprising at least about 5g/L bile acid and deoxycholate, wherein stability is measured by the relative fluorescence intensity of fluorescent lipids incorporated into lipid nanoparticles in a Forster Resonance Energy Transfer (FRET) assay.
In some embodiments, a delivery vehicle is provided comprising (i) a cargo and (ii) a lipid structure, such as a lipid nanoparticle, wherein the lipid nanoparticle comprises at least one saturated cationic lipid and a bile salt, wherein the phase transition temperature of the at least one saturated cationic lipid is at least about 37 ℃. In some embodiments, a delivery vehicle is provided comprising (i) a cargo and (ii) a lipid nanoparticle, wherein the lipid nanoparticle comprises at least one saturated lipid, at least one unsaturated cationic lipid, and a bile salt, wherein the concentration of the at least one unsaturated cationic lipid in the lipid nanoparticle is less than 50 mole%.
In some embodiments, the present disclosure provides a composition comprising a load; and a nanoparticle, the nanoparticle comprising: a first cationic lipid and optionally a second cationic lipid; at least one bile salt; at least one structural lipid; and at least one conjugated lipid conjugated to the hydrophilic polymer. The at least one bile salt may be selected from one or more of deoxycholate, lithocholate, isophthalate, allopsocholate, dehydrolithocholate, xiong Erchun, 5β -cholanic acid, chenodeoxycholate, cholate, taurodeoxycholate, taurochenodeoxycholate, glycocholate, 3-oxo-cholanic acid and porcine deoxycholate. The at least one bile salt may be included in the nanoparticle at a level of about 5 to about 40 mole% of the total nanoparticle lipid. The at least one bile salt may be included in the nanoparticle at a level of about 20 to about 40 mole% of the total nanoparticle lipid. The at least one bile salt may comprise deoxycholate. The first cationic lipid may comprise CL1H6 or CL4H6. The first cationic lipid may be included at a level of about 5 to about 40 mole% of the total nanoparticle lipid. The second cationic lipid may comprise MVL5, MC2 or DODMA. The second cationic lipid may be present at a level of about 5 to about 20 mole% of the total nanoparticle lipid. Each of the first cationic lipid and the second cationic lipid may be present at a level of 5 to about 20 mole% of the total nanoparticle lipid, and may be present in equal amounts. The at least one structural lipid may be selected from one or more of DSPC, DMPC and dioleoyl phosphatidylethanolamine (DOPE). The at least one structural lipid may be present at a level of about 10 to about 70 mole% of the total nanoparticle lipid. The at least one structured lipid may be present at a level of about 30 to about 50 mole% of the total nanoparticle lipid. The at least one structural lipid and the at least one bile salt may be present at a combined level of about 50 to about 80 mole% of the total nanoparticle lipid. The hydrophilic polymer may comprise PEG. The at least one conjugated lipid may comprise DMG-PEG. The at least one conjugated lipid may be present at a level of about 0.5 to about 2.0 mole% of the total nanoparticle lipid. The first cationic lipid may be CL1H6. The nanoparticle may include a second cationic lipid that includes MVL5. At least one bile salt may be deoxycholate. The at least one structural lipid may be DSPC. The at least one conjugated lipid may be DMG-PEG.
In some embodiments, the present disclosure provides a composition comprising a payload and a nanoparticle, wherein the nanoparticle comprises CL1H6, MVL5, and DMG-PEG in a molar ratio of about 1:1:0.08; and deoxycholate and DSPC in a molar ratio of about 0.5 to about 5.0. The molar ratio of deoxycholate to DSPC may be about 2.0 to about 4.0. The nanoparticle may include CL1H6 at a level of about 10 to about 20 mole% of the total nanoparticle lipids; MVL5 at a level of about 10 to about 20 mole% of the total nanoparticle lipid; deoxycholate at a level of about 10 to about 40 mole% of the total nanoparticle lipid; DSPC, DMPC or DOPE at a level of about 30 to about 60 mole% of the total nanoparticle lipid; and DMG-PEG at a level of about 0.5 to about 2.0 mole% of the total nanoparticle lipid. The nanoparticle may comprise: CL1H6 and MVL5 at a level of about 10 to about 15 mole% of the total nanoparticle lipid; deoxycholate at a level of about 20 to about 40 mole% of the total nanoparticle lipid; DSPC at a level of about 35 to about 50 mole% of the total nanoparticle lipid; and DMG-PEG at a level of about 0.75 to about 1.5 mole% of the total nanoparticle lipid. The nanoparticle may comprise: CL1H6 and MVL5 at a level of about 12 to about 14 mole% of the total nanoparticle lipid; deoxycholate at a level of about 27 to about 38 mole% of the total nanoparticle lipid; DSPC at a level of about 38 to about 45 mole% of the total nanoparticle lipid; and DMG-PEG at a level of about 0.75 to about 1.5 mole% of the total nanoparticle lipid. The nanoparticle may comprise: CL1H6 and MVL5 at a level of about 12 mole% of total nanoparticle lipids; deoxycholate at a level of about 33 mole% of the total nanoparticle lipid; DSPC at a level of about 41 mole% of total nanoparticle lipid; and DMG-PEG at a level of about 1 mole% of the total nanoparticle lipid. The hydrophilic polymer may be conjugated to a polypeptide. The polypeptide may include an MPP, such as any of those described in table 3 of international publication No. WO2019222400, the contents of which are incorporated herein by reference in their entirety. MPP may comprise an amino acid sequence according to TVDNDAPTKRASKLFAV (SEQ ID NO: 17). The hydrophilic polymer may comprise PEG. The at least one conjugated lipid may comprise DMG-PEG. The nanoparticle may comprise: CL1H6 and MVL5 at a level of about 12 to about 14 mole% of the total nanoparticle lipid; deoxycholate at a level of about 27 to about 38 mole% of the total nanoparticle lipid; DSPC at a level of about 38 to about 45 mole% of the total nanoparticle lipid; and DMG-PEG at a level of about 0.75 to about 1.5 mole% of the total nanoparticle lipid. The load may include one or more of the following: nucleic acids, proteins, antibodies, peptides, small molecules, biologicals, peptidomimetics, ribozymes, chemicals, viral particles, growth factors, cytokines, immunomodulators, and fluorescent dyes. The load may comprise a nucleic acid. The nucleic acid may comprise DNA. The DNA may comprise plasmid DNA. The molar ratio of nanoparticle cationic lipid to nanoparticle nucleotide may be about 2 to about 20. The molar ratio of nanoparticle cationic lipid to nanoparticle nucleotide may be about 14 to about 18. The nucleic acid may comprise RNA. The molar ratio of nanoparticle cationic lipid to total number of RNA-loaded nucleotides can be about 2 to about 20. The molar ratio of nanoparticle cationic lipid to RNA-loaded nucleotide may be about 2 to about 4.
In some embodiments, the present disclosure provides a composition comprising a payload and a nanoparticle comprising: at least one bile salt; at least one cationic lipid; at least one structural lipid; and at least one conjugated lipid, wherein the conjugated lipid is conjugated to the hydrophilic polymer. The at least one bile salt may be selected from one or more of the following: deoxycholate, lithocholate, isophthalate, allophiacholate, dehydrolithocholate, xiong Erchun, 5β -cholanic acid, chenodeoxycholate, cholate, taurodeoxycholate, glycocholate, 3-oxo-cholanic acid, and porcine deoxycholate. The at least one bile salt may be included in the nanoparticle at a level of about 5 to about 40 mole% of the total nanoparticle lipid. The at least one bile salt may be included in the nanoparticle at a level of about 20 to about 40 mole% of the total nanoparticle lipid. The at least one bile salt may be included in the nanoparticle at a level of about 33 to about 37 mole% of the total nanoparticle lipid. The at least one bile salt may comprise deoxycholate. The composition may include two bile salts. At least one of the two bile salts may comprise lithocholic acid salt. The composition may include deoxycholate at a level of about 20 to about 30 mole% of the total nanoparticle lipid; and a level of lithocholic acid salt of about 5 to about 10 mole% of the total nanoparticle lipids. The at least one cationic lipid may comprise N1- [2- ((1S) -1- [ (3-aminopropyl) amino ] -4- [ bis (3-amino-propyl) amino ] butylcarboxamido) ethyl ] -3, 4-bis [ oleyloxy ] -benzamide (MVL 5). MVL5 may be present at a level of about 5 to about 20 mole% of the total nanoparticle lipid. The at least one cationic lipid may comprise one or more of the following: (6Z, 9Z,28Z, 31Z) -thirty-seven carbon-6,9,28,31-tetraen-19-yl 3- (dimethylamino) propionate (MC 2); 7- (4- (dimethylamino) butyl) -7-hydroxytridecane-1, 13-diyldioleate (CL 1H 6); and 7- (4- (diisopropylamino) butyl) -7-hydroxytridecane-1, 13-diyldioleate (CL 4H 6). Each of the at least one cationic lipid may be present at a level of about 5 to about 20 mole% of the total nanoparticle lipids. The at least one structural lipid may be selected from one or more of 1, 2-distearoyl-sn-glycero-3-phosphorylcholine (DSPC) and 1, 2-dimyristoyl-sn-glycero-3-phosphorylcholine (DMPC). The at least one structured lipid may be present at a level of about 35 to about 45 mole% of the total nanoparticle lipids. The hydrophilic polymer may include polyethylene glycol (PEG). The at least one conjugated lipid may include one or more of 1, 2-dimyristoyl-rac-glycerol (DMG) -PEG and 1, 2-dimyristoyl-sn-glycero-3-phosphoethanolamine (DMPE) -PEG. The at least one conjugated lipid may be present at a level of about 0.5 to about 2.0 mole% of the total nanoparticle lipid. The molar ratios between the components may be: about 1 to about 5 of at least one bile salt; about 0.5 to about 3 of each of at least one cationic lipid; about 2 to about 10 of at least one structural lipid; and from about 0.02 to about 0.10 of at least one conjugated lipid. The at least one bile salt may be selected from one or more of the following: deoxycholate, xiong Erchun, lithocholate, isophthalate, allophiacholate, dehydrolithocholate and 5 beta-cholanic acid. The at least one cationic lipid may comprise MVL5. The at least one cationic lipid may comprise MC2. The at least one structured lipid may comprise DSPC. The at least one conjugated lipid may comprise DMG-PEG. The composition may include at least one bile salt, MVL5, MC2, DSPC, and DMG-PEG in a molar ratio of about 2.592:0.96:0.96:3.168:0.768. At least one bile salt may be deoxycholate. The nanoparticle may comprise: MVL5, MC2, DSPC, deoxycholate, and DMPE-PEG in a molar ratio of about 2.4:2.4:7.9:6.48:0.192; MVL5, CL1H6, DSPC, deoxycholate, and DMG-PEG at a molar ratio of about 2.4:2.4:7.9:6.48:0.192; MVL5, CL4H6, DSPC, deoxycholate, and DMG-PEG at a molar ratio of about 2.4:2.4:7.9:6.48:0.192; MVL5, MC2, DSPC, chenodeoxycholate, and DMG-PEG in a molar ratio of about 2.4:2.4:7.9:6.48:0.192; MVL5, MC2, DMPC, deoxycholate, and DMG-PEG in a molar ratio of about 2.4:2.4:7.9:6.48:0.192; MVL5, MC2, DMPC, deoxycholate, and DMPE-PEG in a molar ratio of about 2.4:2.4:7.9:6.48:0.192; MVL5, CL1H6, DMPC, deoxycholate, and DMG-PEG in a molar ratio of about 2.4:2.4:7.9:6.48:0.192; MVL5, MC2, DSPC, deoxycholate, lithocholate, and DMG-PEG in a molar ratio of about 2.4:2.4:7.9:5.2:1.3:0.192; MVL5, CL1H6, DSPC, deoxycholate, lithocholate, and DMG-PEG in a molar ratio of about 2.4:2.4:7.9:5.2:1.3:0.192; MVL5, MC2, DSPC, allophanate and DMG-PEG in a molar ratio of about 2.4:2.4:7.92:6.48:0.192; or MVL5, MC2, DSPC, dehydrolithocholic acid salt, and DMG-PEG in a molar ratio of about 2.4:2.4:7.92:6.48:0.192. The composition may include 12.4 mole% MVL5, 12.4 mole% MC2, 40.8 mole% DSPC, 33.4 mole% of at least one bile salt, and 1 mole% of at least one conjugated lipid. The at least one conjugated lipid may comprise DMG-PEG or DMPE-PEG. The at least one bile salt may be selected from one or more of the following: taurodeoxycholate, taurochenodeoxycholate, glycocholate, 3-oxo-cholanic acid and deoxycholate. The load may include one or more of the following: nucleic acids, proteins, antibodies, peptides, small molecules, biologicals, peptidomimetics, ribozymes, chemicals, viral particles, growth factors, cytokines, immunomodulators, and fluorescent dyes. The load may comprise a nucleic acid. The nucleic acid may comprise DNA. The DNA may comprise plasmid DNA.
In some embodiments, the present disclosure provides a composition comprising a load; and a nanoparticle comprising: a first cationic lipid comprising CL1H6 or CL4H6; optionally a second cationic lipid; at least one bile salt; at least one structural lipid; and at least one conjugated lipid, wherein the at least one conjugated lipid is conjugated to a hydrophilic polymer. The at least one bile salt may be selected from one or more of the following: deoxycholate, lithocholate, isophthalate, allophiacholate, dehydrolithocholate, xiong Erchun, 5β -cholanic acid, chenodeoxycholate, cholate, taurodeoxycholate, glycocholate, 3-oxo-cholanic acid, and porcine deoxycholate. The at least one bile salt may be included in the nanoparticle at a level of about 5 to about 40 mole% of the total nanoparticle lipid. The at least one bile salt may be included in the nanoparticle at a level of about 20 to about 40 mole% of the total nanoparticle lipid. The at least one bile salt may comprise deoxycholate. The first cationic lipid may comprise about 5 to about 40 mole% of the total nanoparticle lipid. The nanoparticle may include a second cationic lipid comprising MVL5, MC2, or DODMA. The second cationic lipid may be present at a level of about 5 to about 20 mole% of the total nanoparticle lipid. Each of the first cationic lipid and the second cationic lipid may be present at a level of about 5 to about 20 mole% of the total nanoparticle lipid, and each may be present in equal amounts. The at least one structural lipid may be selected from one or more of DSPC, DMPC and dioleoyl phosphatidylethanolamine (DOPE). The at least one structural lipid may be present at a level of about 10 to about 70 mole% of the total nanoparticle lipid. The at least one structured lipid may be present at a level of about 30 to about 50 mole% of the total nanoparticle lipid. The at least one structural lipid and the at least one bile salt may be present at a combined level of about 50 to about 80 mole% of the total nanoparticle lipid. The hydrophilic polymer may comprise PEG. The at least one conjugated lipid may comprise DMG-PEG. The at least one conjugated lipid may be present at a level of about 0.5 to about 2.0 mole% of the total nanoparticle lipid. The first cationic lipid may comprise CL1H6. The nanoparticle may include a second cationic lipid that includes MVL5. The at least one bile salt may comprise deoxycholate. The at least one structured lipid may comprise DSPC. The at least one conjugated lipid may comprise DMG-PEG. CL1H6, MVL5, and DMG-PEG may be included in a molar ratio of about 1:1:0.08; and deoxycholate and DSPC may be included in a molar ratio of about 0.5 to about 5.0. The molar ratio of deoxycholate to DSPC may be about 2.0 to about 4.0.CL1H6 can be included at a level of about 10 to about 20 mole% of the total nanoparticle lipids; MVL5 may be included at a level of about 10 to about 20 mole% of the total nanoparticle lipid; deoxycholate may be included at a level of about 10 to about 40 mole% of the total nanoparticle lipid; DSPC, DMPC or DOPE may be included at a level of about 30 to about 60 mole% of the total nanoparticle lipid; and DMG-PEG may be included at a level of about 0.5 to about 2.0 mole% of the total nanoparticle lipid. The nanoparticle may comprise: CL1H6 and MVL5 at a level of about 10 to about 15 mole% of the total nanoparticle lipid; deoxycholate at a level of about 20 to about 40 mole% of the total nanoparticle lipid; DSPC at a level of about 35 to about 50 mole% of the total nanoparticle lipid; and DMG-PEG at a level of about 0.75 to about 1.5 mole% of the total nanoparticle lipid. The nanoparticle may comprise: CL1H6 and MVL5 at a level of about 12 to about 14 mole% of the total nanoparticle lipid; deoxycholate at a level of about 27 to about 38 mole% of the total nanoparticle lipid; DSPC at a level of about 38 to about 45 mole% of the total nanoparticle lipid; and DMG-PEG at a level of about 0.75 to about 1.5 mole% of the total nanoparticle lipid. The nanoparticle may comprise: CL1H6 and MVL5 at a level of about 12 mole% of total nanoparticle lipids; deoxycholate at a level of about 33 mole% of the total nanoparticle lipid; DSPC at a level of about 41 mole% of total nanoparticle lipid; and DMG-PEG at a level of about 1 mole% of the total nanoparticle lipid. The hydrophilic polymer may be conjugated to a polypeptide. The polypeptide may be a Mucus Penetrating Polypeptide (MPP). MPP may comprise an amino acid sequence according to SEQ ID NO. 17. The hydrophilic polymer may comprise PEG. The at least one conjugated lipid may comprise DMG-PEG. The nanoparticle may comprise: CL1H6 and MVL5 at a level of about 12 to about 14 mole% of the total nanoparticle lipid; deoxycholate at a level of about 27 to about 38 mole% of the total nanoparticle lipid; DSPC at a level of about 38 to about 45 mole% of the total nanoparticle lipid; and DMG-PEG at a level of about 0.75 to about 1.5 mole% of the total nanoparticle lipid. The load may include one or more of the following: nucleic acids, proteins, antibodies, peptides, small molecules, biologicals, peptidomimetics, ribozymes, chemicals, viral particles, growth factors, cytokines, immunomodulators, and fluorescent dyes. The load may comprise a nucleic acid. The nucleic acid may comprise DNA. The DNA may comprise plasmid DNA. The molar ratio of total nanoparticle cationic lipid to the total number of nucleic acid-loaded nucleotides can be from about 2 to about 20. The molar ratio of total nanoparticle cationic lipid to the total number of nucleic acid-loaded nucleotides can be from about 14 to about 18. The nucleic acid may comprise RNA. The molar ratio of total nanoparticle cationic lipid to the total number of nucleic acid-loaded nucleotides can be from about 2 to about 20. The molar ratio of total nanoparticle cationic lipid to the total number of nucleic acid-loaded nucleotides can be from about 2 to about 4.
Improved function of the described delivery vehicle
Improved stability in bile salt environments
In some embodiments, the stability of the delivery vehicle may be measured by a bile salt stability assay in a high bile salt mimetic environment. For example, bile salt stability can be measured in Forster Resonance Energy Transfer (FRET) assays by fluorescence spectroscopy, such as the relative fluorescence of delivery vehicles containing bile salts or bile acids at different concentrations. In some embodiments, the incorporated bile salts and/or bile acids may increase the stability of the delivery vehicle by about 80% to about 10%, for example about 80% to about 70%, about 65% to about 55%, about 60% to about 50%, about 55% to about 45%, about 50% to about 40%, about 45% to about 35%, about 40% to about 30%, about 35% to about 25%, about 30% to about 20%, about 25% to about 15%, about 20% to about 10%, about 15% to about 10%, about 60% to about 20%, about 25.9%, about 30.4%, about 34.9%, about 39.4%, about 37.1%, about 43.9%, or about 45%. In some embodiments, the incorporated bile salts and/or bile acids may increase the stability of the delivery vehicle as compared to a delivery vehicle comprising only a single cationic lipid, lacking bile salts or bile acids, or any combination thereof.
In some embodiments, the delivery vehicle stability may increase with the incorporation of bile salts and/or bile acids. For example, bile salt stability can be measured in Forster Resonance Energy Transfer (FRET) assays by fluorescence spectroscopy, such as the relative fluorescence of delivery vehicles containing bile salts at different concentrations. In some embodiments, the incorporated bile salts and/or bile acids may increase the stability of the delivery vehicle by about 80% to about 10%, such as about 80% to about 70%, about 65% to about 55%, about 60% to about 50%, about 55% to about 45%, about 50% to about 40%, about 45% to about 35%, about 40% to about 30%, about 35% to about 25%, about 30% to about 20%, about 25% to about 15%, about 20% to about 10%, about 15% to about 10%, about 60% to about 20%, about 25.9%, about 30.4%, about 34.9%, about 39.4%, about 37.1%, about 43.9%, or about 45%, as compared to the stability of a similar delivery vehicle comprising only a single cationic lipid, lacking bile salt or bile acid, or any combination thereof.
In some examples, the percent increase in stability can be measured by determining (e.g., FRET) the relative fluorescence units or relative luminescence units that are increased. In some embodiments, the FRET assay is performed by: (i) Incorporating fluorescent dyes, such as Dil and DiO, as FRET pairs into a delivery vehicle; (ii) Treating the delivery vehicle with a simulated bile salt environment (e.g., a mixture of cholic acid and deoxycholate at different concentrations); (iii) Determining Relative Fluorescence Units (RFU) by exciting the fluorescence die and reading the emission at a wavelength appropriate for the dye used; and (iv) normalizing the reading to the FRET intensity of the system without any treatment. In some embodiments, a lower normalized FRET strength indicates a lower stability of the delivery vehicle in a bile salt environment.
In some embodiments, the delivery vehicle exhibits increased stability in a solution containing at least about 0.5g/L, 1g/L, 5g/L, 7g/L, 9g/L, 11g/L, 13g/L, 15g/L, 17g/L, 19g/L, 21g/L, 23g/L, or up to about 25g/L bile acid (e.g., a mixture of about 40%, 45%, 50%, or up to about 55% bile acid and about 40%, 45%, 50%, 55%, or up to about 60% deoxycholate) as compared to the stability of a similar delivery vehicle comprising only a single cationic lipid, lacking bile salt or bile acid, or any combination thereof, wherein stability is measured by the relative fluorescence intensity of fluorescent lipids incorporated into the lipid nanoparticle in a Forster Resonance Energy Transfer (FRET) assay.
Improved mucus penetration/transport
In some embodiments, the delivery vehicles provided herein comprising bile salts or bile acids may have improved transport, transfection of target cells, epithelial arrival, or a combination thereof, as compared to similar delivery vehicles lacking bile salts. In some embodiments, the improvement is about 1-fold, 50-fold, 99-fold, 148-fold, 197-fold, 246-fold, 295-fold, 344-fold, 393-fold, 442-fold, 491-fold, 540-fold, 589-fold, 638-fold, 687-fold, 736-fold, 785-fold, 834-fold, 883-fold, 932-fold, 981-fold, or up to about 1000-fold compared to a similar delivery vehicle comprising only a single cationic lipid, lacking bile salt or bile acid, or any combination thereof. In some examples, the percent increase in stability can be measured by relative fluorescence units or relative luminescence units that increase in an assay such as in vivo or ex vivo FRET.
Improved cellular uptake
In some embodiments, delivery vehicles described herein that include bile salts or bile acids can allow efficient penetration and transport through the mucus layer to target cells. In some embodiments, effective penetration and transport through the mucus layer increases effective uptake by the target cell. For example, the delivery vehicle may be ingested by about 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or more than 99.9% of the total number of cells contacted. In some embodiments, the composition may have a higher percentage of cellular uptake than a similar delivery vehicle that does not include bile salts or bile acids. The improvement may be more preferably about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70% or up to about 80%.
In some embodiments, the efficiency of transfection or integration of polynucleic acid load delivered to cells by a delivery vehicle may be about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, or up to 65% better than a similar delivery vehicle that does not include bile salts, bile acids, MPPs (or other additional components), the specific composition of the delivery vehicle lipids disclosed herein, or any combination thereof. In some embodiments, transfection or integration of polynucleic acid loads delivered to cells by a delivery vehicle composition described herein may be about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60% or up to 65% better than a similar delivery vehicle that does not include bile salts, bile acids or charge separation. In some embodiments, the transfection or integration efficiency of polynucleic acid load delivered to a cell by a delivery vehicle composition described herein may be about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60% or up to 65% better than a similar delivery vehicle comprising only a single cationic lipid, lacking bile salts or bile acids, or any combination thereof.
In some embodiments, the delivery vehicle provides a proximity distance to the cell, such as an epithelial cell. In some embodiments, such proximity distances are less than about 50, 40, 30, 25, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 micron. In some embodiments, the delivery vehicle herein is contacted with a cell. In some embodiments, the delivery vehicle is internalized into the cell and the load carried by the delivery vehicle is released within the cell. In some embodiments, the delivery vehicle contacts the cell (e.g., epithelial cell) and the load from the delivery vehicle is released extracellularly.
In some embodiments, the delivery vehicles provided herein provide closer proximity than similar delivery vehicles that include only a single cationic lipid, lack bile salts or bile acids, or any combination thereof. In some embodiments, the delivery vehicle provides a closer proximity of 1X, 5X, 10X, 15X, 20X, 25X, 50X, 75X, 100X, 200X, 300X, 400X, 500X, 1,000X, 5,000X, 10,000X, or more times than a similar delivery vehicle comprising only a single cationic lipid, lacking bile salts or bile acids, or any combination thereof.
IV. load
The delivery vehicle of the present disclosure may comprise, encapsulate, or be conjugated to a load. The term "cargo" as used herein may refer to one or more molecules or structures contained in a delivery vehicle for delivery to or into a cell or tissue. Non-limiting examples of the cargo may include nucleic acids, polypeptides, peptides, proteins, liposomes, labels, tags, small chemical molecules, large biomolecules, antibodies, biologicals, peptidomimetics, ribozymes, chemicals, viral particles, growth factors, cytokines, immunomodulators, fluorescent dyes, and any combination or fragment thereof. Wherein the load can comprise a nucleic acid, such nucleic acid can comprise DNA (e.g., plasmid DNA), RNA, and any combination thereof.
Therapeutic agent
In some embodiments, the load may include a therapeutic agent. Exemplary therapeutic agents may include nucleic acids, proteins, antibodies, peptides, small molecules (including organic small molecules or compounds), biologicals, antisense oligonucleotides, peptidomimetics, ribozymes, chemical agents (e.g., chemotherapeutic agent molecules), small molecule drugs, fluorochromes, anti-inflammatory compounds, antidepressants, agonists, analgesics, antibiotics, contraceptives, antipyretics, vasodilators, anti-angiogenic agents, cellular vascular agents, signal transduction inhibitors, cardiovascular agents (e.g., anti-arrhythmics, vasoconstrictors, hormones and steroids), cytokines, growth factors, apoptosis factors, differentiation-inducing factors, cell surface receptors, antibodies (e.g., polyclonal antibodies, monoclonal antibodies, antibody fragments; humanized antibodies, recombinant human antibodies and Primatized TM Antibodies), viral particles, growth factor cytokines, immunomodulators, polysaccharides, sugars, or any combination thereof.
In some embodiments, the delivery vehicle may include any molecule or compound capable of exerting a desired effect on a cell, tissue, organ, or subject. Such an effect may be, for example, biological, physiological or cosmetic.
In one embodiment, the molecule or compound may be a therapeutic agent or a salt or derivative thereof. The therapeutic agent derivatives may themselves be therapeutically active, or they may be prodrugs which become active upon further modification. Thus, in one embodiment, the molecule or compound derivative may retain some or all of the therapeutic activity as compared to the unmodified agent, while in another embodiment, the therapeutic derivative lacks the therapeutic activity.
In some embodiments, the load may be a drug. In some embodiments, the drug may be a substance that can cause a physiological change in the subject when administered. In some embodiments, the drug may be a drug for treating a disease, such as cancer. In some embodiments, the drug may be fully embedded in the liposomal lipid bilayer, the aqueous compartment, or both the liposomal lipid bilayer and the aqueous compartment. In some embodiments, the strongly lipophilic drug may be almost entirely embedded in the lipid membrane. In some embodiments, the strongly hydrophilic drug may be located only in the inter-nanoparticle space. In some embodiments, a drug with intermediate log p can be easily partitioned between the lipid layer and the lipid and aqueous phase in the space between the aqueous nanoparticles. In some embodiments, exemplary drugs may include drugs such as, but not limited to, adalimumab (adalimumab), anti-TNF, insulin-like growth factor, interleukin, mesalamine (Mesalamine), GLP-1 analogs, GLP-2 analogs, and combinations thereof.
Nucleic acid
In some embodiments, the load may be a nucleic acid compound. In some embodiments, the nucleic acid compound may be DNA or RNA based. In some embodiments, the nucleic acid may be a vector. In some embodiments, the DNA-based vector may be non-viral and may include molecules such as plasmids, mini loops, nanoplasmms, closed linear DNA (dog bone), linear DNA, and single stranded DNA. In some embodiments, the nucleic acid compound may comprise any form of nucleic acid known. In some embodiments, the nucleic acid compound may comprise single-stranded DNA or RNA or double-stranded DNA or RNA or DNA-RNA hybrids. In some embodiments, double-stranded DNA may include, but is not limited to, structural genes, genes including control and termination regions, and self-replicating systems such as viral or plasmid DNA. In some embodiments, double stranded RNAs can include, but are not limited to, sirnas and other RNA interfering agents. In some embodiments, single stranded nucleic acids may include, but are not limited to, messenger RNA (mRNA) antisense oligonucleotides, ribozymes, micrornas, and triplex forming oligonucleotides. In some embodiments, the nucleic acid compounds may include, but are not limited to, one or more of the oligonucleotide modifications described herein.
In some embodiments, the nucleic acid may have various lengths, depending generally on the particular form of the nucleic acid. In some embodiments, the plasmid or gene may be about 1,000 to 100,000 nucleotide residues in length. In some embodiments, the oligonucleotide may be about 10 to 100 nucleotides in length. In some embodiments, the length of the oligonucleotides (single, double, and triple) can be about 10 to about 50 nucleotides, about 20 to about 50 nucleotides, about 15 to about 30 nucleotides, about 20 to about 30 nucleotides. In some embodiments, the oligonucleotide may be about 2 nucleotides to 10 nucleotides in length.
In some embodiments, nucleic acid compounds, such as polynucleic acids, may be delivered to cells, such as cells of the intestinal tract. In some embodiments, the nucleic acid compounds may be delivered to intestinal crypt stem cells by a delivery vehicle herein. In some embodiments, the nucleic acid compound being delivered may be: (1) are not normally present in intestinal epithelial stem cells; (2) Are typically present in intestinal epithelial stem cells, but are not expressed at physiologically significant levels; (3) Are typically present in intestinal epithelial stem cells and are typically expressed at physiologically desirable levels in stem cells or their progeny; (4) Any other DNA that can be modified for expression in intestinal epithelial stem cells; and (5) any combination of the above.
In some embodiments, the small loop (MC) DNA may be delivered as a payload from a delivery vehicle. In some embodiments, the MC may resemble plasmid DNA in that both may contain expression cassettes, which may allow for the production of transgenic products at high levels shortly after delivery. In some embodiments, the MC may differ in that the MC DNA may lack prokaryotic sequence elements (e.g., bacterial origins of replication and antibiotic resistance genes). In some embodiments, removal of prokaryotic sequence elements from backbone plasmid DNA may be accomplished by site-specific recombination in e.coli prior to episomal DNA isolation. In some embodiments, the lack of a prokaryotic sequence element may reduce the size of the MC relative to its parent Full Length (FL) plasmid DNA, which may result in increased transfection efficiency. The result may be that MC can transfect more cells than their corresponding FL plasmid DNA and can allow sustained high levels of transgene expression at the time of delivery. In some embodiments, the small loop DNA may be free of a bacterial origin of replication. In some embodiments, the small loop DNA or closed linear DNA may be free of bacterial origin of replication from about 50% of the bacterial origin of replication sequences or up to 100% of the bacterial origin of replication. In some embodiments, the bacterial origin of replication is truncated or inactivated. In some embodiments, the polynucleic acid may be derived from a vector that initially encodes a bacterial origin of replication. In some embodiments, a method may be used to remove the entire bacterial origin of replication or a portion thereof, leaving the polynucleic acid free of the bacterial origin of replication. In some embodiments, bacterial origins of replication can be identified by their high adenine and thymine content. In some embodiments, the small loop DNA vector may be a supercoiled minimal expression cassette derived from conventional plasmid DNA by site-specific recombination in e.coli for non-viral gene therapy and vaccination. In some embodiments, the small loop DNA may lack a bacterial backbone sequence or have reduced bacterial backbone sequences, such as antibiotic resistance genes, origins of replication, and/or inflammatory sequences inherent to bacterial DNA. In addition to its increased safety, the small loop can also greatly increase the efficiency of transgene expression.
In some embodiments, a portion of a gene may be delivered by a polynucleic acid load. In some embodiments, a portion of a gene may be from three nucleotides to the entire genomic sequence. In some embodiments, a portion of a gene may be about 1% up to about 100% of the endogenous genomic sequence. In some embodiments, a portion of a gene may be about 1%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or up to about 100% of the entire genomic sequence of the gene.
In some embodiments, the nucleic acid encodes an antibody. The term "antibody" as used herein is used in its broadest sense and specifically covers various antibody forms, including but not limited to monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies formed from at least two intact antibodies), and antibody fragments (e.g., diabodies), so long as they exhibit the desired biological activity (e.g., are "functional" fragments). The encoded antibody may bind to a target comprising one or more of the following: IL-18, IL-18 receptor 1 (IL 18R 1), IL-23, tumor necrosis factor alpha (TNF alpha), proprotein convertase subtilisin 9 (proprotein convertase subtilisin kexin, PCSK9) and protein 19 (P19). The encoded antibody may comprise a bispecific antibody. Bispecific antibodies can bind cluster of differentiation 3 (CD 3) for recruiting immune cells to a target of a second bispecific antibody epitope.
In some embodiments, the polynucleic acid used as a cargo with the delivery vectors herein comprises a nucleic acid encoding a tumor suppressor gene. In some embodiments, a tumor suppressor gene may generally encode a protein that may inhibit cell proliferation in one way or another.
Without wishing to be bound by theory, the loss of one or more of these "brakes" may lead to the development of cancer. Five general classes of proteins are generally considered to be encoded by tumor suppressor genes: intracellular proteins, such as p16 cyclin kinase inhibitors, which may regulate or inhibit progression through a particular phase of the cell cycle; receptors that secrete hormones (e.g., tumor-derived growth factor beta) that may act to inhibit cell proliferation; checkpoint control proteins, which prevent the cell cycle if DNA may be damaged or chromosomal abnormalities; proteins that may promote apoptosis; enzymes involved in DNA repair; or a combination thereof. Although DNA repair enzymes may not directly act to inhibit cell proliferation, cells that lose the ability to repair errors, nicks, or breaks in DNA accumulate mutations in many genes, including those genes that are critical to control cell growth and proliferation. Thus, loss-of-function mutations in the gene encoding the DNA repair enzyme may promote inactivation of other tumor suppressor genes and activation of oncogenes. Since usually one copy of the tumor suppressor gene is sufficient to control cell proliferation, both alleles of the tumor suppressor gene must be lost or inactivated to promote tumor progression.
In some embodiments, the oncogenic loss-of-function mutation in the tumor suppressor gene functions in a recessive manner. Tumor suppressor genes in many cancers have deletions or point mutations that prevent the production of any protein or result in the production of nonfunctional proteins.
In some embodiments, the introduction of a tumor suppressor gene encoding a protein may ameliorate, prevent, or treat a disease in a subject.
In some embodiments, tumor suppressor genes may include, but are not limited to, APC, ARHGEF12, ATM, BCL11B, BLM, BMPR1A, BRCA, BRCA2, CARS, CBFA2T3, CDH1, CDH11, CDK6, CDKN2C, CEBPA, CHEK2, CREB1, CREBBP, CYLD, DDX5, EXT1, EXT2, FBXW7, FH, FLT3, FOXP1, GPC3, IDH1, IL2, JAK2, MAP2K4, MDM4, MEN1, MLH1, MSH2, NF1, NF2, NOTCH1, NPM1, NR4A3, NUP98, PALB2, PML, PTEN, RB1, RUNX1, SDHB, SDHD, SMARCA4, SMARCB1, SOCS1, STK11, SUFU, SUZ12, SYK, TCF3, TNFAIP3, TP53, TSC1, TSC2, VHL, WRN, WT1, and any combination thereof.
In some embodiments, gastrointestinal cells may be transfected with a nucleic acid load comprising non-coding RNA. The term "non-coding RNA" as used herein refers to RNA molecules having sequences that do not encode proteins but are generally of significance in certain other RNA functions. Non-coding RNAs can include, but are not limited to, interfering short RNAs (siRNA), micrornas (miRNA), long non-coding RNAs, piwi protein-interacting RNAs (piRNA), nucleolar micrornas (snoRNA), cajal body-specific micrornas (scaRNA), transfer RNAs (tRNA), ribosomal RNAs (rRNA), and intranuclear micrornas (snRNA).
Carrier body
In some embodiments, DNA-based vectors may also be viral and include adeno-associated viruses, lentiviruses, adenoviruses, and the like. In some embodiments, the vector may also be RNA. In some embodiments, the RNA vector may be a linear or circular form of unmodified RNA. In some embodiments, the nucleic acid compounds may also include various nucleotide modifications designed to increase half-life, reduce immunogenicity, and/or increase translational levels. In some embodiments, the vector may consist of DNA or RNA. In some embodiments, the vector may consist of DNA. In some embodiments, the vector may consist of RNA. In some embodiments, the vector may be capable of autonomous replication in a prokaryote such as e.coli, which may be used for growth, for example. In some embodiments, the vector may be stably integrated into the genome of the organism. In some embodiments, the vector may remain isolated in the cytoplasm or nucleus. In some embodiments, the vector may contain a targeting sequence. In some embodiments, the vector may contain an antibiotic resistance gene. In some embodiments, the vector may contain regulatory elements for regulating gene expression. In some embodiments, the small loop may be encapsulated within a delivery vehicle.
Nuclear Localization Sequence (NLS)
In some embodiments, the polynucleic acid may encode a heterologous sequence. In some embodiments, the heterologous sequence may provide subcellular localization (e.g., nuclear Localization Signal (NLS) for targeting the nucleus, mitochondrial localization signal for targeting mitochondria, chloroplast localization signal for targeting chloroplasts, ER retention signal, etc.). In some embodiments, a polynucleic acid, such as a small circular DNA or a closed linear DNA, may comprise a Nuclear Localization Sequence (NLS).
In some embodiments, the payload may comprise one or more Nuclear Localization Sequences (NLS). In some embodiments, the plurality of NLS sequences may be about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more NLS. In some embodiments, the vector comprises about or more than about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more NLSs at or near the amino terminus, about or more than about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more NLSs at or near the carboxy terminus, or a combination of these (e.g., one or more NLSs at the amino terminus and one or more NLSs at the carboxy terminus). In some embodiments, when more than one NLS is present, each may be selected independently of the others, such that a single NLS may be present in more than one copy and/or in combination with one or more other NLSs present in one or more copies. In some embodiments, non-limiting examples of NLS may include NLS sequences derived from: NLS of the SV40 viral large T antigen having the amino acid sequence PKKKRKV (SEQ ID NO: 1); an NLS from a nucleoplasmin (e.g., a nucleoplasmin bipartite NLS having the sequence KRPAATKKAGQAKKKK (SEQ ID NO: 2); c-myc NLS with amino acid sequence PAAKRVKLD (SEQ ID NO: 3) or RQRRNELKRSP (SEQ ID NO: 4); hRNPA 1M 9 NLS with sequence NQSSNFGPMKGGNFGGRSSGPYGGGGQYFAKPRNQGGY (SEQ ID NO: 5); the sequence rmrimzfknkkkkdtaperrrrrrrrvsverlkkakkdeqilkrnv (SEQ ID NO: 6) from the IBB domain of input protein α; the sequence VSRKRPRP (SEQ ID NO: 7) and PPKKARED (SEQ ID NO: 8) of the myoma T protein; the sequence PQPKKPL of human p53 (SEQ ID NO: 9); sequence SALIKKKKKMAP of mouse c-abl IV (SEQ ID NO: 10); the sequences DRLRR (SEQ ID NO: 11) and PKQKKRK (SEQ ID NO: 12) of influenza virus NS 1; sequence RKLKKKIKKL of hepatitis virus delta antigen (SEQ ID NO: 13); sequence REKKKFLKRR of mouse Mx1 protein (SEQ ID NO: 14); sequence KRKGDEVDGVDEVAKKKSKK of human poly (ADP-ribose) polymerase (SEQ ID NO: 15); and the sequence RKCLQAGMNLEARKTKK of the steroid hormone receptor (human) glucocorticoid (SEQ ID NO: 16). In some embodiments, one or more NLS may have sufficient strength to drive accumulation of small loop DNA vectors or short linear DNA vectors in the nucleus of eukaryotic cells in a detectable amount. In some embodiments, the eukaryotic cell may be a human intestinal crypt cell.
In some embodiments, the nanoparticle may contain a dnase inhibitor. In some embodiments, the dnase inhibitors may be located within or on the nanoparticle. In some embodiments, the polynucleic acid encoding the inhibitor may be encapsulated within a nanoparticle. In some embodiments, the inhibitor may be a DNA methyltransferase inhibitor, such as, but not limited to, DNA methyltransferase inhibitor-2 (DMI-2). In some embodiments, DMI-2 may be produced by Streptomyces sp.strain number 560. In some embodiments, the structure of DMI-2 may be 4' "R, 6ar,10s,10 as-8-acetyl-6 a,10 a-dihydroxy-2-methoxy-12-methyl-10- [4' - [3" -hydroxy-3 ",5" -dimethyl-4 "(Z-2 '", 4' "-dimethyl-2 '" -heptenoyloxy) tetrahydropyran-1 "-yloxy ] -5' -methylcyclohex-1 ' -yloxy ] -1,4,6,7,9-pentoxy-1, 4, 6a,7,8,9,10 a, 11-decahydrobenzanthracene. In some embodiments, other inhibitors, such as chloroquine, may also be encapsulated within or on the nanoparticle, such as on the surface of the nanoparticle.
In some embodiments, detection of accumulation in the nucleus may be performed by any suitable technique. In some embodiments, the detectable marker can be fused to a carrier such that the location within the cell can be visualized, for example in combination with a means for detecting the location of the cell nucleus (e.g., a cell nucleus specific stain such as DAPI). In some embodiments, the nuclei may also be isolated from the cells and their contents may then be analyzed by any suitable method for detecting proteins, such as, but not limited to, immunohistochemistry, western blotting, or enzymatic activity assays. In some embodiments, time-dependent pH triggered release of the load to the target site may occur. In some embodiments, the delivery vehicle may contain and provide complex, multiple-payload cell delivery. In some embodiments, the additional load may be a small molecule, an antibody, an inhibitor such as a dnase inhibitor or an rnase inhibitor.
Nucleic acid loading
In some embodiments, the nucleic acid compound loading concentration in the delivery vehicle may be from 0.5 nanograms to 50 micrograms. In some embodiments, such a concentration may be about 0.5ng, 1ng, 2ng, 5ng, 10ng, 50ng, 100ng, 150ng, 200ng, 300ng, 400ng, 500ng, 600ng, 700ng, 800ng, 900ng, 1000ng, 1 μg, 2 μg, 5 μg, 10 μg, 20 μg, 30 μg, 40 μg, 50 μg, 60 μg, or up to 50 μg or more. In some embodiments, the amount of nucleic acid (e.g., ssDNA, dsDNA, RNA) that can be introduced into the cell by the delivery vector can be varied to optimize transfection efficiency and/or cell viability. In some embodiments, less than about 100 picograms of nucleic acid may be introduced to a subject. In some embodiments, at least about 100 picograms, at least about 200 picograms, at least about 300 picograms, at least about 400 picograms, at least about 500 picograms, at least about 600 picograms, at least about 700 picograms, at least about 800 picograms, at least about 900 picograms, at least about 1 microgram, at least about 1.5 micrograms, at least about 2 micrograms, at least about 2.5 micrograms, at least about 3 micrograms, at least about 3.5 micrograms, at least about 4 micrograms, at least about 4.5 micrograms, at least about 5 micrograms, at least about 5.5 micrograms, at least about 6 micrograms, at least about 6.5 micrograms, at least about 7 micrograms, at least about 7.5 micrograms, at least about 8 micrograms, at least about 8.5 micrograms, at least about 9 micrograms, at least about 9.5 micrograms, at least about 10 micrograms, at least about 11 micrograms, at least about 12 micrograms, at least about 13 micrograms, at least about 14 micrograms, at least about 15 micrograms, at least about 20 micrograms, at least about 25 micrograms, at least about 30 micrograms, at least about 35 micrograms, at least about 40 micrograms, at least about 45 micrograms, or at least about 50 micrograms of nucleic acid may be added to each cell (e.g.) or to be used to deliver a target cell or cell to a cell in an electroload or other manner. In some embodiments, the amount of nucleic acid (e.g., dsDNA, RNA) required for optimal transfection efficiency and/or cell viability may be specific to the cell type.
In some embodiments, the delivery vehicle may contain at least one nucleic acid, wherein the molar ratio of total nanoparticle cationic lipid to the total number of nucleotides contained by the nucleic acid load (abbreviated herein as cationic lipid to nucleotide ratio, cationic lipid to nucleotide molar ratio, or CL: N) is about 1 to 100. For example, the cationic lipid: nucleotide ratio may be, but is not limited to, about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, and any combination thereof.
In some embodiments, the molar ratio of total nanoparticle cationic lipid to the total number of nucleotides comprised by the nucleic acid load is from about 2 to about 20.
In some embodiments, the molar ratio of total nanoparticle cationic lipid to the total number of nucleotides comprised by the nucleic acid load is from about 14 to about 18.
In some embodiments, the molar ratio of total nanoparticle cationic lipid to the total number of nucleotides comprised by the nucleic acid load is from about 2 to about 20.
In some embodiments, the molar ratio of total nanoparticle cationic lipid to the total number of nucleotides comprised by the nucleic acid load is from about 2 to about 4.
In some embodiments, the polynucleic acids may be condensed to be suitably encapsulated by the lipid structure. In some embodiments, condensation of DNA may be accomplished by divalent metal ions such as Mn 2+ 、Ni 2+ 、Co 2+ And Cu 2+ These divalent metal ions can be carried out by neutralizing the phosphate groups of the DNA backbone and deforming the B-DNA structure by forming hydrogen bonds with the bases, allowing localized bending and helical association of the DNA to condense the DNA. In some embodiments, the concentration of metal ions used for condensation may depend on the dielectric constant of the medium used for condensation. In some embodiments, the addition of ethanol or methanol may also reduce the concentration of metal ions required for condensation. In some embodiments, ethanol may be used to condense DNA at a concentration of about 0.5% up to about 60% by volume. In some embodiments, ethanol may be used to condense DNA at a concentration of about 0.5%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, or up to 60% by volume. In some embodiments, calcium may also be used for condensation. In some embodiments, calcium not only binds to DNA phosphate, but can also form complexes with guanine nitrogen and oxygen, disrupting base pairing.
In some embodiments, the polynucleic acid may be fully encapsulated in a lipid structure. In some embodiments, fully encapsulated may mean that the polynucleic acids in the lipid structure may not be significantly degraded after exposure to serum or nuclease or protease assays that would significantly degrade free DNA, RNA, or proteins. In some embodiments, in a fully encapsulated system, preferably less than about 25% of the polynucleic acids in the lipid structure can be degraded, more preferably less than about 10%, and most preferably less than about 5% of the polynucleic acids in the lipid structure can be degraded in a process that would normally degrade 100% of the free polynucleic acids. In some embodiments, in the case of polynucleic acids, complete encapsulation may be achieved byAnd (3) determining by measurement. />Is an ultrasensitive fluorescent nucleic acid stain for the quantification of oligonucleotides and single stranded DNA or RNA in solution (available from Invitrogen Corporation; carlsbad, calif.). In some embodiments, "fully encapsulated" may also mean that the lipid structures may be serum stable, i.e., they do not rapidly break down into their constituent parts after in vivo administration.
Other therapeutic Agents
Cancer treatment
In certain embodiments, the cargo may include molecules or compounds, such as oncology agents, which may also be referred to as antitumor agents, anticancer agents, oncology agents, antitumor agents, and the like.
Examples of oncology agents that may be used include, but are not limited to, doxorubicin, malaytea (alkeran), allopurinol, altretamine, amifostine, anastrozole, araC, arsenic trioxide, azathioprine, bexarotene, biCNU, bleomycin, intravenous busulfan, oral busulfan, capecitabine (Xeloda)), carboplatin, carmustine, CCNU, celecoxib, chlorambucil, cisplatin, cladribine, cyclosporin A, cytarabine, cytosine arabinoside, daunorubicin, cyclophosphamide, daunorubicin, dexamethasone, dexrazoxane, docetaxel, doxorubicin, DTIC, epirubicin, estramustine, etoposide phosphate, etoposide and VP-16, exemestane, FK506, fludarabine fluorouracil, 5-FU, gemcitabine (Gemzar)), gemtuzumab-Ozomib, goserelin acetate, hydroxyurea (hydroea), hydroxyurea (hydroxyurea), idarubicin, ifosfamide, imatinib mesylate, interferon, irinotecan (Camptostar, CPT-111), letrozole, folinic acid, cladribine (leupeptin), leuprorelin, levamisole, litretinin, megestrol (megamol), melphalan, L-PAM, mesna, methotrexate, methoxalin, mithramycin, mitomycin, mitoxantrone, nitrogen mustard, paclitaxel, pamidronate, pegasin, pravastatin, phenam sodium, prednisone, rituximab, streptozotocin, STI 571, tamoxifen, taxotere (xotec), temozolomide, teniposide, VM-26, topotecan (Hycarntin), toremifene, retinoic acid, ATRA, valrubicin, vinblastine (velban), vinblastine (vinblastine), vincristine, VP16, and vinorelbine. Other examples of oncology agents that may be used are ellipticine (ellipticin) and ellipticine analogs or derivatives, epothilones, intracellular kinase inhibitors and camptothecins.
Imaging and diagnostic agents
In some embodiments, the carrier may comprise an imaging agent, which may be further linked to a detectable label (e.g., the label may be a radioisotope, a fluorescent compound, an enzyme, or an enzyme cofactor). In some embodiments, the active moiety of the imaging agent may be a radioactive agent, such as: radioactive heavy metals such as iron chelates, radioactive chelates of gadolinium or manganese, positron emitters of oxygen, nitrogen, iron, carbon or gallium, 43 K、 52 Fe、 57 Co、 67 Cu、 67 Ga、 68 Ga、 123 I、 125 I、 131 I、 132 i or 99 Tc. In some embodiments, delivery vehicles comprising such moieties may be used as imaging agents and administered in amounts effective for diagnostic use in mammals such as humans. In some embodiments, localization and accumulation of imaging agents may be detected. In some embodiments, localization and accumulation of imaging agents may be detected by radioscintigraphy, nuclear magnetic resonance imaging, computed tomography, or positron emission tomography.
It will be apparent to the skilled person that the amount of radioisotope to be administered depends on the radioisotope. One of ordinary skill in the art can readily formulate the amount of imaging agent to be administered based on the specific activity and energy of a given radionuclide used as the active moiety. Typically, imaging agents of 0.1 to 100 millicuries, 1 to 10 millicuries, and 2 to 5 millicuries per dose may be administered.
In some embodiments, a composition for use as an imaging agent may comprise a targeting moiety conjugated to a radioactive moiety, which may comprise 0.1-100 millicuries, 1-10 millicuries, 2-5 millicuries, or 1-5 millicuries.
In some embodiments, the detection means for detecting the label depends on the nature of the label used and the nature of the biological sample used, and may include, but is not limited to, fluorescence polarization, high performance liquid chromatography, antibody capture, gel electrophoresis, differential precipitation, organic extraction, size exclusion chromatography, fluorescence microscopy, or Fluorescence Activated Cell Sorting (FACS) assays.
In some embodiments, the imaging agent targeting moiety may also refer to a protein, nucleic acid analog, carbohydrate, or small molecule. The imaging entity may be, for example, a therapeutic compound such as a small molecule, or a diagnostic entity such as a detectable label. The locus may be a tissue, a particular cell type, or a subcellular compartment. In one embodiment, the targeting moiety may direct the localization of the active entity. The active entity may be a small molecule, a protein, a polymer or a metal. Active entities, such as liposomes comprising nucleic acids, may be used for therapeutic, prophylactic or diagnostic purposes. In some embodiments, the moiety may allow the delivery vehicle to penetrate the blood brain barrier.
Loading Capacity (loadingCapacities)
In some embodiments, the lipid structure may carry up to a capacity of more than 100% by weight: defined as (weight loaded/weight of lipid structure) ×100. In some embodiments, the optimal loading of the load may be or may be about 1% to 100% by weight of the lipid structure. In some embodiments, the lipid structure may contain, but is not limited to, a polynucleic acid load of about 1% to about 10%, about 10% to about 20%, about 20% to about 30%, about 30% to about 40%, about 40% to about 50%, about 50% to about 60%, about 60% to about 70%, about 70% to about 80%, about 80% to about 90%, about 90% to about 100%, about 100% to about 200%, about 200% to about 300%, about 300% to about 400%, about 400% to about 500% or more by weight of the structure.
V. pharmaceutical compositions and routes of administration
Pharmaceutical composition and formulation
The delivery vehicles provided herein may be formulated with one or more excipients into pharmaceutical compositions and/or pharmaceutical agents. In some embodiments, the pharmaceutical compositions and/or medicaments may be used to treat any human or mammal in need thereof.
The composition to be administered may contain an amount of a delivery vehicle that is a pharmaceutically effective amount for therapeutic use in biological systems, including patients or subjects.
In some embodiments, the delivery vehicle (e.g., liposome) can be administered as a liquid formulation (e.g., a solution or suspension), a semi-solid formulation (e.g., a lotion or ointment), or a solid formulation. In some embodiments, liposomes can be formulated as liquids, including solutions and suspensions, such as eye drops, or semi-solid formulations, such as ointments or lotions, for topical application to mucous membranes, such as ocular or vaginal or rectal application. The formulation may contain one or more excipients, such as emollients, surfactants, emulsifiers, and penetration enhancers.
As used herein, "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, sweetening agents, salts, buffers and the like. Pharmaceutically acceptable carriers can be prepared from a wide range of materials including, but not limited to, flavoring agents, sweetening agents, and various materials such as buffers and absorbents that may be required to prepare a particular therapeutic composition.
Pharmaceutical salts
In some embodiments, the pharmaceutical composition may include a salt. The salt may be relatively non-toxic. Examples of pharmaceutically acceptable salts include those derived from inorganic acids such as hydrochloric acid and sulfuric acid, and those derived from organic acids such as ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like. Examples of suitable inorganic bases for salt formation include hydroxides, carbonates and bicarbonates of ammonia, sodium, lithium, potassium, calcium, magnesium, aluminum, zinc, and the like. Salts may also be formed with suitable organic bases, including those that are non-toxic and strong enough to form such salts. For illustrative purposes, the types of such organic bases can include mono-, di-and trialkylamines, such as methylamine, dimethylamine and triethylamine; mono-, di-or tri-hydroxyalkylamines, such as mono-, di-and triethanolamine; amino acids such as arginine and lysine; guanidine; n-methyl glucamine; n-methyl reducing glucosamine; l-glutamine; n-methylpiperazine; morpholine; ethylenediamine; n-benzyl phenethylamine; (trimethylol) aminoethane, and the like. In some embodiments, if desired, the pharmaceutical composition comprising the delivery vehicle may also contain minor amounts of non-toxic auxiliary substances, such as wetting agents, emulsifying agents, or buffering agents.
Coating layer
In some embodiments, the provided delivery vehicle may comprise a coating. In some embodiments, the coating may be an enteric coating. Generally, an enteric coating may be used to prevent or minimize dissolution in the stomach but allow dissolution in the small intestine. In some embodiments, the coating may comprise an enteric coating. In some embodiments, the enteric coating may be a barrier applied to oral drugs that prevents release of the drug before reaching the small intestine. Delayed release formulations, such as enteric coatings, may avoid gastric irritation by the administered drug by preventing dissolution of the pharmaceutical composition in the stomach. Such coatings also serve to protect acid labile drugs from acidic exposure of the stomach, but rather deliver them to alkaline pH environments (pH 5.5 and above in the intestinal tract) where they may not degrade.
In some embodiments, the eluting may occur in an organ. For example, the dissolution may occur in the duodenum, jejunum, ileum, and/or colon or any combination thereof. In some embodiments, the elution may occur near the duodenum, jejunum, ileum, and/or colon. Some enteric coatings work by presenting a surface that is stable at the highly acidic pH found in the stomach but rapidly breaks down at the less acidic (relatively more basic) pH. Thus, an enteric coated pill may not be soluble in the acidic environment of the stomach, but may be soluble in the alkaline environment present in the small intestine. Examples of enteric coating materials include, but are not limited to, methyl acrylate-methacrylic acid copolymer, cellulose acetate succinate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate (hydroxypropyl methylcellulose acetate succinate), polyvinyl acetate phthalate (PVAP), methyl methacrylate-methacrylic acid copolymer, sodium alginate, and stearic acid.
In some embodiments, the enteric coating may be applied at a functional concentration. In some embodiments, the enteric coating may be cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose acetate succinate, poly (ethyl methacrylate-co-acrylate) 1:1, poly (methacrylic acid-co-ethyl acrylate) 1:1, poly (methacrylic acid-co-methyl methacrylate) 1:2, poly (methyl acrylate-co-methyl methacrylate-co-methacrylic acid) 7:3:1, or any combination thereof. Can be applied at about 6 mg/(cm) 2 ) To about 12 mg/(cm) 2 ) Is coated with an enteric coating. The enteric coating may also be present at about 1 mg/(cm) 2 )、2mg/(cm 2 )、3mg/(cm 2 )、4mg/(cm 2 )、5mg/(cm 2 )、6mg/(cm 2 )、7mg/(cm 2 )、8mg/(cm 2 )、9mg/(cm 2 )、10mg/(cm 2 )、11mg/(cm 2 )、12mg/(cm 2 )、13mg/(cm 2 )、14mg/(cm 2 )、15mg/(cm 2 )、16mg/(cm 2 )、17mg/(cm 2 )、18mg/(cm 2 )、19mg/(cm 2 ) To about 20 mg/(cm) 2 ) Applied to the structure.
Route of administration
The composition may be administered orally, by subcutaneous or other injection, intravenously, intracerebrally, intramuscularly, parenterally, transdermally, nasally or rectally. The form of administration of the compound or composition depends, at least in part, on the route of administration of the compound.
Oral administration
In some embodiments, the composition may be used in the form of a solid formulation for oral administration; the preparation can be tablet, granule, powder, capsule, etc. In tablet formulations, the composition is typically formulated with additives, for example excipients such as sugar or cellulose formulations, binders such as starch paste or methylcellulose, fillers, disintegrants, and other additives commonly used in the manufacture of pharmaceutical formulations.
For oral administration, the compositions may take the form of, for example, tablets or capsules, which are prepared by conventional techniques with pharmaceutically acceptable excipients such as binding agents (e.g., pregelatinized corn starch, polyvinylpyrrolidone, or); fillers (e.g., lactose); lubricants (e.g., magnesium stearate, talc, or); disintegrants (e.g. potato starch or); or wetting agents (e.g., sodium lauryl sulfate).
In some embodiments, solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active ingredient is admixed with at least one inert, pharmaceutically acceptable excipient, such as sodium citrate or dicalcium phosphate and/or fillers or extenders (e.g., starches, lactose, sucrose, glucose, mannitol, microcrystalline cellulose, dibasic calcium phosphate, or silicic acid), binders (e.g., carboxymethyl cellulose, alginates, gelatin, hydroxypropyl methylcellulose, polyvinylpyrrolidone, sucrose, pregelatinized corn starch, and acacia), humectants (e.g., glycerin), disintegrants (e.g., agar-agar, calcium carbonate, sodium starch glycolate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate), solution retarders (e.g., paraffin), absorption accelerators (e.g., quaternary ammonium compounds), wetting agents (e.g., cetyl alcohol and glyceryl monostearate), absorbents (e.g., kaolin and bentonite clay), and lubricants (e.g., talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or silica), and mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may comprise buffering agents.
In some embodiments, the tablets may be coated.
In some embodiments, for oral administration, excipients may include pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, gelatin, sucrose, magnesium carbonate, and the like.
Liquid formulations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid formulations may be prepared by conventional techniques with pharmaceutically acceptable additives, such as suspending agents (e.g., sorbitol syrup, cellulose derivatives, or hydrogenated edible fats); emulsifying agents (e.g., lecithin or acacia); a non-aqueous carrier (e.g., almond oil, oily esters, ethyl alcohol, or fractionated vegetable oils); and a preservative (e.g., methyl or propyl-p-hydroxybenzoate or sorbic acid). The formulation may optionally also contain buffer salts, flavoring agents, coloring agents and sweetening agents.
In some embodiments, the oral compositions may include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and/or perfuming agents. In some embodiments, formulations for oral administration may be suitably formulated to provide controlled release of the active compound.
Injection and parenteral administration
In some embodiments, the pharmaceutical compositions and/or formulations described herein may be administered parenterally. Liquid dosage forms for oral and parenteral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and/or elixirs. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1, 3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
In some embodiments for parenteral administration, the composition is combined with a solubilizing agent, e.g.Alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers and/or combinations thereof. In other embodiments, surfactants such as hydroxypropyl cellulose are included.
In some embodiments, injectable formulations, such as sterile injectable aqueous or oleaginous suspensions, may be formulated according to the known art using suitable dispersing, wetting and/or suspending agents. In some embodiments, the sterile injectable preparation may be a sterile injectable solution, suspension and/or emulsion in a non-toxic parenterally acceptable diluent and/or solvent, for example, as a solution in 1, 3-butanediol. Acceptable carriers and solvents that may be used include water, ringer's solution (u.s.p.) and isotonic sodium chloride solution. Sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono-or diglycerides. Fatty acids such as oleic acid find use in the preparation of injectables.
In some embodiments, the injectable formulation may be sterilized, for example, by filtration through a bacterial-retaining filter, and/or by incorporating sterilizing agents in the form of sterile solid compositions which may be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
In order to prolong the effect of the active ingredient, it is often desirable to slow the absorption of the active ingredient in subcutaneous or intramuscular injections. This can be achieved by using liquid suspensions of crystalline or amorphous materials that are poorly water soluble. The rate of absorption of the active ingredient depends on the dissolution rate, which in turn may depend on the crystal size and crystalline form. Alternatively, delayed absorption of parenterally administered pharmaceutical forms is accomplished by dissolving or suspending the drug in an oil carrier. The injectable depot form is prepared by forming a microencapsulated matrix of the drug in a biodegradable polymer (e.g., polylactide-polyglycolide). Depending on the ratio of drug to polymer and the nature of the particular polymer used, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly (orthoesters) and poly (anhydrides). Depot injectable formulations are prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissues.
Suitable formulations may include aqueous and non-aqueous sterile injection solutions which may contain antioxidants, buffers, bacteriostats, bactericidal antibiotics and solutes which render the formulation isotonic with the body fluid of the intended recipient; aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. Suitable inert carriers may include sugars, such as lactose. In some embodiments, the composition may take the form of a suspension, solution or emulsion, such as in an oily or aqueous vehicle, and may contain a formulation such as a suspending, stabilizing and/or dispersing agent. Alternatively, the active ingredient may be in powder form for reconstitution with a suitable carrier, such as sterile pyrogen-free water, prior to use.
The carrier may be a solvent or dispersion medium containing, for example, water, ethanol, one or more polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), oils such as vegetable oils (e.g., peanut oil, corn oil, sesame oil, and the like), and combinations thereof. Proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersions and/or by the use of surfactants. In many cases, it is preferable to include isotonic agents, for example, sugars or sodium chloride. Solutions and dispersions of the active compound as a free acid or base or a pharmacologically acceptable salt thereof can be prepared in water or another solvent or dispersion medium suitably mixed with one or more pharmaceutically acceptable excipients including, but not limited to, surfactants, dispersants, emulsifiers, pH adjusting agents, and combinations thereof. Suitable surfactants may be anionic, cationic, amphoteric or nonionic. Suitable anionic surfactants include, but are not limited to, those containing carboxylate, sulfonate, and sulfate ions. Examples of anionic surfactants include sodium, potassium, ammonium salts of long chain alkyl and alkylaryl sulfonates, such as sodium dodecyl benzene sulfonate; sodium dialkylsulfosuccinates, such as sodium dodecylbenzenesulfonate; dialkyl sulfos Sodium sulfosuccinates, such as sodium bis- (2-ethylsulfanyl) -sulfosuccinate; and alkyl sulfates such as sodium dodecyl sulfate. Cationic surfactants include, but are not limited to, quaternary ammonium compounds such as benzalkonium chloride, benzethonium chloride, cetrimonium bromide, stearyl dimethylbenzyl ammonium chloride, polyoxyethylene and cocoamine. Examples of nonionic surfactants include ethylene glycol monostearate, propylene glycol myristate, glycerol monostearate, glycerol stearate, polyglycerol 4-oleate, sorbitan acylate, sucrose acylate PEG-150 laurate, PEG-400 monolaurate, polyoxyethylene monolaurate, polysorbate, polyoxyethylene octylphenyl ether, PEG-1000 cetyl ether, polyoxyethylene tridecyl ether, polypropylene glycol butyl ether,401. Stearoyl monoisopropanolamide and polyoxyethylene hydrogenated tallow amide. Examples of zwitterionic surfactants include sodium N-dodecyl-beta-alaninate, sodium N-lauryl-beta-iminodipropionate, myristoyl amphoacetate (myristoacetate), lauryl betaine and lauryl sulfobetaine. The formulation may contain a preservative to prevent the growth of microorganisms. Suitable preservatives include, but are not limited to, parabens, chlorobutanol, phenol, sorbic acid, and thimerosal. The formulation may also contain antioxidants to prevent degradation of the active agent. The formulation is typically buffered to a pH of 3-8 for parenteral administration after reconstitution. Suitable buffers include, but are not limited to, phosphate buffers, acetate buffers, and citrate buffers. The water-soluble polymers may be commonly used in formulations for parenteral administration. Suitable water-soluble polymers include, but are not limited to, polyvinylpyrrolidone, dextran, carboxymethyl cellulose, and polyethylene glycol.
Sterile injectable solutions may be prepared by incorporating the active compounds in the required amount in the appropriate solvent or dispersion medium with one or more of the excipients enumerated above, as required, followed by filtered sterilization. In general, dispersions can be prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those listed above. In the case of sterile powders for the preparation of sterile injectable solutions, the methods of preparation may be vacuum-drying and freeze-drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof. The powder may be prepared in such a way that the particles are porous in nature, which may increase the dissolution of the particles. Methods of preparing porous particles are well known in the art.
Topical or transdermal administration
In some embodiments, the liposomes can be formulated for topical administration to the mucosa. Suitable dosage forms for topical administration include creams, ointments, salves, sprays, gels, lotions, emulsions, liquids and transdermal patches. The formulations may be formulated for transmucosal, transdermal, endothelial, or transdermal administration. The composition may contain one or more chemical penetration enhancers, membrane permeabilizers, membrane transport agents, emollients, surfactants, stabilizers, and combinations thereof.
In some embodiments, the pharmaceutical compositions and/or formulations described herein may be formulated for topical administration. Skin may be an ideal delivery target site because it is easily accessible. Three routes are generally considered for delivering the pharmaceutical compositions and/or formulations described herein to the skin: (a) Topical application (e.g., for topical/regional treatment and/or cosmetic applications); (b) Intradermal injection (e.g., for topical/regional therapeutic and/or cosmetic applications); and (c) systemic delivery (e.g., for treating dermatological disorders affecting the skin and the extracellular region).
In some embodiments, the pharmaceutical compositions and/or formulations described herein may be delivered using a variety of dressings (e.g., wound dressing) or bandages (e.g., adhesive bandages) to facilitate and/or effectively perform the methods described herein. In general, the dressing or bandage may contain a sufficient amount of the pharmaceutical compositions and/or formulations described herein to allow the user to perform multiple treatments.
Dosage forms for topical and/or transdermal administration may include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants and/or patches. Typically, the active ingredient is admixed under sterile conditions with pharmaceutically acceptable excipients and/or any required preservatives and/or buffers. Furthermore, the use of transdermal patches is contemplated herein, which generally has the added advantage of providing controlled delivery of the pharmaceutical compositions and/or formulations described herein to the body. Such dosage forms may be prepared, for example, by dissolving and/or partitioning the pharmaceutical compositions and/or formulations described herein in a suitable medium. Alternatively, or in addition, the rate may be controlled by providing a rate controlling membrane and/or by dispersing the pharmaceutical compositions and/or formulations described herein in a polymer matrix and/or gel.
Formulations suitable for topical application include, but are not limited to, liquid and/or semi-liquid formulations, such as liniments, lotions, oil-in-water and/or water-in-oil emulsions, such as creams, ointments and/or pastes, and/or solutions and/or suspensions.
Formulations that can be administered topically may, for example, contain from about 1% to about 10% (w/w) of the active ingredient, although the concentration of the active ingredient may be up to the solubility limit of the active ingredient in the solvent. Formulations for topical administration may also include one or more additional ingredients described herein.
Ocular or otic administration
In some embodiments, the pharmaceutical compositions described herein may be prepared, packaged, and/or sold in a formulation suitable for ocular and/or otic administration. Such formulations may, for example, be in the form of eye and/or ear drops, which include, for example, 0.1/1.0% (w/w) solutions and/or suspensions of the active ingredient in aqueous and/or oily liquid vehicles. Such drops may also comprise buffers, salts, and/or one or more of any of the other additional ingredients described herein. Other ophthalmically administrable formulations that may be useful include those comprising an active ingredient in microcrystalline form and/or in liposomal formulations. Subretinal inserts may also be used as administration forms.
Pharmaceutical formulations for ocular administration may be in the form of sterile aqueous solutions or suspensions of particles formed from one or more polymer-drug conjugates. Acceptable solvents include, for example, water, ringer's solution, phosphate Buffered Saline (PBS), and isotonic sodium chloride solution. The formulation may also be a sterile solution, suspension or emulsion in a non-toxic, parenterally acceptable diluent or solvent, such as 1, 3-butanediol.
Reservoir administration
In some embodiments, the composition may also be formulated as a formulation for implantation or injection. Thus, for example, the structure may be formulated with suitable polymers, aqueous and/or hydrophilic materials or resins, or as sparingly soluble derivatives (e.g., as a sparingly soluble salt).
In some embodiments, the pharmaceutical compositions and/or formulations described herein are formulated in a depot for sustained release.
Intranasal, nasal or buccal administration
For buccal administration, the compositions may take the form of tablets or lozenges formulated in a conventional manner.
Formulations suitable for nasal administration may, for example, comprise about as little as 0.1% (w/w) and as much as 100% (w/w) of the active ingredient, and may comprise one or more additional ingredients as described herein. The pharmaceutical compositions may be prepared, packaged and/or sold in a formulation suitable for buccal administration. Such formulations may be in the form of tablets and/or lozenges, for example, made using conventional methods, and may be, for example, 0.1% to 20% (w/w) of the active ingredient, the balance comprising the orally-soluble and/or degradable composition and optionally one or more additional ingredients described herein. Alternatively, formulations suitable for buccal administration may include powders and/or aerosolised (aerosolised) solutions and/or suspensions comprising the active ingredient. Such powdered, aerosolized, and/or atomized formulations may comprise an average particle and/or droplet size of about 0.1nm to about 200nm when dispersed, and may further comprise one or more of any of the additional ingredients described herein.
Rectal and vaginal administration
These compounds may also be formulated as rectal compositions, creams or lotions.
In some embodiments, the pharmaceutical compositions and/or formulations described herein may be administered rectally and/or vaginally. Compositions for rectal or vaginal administration are generally suppositories which can be prepared by mixing the composition with suitable non-irritating excipients such as cocoa butter, polyethylene glycols or suppository waxes, which are solid at the ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active ingredient.
Time period for formulation
In some embodiments, the composition comprising the delivery vehicle may be formulated under sterile conditions within a reasonable time prior to administration. For example, a composition comprising a delivery vehicle may be formulated about 1 month, 2 weeks, 1 week, 5 days, 3 days, 2 days, 1 day, 10 hours, 5 hours, or immediately prior to administration to a subject. In one aspect, the delivery vehicle may be frozen and thawed prior to administration. The delivery vehicle provided may be used in combination with a secondary therapy. For example, a secondary therapy such as chemotherapy or radiation therapy may be performed before or after administration of the delivery vehicle, e.g., within 12 hours to 7 days. In addition to administration of the delivery vehicle, combination therapies, such as both chemotherapy and radiation therapy, may also be employed.
Delayed and targeted release
In some embodiments, the pharmaceutical composition comprising the subject delivery vehicle may be administered orally from a variety of pharmaceutical formulations designed to provide delayed release. Delayed oral dosage forms include, for example, tablets, capsules, caplets, and may also contain a plurality of granules, beads, powders, or pellets (pellets), which may or may not be encapsulated. Tablets and capsules may represent oral dosage forms in which case solid pharmaceutical carriers may be used. In a delayed release formulation, one or more barrier coatings may be applied to the pellets, tablets or capsules to promote slow dissolution of the drug and concomitant release into the intestine. Typically, the barrier coating may contain one or more polymers that wrap, surround or form a layer or film around the therapeutic composition or active core. In some embodiments, an active agent, such as a polynucleic acid, may be delivered in a formulation to provide delayed release at a predetermined time after administration. The delay may be up to about 10 minutes, about 20 minutes, about 30 minutes, about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, or up to 1 week. In some embodiments, the particles may be coated without an enteric coating.
In some embodiments, the polymer or coating useful for achieving enteric release may be an anionic polymethacrylate (a copolymer of methacrylic acid with methyl methacrylate or ethyl acrylateCellulose-based polymers, e.g. cellulose acetate phthalate>Or polyvinyl derivatives, e.g. polyvinyl acetate phthalate +>
Dosing schedule and amount
In some embodiments, the pharmaceutical composition containing the delivery vehicle and its loading may be administered chronically. In some embodiments, administration may encompass administration of the structure to the subject hourly, daily, monthly, or yearly. In some embodiments, the pharmaceutical composition may be administered to the subject daily throughout the life of the subject. In some embodiments, the pharmaceutical composition may be administered daily for the duration of the disease present in the subject. In some embodiments, a pharmaceutical composition, e.g., comprising a delivery vehicle and a polynucleic acid load, may be administered to a subject to treat a disease or disorder until the disease or disorder is reduced, controlled, or eliminated. In some embodiments, disease control may encompass stabilization of a disease. In some embodiments, the controlled cancer may have stopped growing or spreading as measured by CT scanning. In some embodiments, the cancer may be colon cancer.
In some embodiments, the appropriate dosage of the active agent in the composition (a "therapeutically effective amount") may depend, for example, on the severity and course of the condition, the mode of administration, the bioavailability of the particular agent, the age and weight of the subject, the clinical history and response of the subject to the active agent, the judgment of the physician, or any combination thereof. In some embodiments, a therapeutically effective amount of an active agent in a composition to be administered to a subject may be from about 100 μg/kg body weight/day to about 1000mg/kg body weight/day, whether by one or more administrations. In some embodiments, each active agent administered daily may range from about 100 μg/kg body weight/day to about 50mg/kg body weight/day, from 100 μg/kg body weight/day to about 10mg/kg body weight/day, from 100 μg/kg body weight/day to about 1mg/kg body weight/day, from 100 μg/kg body weight/day to about 10mg/kg body weight/day, from 500 μg/kg body weight/day to about 100mg/kg body weight/day, from 500 μg/kg body weight/day to about 50mg/kg body weight/day, from 500 μg/kg body weight/day to about 5mg/kg body weight/day, from 1mg/kg body weight/day to about 100mg/kg body weight/day, from 1mg/kg body weight/day to about 10mg/kg body weight/day, from 5mg/kg body weight/dose to about 100mg/kg body weight/day, from 5mg/kg body weight/dose to about 50mg/kg body weight/day, from 500 μg/kg body weight/day to about 5mg/kg body weight/day, from about 10mg/kg body weight/day to about 50mg/kg body weight/day, and from about 10mg/kg body weight/day to about 50mg/kg body weight/day.
In some embodiments, the pharmaceutical composition may be administered daily or on demand.
In some embodiments, a delivery vehicle or pharmaceutical composition disclosed herein may be delivered to a subject more than once, which may be referred to as "re-administration" or "re-administration". In some embodiments, the re-administration may be performed 1, 2, 3, 4 or more times without significantly reducing the effectiveness of the delivery vehicle in delivering the load to the subject.
In some embodiments, the drug may be co-administered with any additional therapy.
VI target region, tissue or cell of delivery
The delivery vehicles described herein can deliver a load systemically and/or to a local target in a subject. In some embodiments, the local target may include, but is not limited to, a particular cell, tissue, organ, physiological system of the subject, or any combination thereof. In some embodiments, the local target may be a tumor.
In some embodiments, the delivery vehicles provided herein can be used to carry a load to a target cell. In some embodiments, the target cells are present in the gastrointestinal tract, the genital tract, the circulatory system, the respiratory system, the musculoskeletal system, the excretory system, the nervous system, the ocular system, and combinations thereof. In some embodiments, suitable target cells may be present in any major organ of the body, including but not limited to skin, lung, heart, liver, stomach, urinary system, reproductive system, intestine, pancreas, kidney, thymus, thyroid, and/or brain. In some embodiments, the target cell is a portion of the gastrointestinal tract and is in the anus, rectum, large intestine, small intestine, liver, stomach, esophagus, or oral cavity. In some embodiments, the target cell is an enteroendocrine cell, a mast cell, an intestinal epithelial cell (entercell), a brush cell (brush cell), a panda cell, or a goblet cell. In some embodiments, the target cell is an enteroendocrine cell and is an EC cell, a D cell, a CCK cell, an L cell, a P/D1 cell, or a G cell. In some embodiments, the target cell is in an intestinal epithelium and is selected from an intestinal stem cell, a panda cell, a goblet cell, an intestinal epithelial cell, a transitional amplifying cell (transit amplifying cell), an enteroendocrine cell, or any combination thereof. In some embodiments, the target cell is an intestinal stem cell. In some embodiments, the target cell is a crypt cell.
Cells
In some embodiments, the delivery vehicle may deliver the load to a particular cell type. Non-limiting examples of cells include adipocytes, adrenergic nerve cells, alpha cells, amacrine cells, amenorrhea cells, anterior lens epithelial cells, anterior/central somatic cells, apocrine sweat gland cells, astrocytes, auditory endo-hair cells of the pedicel's, b cells, vestibular large gland cells (Bartholin's gland cells), cornea, tongue, mouth, nasal cavity, distal anal canal, basal cells of distal urinary tract and distal vagina (stem cells), basal cells of olfactory epithelium, basket cells, basophils, precursor cells, beta cells, betz cells, bone marrow reticulocytes, border cells, olfactory gland cells (bowman's gland cells), brown adipocytes, duodenal gland cells (Brunner's gland cells), globus gland cells, shrouding cells, c cells, jal-renzius cardiomyocytes, cardiac muscle cells, cord, bone hormone-producing, bone marrow, band tissue hormone producing bone marrow cells, bone marrow tissue hormone producing cells, earwax gland cells, pendant lamp-like cells, chemoreceptor globus cells of carotid somatic cells, master cells, cholinergic neurons, pheochromocytes, rod-like cells, cold sensitive primary sensory neurons, connective tissue macrophages (of all types), corneal fibroblasts (corneal keratocytes of the cornea), progesterone-secreting ruptured follicular corpus luteum cells, cortical hair stem cells, adrenocorticotropic hormone cells (corticotrope), crystallin-containing lens fibroblasts, stratum corneum hair stem cells, cytotoxic t cells, d cells, delta cells, dendritic cells, double brush cells, ductal cells, exocrine sweat gland dark cells, output tubule cells, elastic cartilage chondrocytes, endothelial cells, enteric glial cells, enterochromaffin cells, enterochromophil-like cells, enteroendocrine cells, eosinophil granulocytes and precursors, ependymal cells, epidermal basal cells, epidermal langerhans cells, epididymal basal cells, epididymal master cells, epithelial reticulocytes, epsilon cells, erythrocytes, fibrocartilage chondrocytes, forked neurons, fovea cells, g cells, gall bladder epithelial cells, germ cells, litttgland cells, moll gland cells in the eyelid, glial cells, golgi cells, gonadotropic stromal cells, gonadotrope cells, granulosa cells, follicular cells, granulosa cells, luteal cells, and head orientation cells.
Tissue of
In some embodiments, the delivery vehicle may deliver the load to a particular tissue. Non-limiting examples of tissue are adrenal medulla, adult fibrous tissue, blood vessels, bone, breast, bronchial lining (lining), carotid body, cartilage, connective tissue, embryonic (myxoma) fibrous tissue, involucra, epithelium, fat, glandular epithelium (liver, kidney, bile duct), gonads, hematopoietic cells, lymphatic vessels, lymphoid tissue, meninges, mesothelial, muscle, nerve sheath, nerve, spinal cord, ovary, pancreas, parathyroid, pituitary, placenta, renin, smooth muscle, stomach and intestine, stratified squamous epithelium, striated muscle, stroma, testis, thyroid, and transitional epithelium. As one non-limiting example, the tissue is stomach and intestinal tissue.
Organ
In some embodiments, the delivery vehicle may deliver the load to a particular organ. Non-limiting examples of organs include anal canal, artery, ascending colon, bladder, bone marrow, brain, bronchi, bronchioles, glomerulonephritis, capillaries, cecum, cerebellum, hemispheres of the brain, cervix, choroid plexus, clitoris, cranial nerves, descending colon, metaencephala, brain the duodenum, ear, enteric nervous system, epididymis, esophagus, external genitalia, fallopian tube, gall bladder, ganglion, taste sense, intestinal related lymphoid tissue, heart, ileum, internal genital organ, interstitium, jejunum, joint, kidney, large intestine, larynx, ligament, liver, lung, lymph node lymphatic vessels, breast, medulla oblongata, mesenteric, midbrain, mouth, respiratory muscles, nasal cavities, nerves, olfactory organs, ovaries, pancreas, parotid glands, penis, pharynx, placenta, brain bridge, prostate, rectum, salivary glands, scrotum, seminal vesicles, sigmoid colon, bones, skin, small intestine, spinal nerves, spleen, stomach, subcutaneous tissue, sublingual glands, submandibular glands, teeth, tendons, testes, brainstem, spinal cord, ventricular system, thymus, tongue, tonsils, trachea, transverse colon, ureters, urethra, uterus, vagina, vas deferens, veins and vulva.
Physiological system
In some embodiments, the delivery vehicle may deliver the load to a particular physiological system. Non-limiting examples of physiological systems include the auditory system, cardiovascular system, central nervous system, chemical receptor system, circulatory system, digestive system, endocrine system, enteric nervous system, excretory system, exocrine system, reproductive system, epidermal (integrated) system, lymphatic system, muscular system, musculoskeletal system, nervous system, peripheral nervous system, renal system, reproductive system, respiratory system, urinary system, and visual system.
In some embodiments, the physiological system is the digestive system or the enteric nervous system.
Tumor(s)
In some embodiments, the delivery vehicle may deliver the load to the tumor. The tumor may be a benign tumor or a malignant tumor.
VII methods of use
Provided herein are various methods of using the disclosed delivery vehicles and pharmaceutical compositions. In some embodiments, methods of delivering a load to a subject are provided. In some embodiments, methods of treating a subject in need thereof are provided. In some embodiments, methods of preventing the occurrence or exacerbation of an indication are provided. In some embodiments, methods of using the disclosed delivery vehicles and pharmaceutical compositions in diagnostic, imaging, or scientific research are provided. In some embodiments, assays are provided that utilize or evaluate the disclosed delivery vehicles and pharmaceutical compositions.
Method of delivering a load
In some embodiments, the method of delivering a load to a subject comprises administering to the subject a delivery vehicle or pharmaceutical composition described herein. In some embodiments, the method comprises delivering the load to cells of the subject.
In some embodiments, the present disclosure provides methods of delivering a cargo to a target cell by contacting the target cell with a composition described herein (e.g., a composition comprising a cargo and a delivery vehicle nanoparticle). In some embodiments, the target cell may comprise a human cell. In some embodiments, the target cell may be part of a mucosal tissue. In some embodiments, the target cell mucosal tissue may be a portion of the gastrointestinal tract. In some embodiments, the target cell may comprise a gastrointestinal cell. In some embodiments, the gastrointestinal cells may include, but are not limited to, intestinal epithelial cells, lamina propria cells, intraepithelial lymphocytes, intestinal muscle cells, and intestinal neurons. In some embodiments, the target cell may comprise an epithelial cell. In some embodiments, the epithelial cells may include intestinal epithelial cells.
In some embodiments, the present disclosure provides methods of introducing a load into a target cell using the delivery vehicles provided herein. In some embodiments, introducing comprises contacting the target cell with a load. In some embodiments, introducing comprises transfecting or transducing the target cell with a load. In some embodiments, the load may modify the genome of the cell or be present within the cell outside the genome.
In some embodiments, the delivery method can deliver any cargo, such as the cargo described throughout this disclosure, including but not limited to therapeutic agents, nucleic acids, polypeptides, proteins, biologicals, antibodies, enzymes, hormones, cytokines, immunogens, and genetic epigenetic editing system components, or any combination thereof.
Methods of delivery through the gastrointestinal tract
In some embodiments, a method of delivering a payload to a subject comprises introducing a composition into the gastrointestinal tract of the subject, wherein the composition comprises the payload and a delivery vehicle nanoparticle associated (e.g., encapsulated) with the payload.
In some embodiments, a method of delivering a payload to a subject comprises administering to the subject at least one delivery vehicle comprising the payload, wherein the delivery vehicle is or comprises a nanoparticle.
In some embodiments, a method of delivering a load to a subject may include introducing a composition (i.e., a composition including a delivery vehicle and at least one load) into the gastrointestinal tract of the subject, which may include administering the composition to the subject by, for example, oral administration and/or intrarectal administration. In some embodiments, the delivery vehicle nanoparticle may target gastrointestinal cells. In some embodiments, the gastrointestinal cells that are targeted may include, but are not limited to, intestinal epithelial cells, lamina propria cells, intraepithelial lymphocytes, intestinal muscle cells, and intestinal neurons. In some embodiments, any route of administration may be used.
In some embodiments of the method, the delivery vehicle load may be delivered to a gastrointestinal cell. In some embodiments, the load may be delivered to the intracellular space of the gastrointestinal cells.
Method of delivering gene editing/transgene payload
In some embodiments, transfected gastrointestinal cells may express a nucleic acid load encoding a component of a gene editing system. The term "gene editing system" as used herein refers to any technical method for modifying nucleic acids together with the relevant components for carrying out the method. Gene editing systems may include, but are not limited to, systems that utilize Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) and CRISPR-associated (Cas) protein technology.
In some embodiments, the gene editing system may comprise an epigenetic editing system. Typically, the epigenetic editing system is a genetic editing system that alters a characteristic of a non-sequence related nucleic acid, such as methylation and organization into chromatin.
In some embodiments, the nucleic acid load encoding components of the gene editing system can be used to correct mutations in epithelial cell genes, including, but not limited to, CFTR gene mutations, GPR35 gene mutations, RNF186 a64T germline mutations associated with increased risk of ulcerative colitis (see beaudein, m.et al. Plos genetics.2013.9 (9): e1003723, the contents of which are incorporated herein by reference in their entirety), mutations associated with very early-onset IBD (see Leung, g. And muse, a.m., physiolog.2018.33:360-9, the contents of which are incorporated herein by reference in their entirety, including the genes listed in table 1) and/or somatic mutations in genes that affect IL-17 signaling (e.g., NFKBIZ, ZC3H12A and PIGR; see Nanki, k. Et. Nature.2020.577 (7789): 254-9, the contents of which are incorporated herein by reference in their entirety).
In some embodiments, the nucleic acid encoding a component of the gene editing system may be used to delete or silence a gene encoding IL-18 and/or IL-18R1 in gastrointestinal stem cells (in vivo or in vitro) to treat or prevent IBD.
In some embodiments, the nucleic acid load encoding a component of the gene editing system may be used to generate RNF186 (179X) mutations in gastrointestinal stem cells to confer protection against IBD. Nucleic acid payloads encoding components of the gene editing system can be used to insert transgenes into gastrointestinal cell DNA (e.g., via CRISPR or RNA-mediated retrotransposons) to provide a permanent source for expression of therapeutic proteins or other factors.
In some embodiments, the inserted transgene encodes an anti-tnfα antibody, an anti-P19 antibody, or an anti-IL-23 antibody to treat or prevent IBD.
In some embodiments, the inserted transgene expresses GLP-1 or FGF21 for use in the treatment or prevention of a metabolic disorder.
In some embodiments, genes for any protein or peptide that can correct defects in phenylketonuria, diabetes, organic acid urine, tyrosinemia, urea cycle disorders, familial hypercholesterolemia (familial hypercholesteremia) can be introduced into stem cells such that the protein or peptide product is expressed by the intestinal epithelium.
In some embodiments, clotting factors such as antihemophilic factor (factor 8), christmas factor (factor 9) and factor 7 may also be produced in intestinal epithelium. In some embodiments, proteins useful in the treatment of circulatory protein deficiencies may also be expressed in intestinal epithelium. In some embodiments, the protein useful for treating circulatory protein deficiency may be, for example, albumin, alpha-1-antitrypsin, hormone binding protein useful for treating albumin.
In some embodiments, intestinal symptoms of cystic fibrosis may be treated by inserting a gene for a normal cystic fibrosis transmembrane conductance regulator into stem cells of the intestinal epithelium.
In some embodiments, the beta-free lipoproteinemia can be treated by inserting apolipoprotein B.
In some embodiments, the disaccharide enzyme intolerance can be treated by inserting a sucrase-isomaltose, a lactase-phlorizin hydrolase and a maltase-glucoamylase.
In some embodiments, an insert for absorbing an intrinsic factor of vitamin B12 or for absorbing a receptor of an intrinsic factor/cobalamin complex of vitamin B12 and a bile acid transporter may be inserted into the intestinal epithelium.
In some embodiments, any drug that may be encoded by a nucleic acid may be inserted into stem cells of the intestinal epithelium for secretion at high concentrations locally for the treatment of cancer. In this regard, one of skill in the art will readily recognize that antisense RNA can be encoded into stem cells after antisense is produced, which can be incorporated into cancer cells to treat cancer.
Delivery to a subject by expression and/or secretion from a target cell
In some embodiments, a method of delivering a load to a subject may comprise: (i) Introducing the composition into the gastrointestinal tract of a subject such that (ii) the payload, the payload component, and/or the payload expression product is secreted from the gastrointestinal cells after delivery.
The term "expression product" as used herein refers to a nucleic acid, amino acid polymer, protein, biomolecule, or other structure that is synthesized or "expressed" from a coded template (e.g., DNA or RNA).
In some embodiments, the cargo expression product may be expressed directly from the nucleic acid cargo component or may be expressed by a cell that is responsive to some other cargo component or component activity (e.g., enzymatic activity, cell signaling activity, transcriptional/translational activation/inhibition, etc.).
In some embodiments, secretion of the payload, the payload component, and/or the payload expression product may be secreted by the apical secretion or basal secretion of the gastrointestinal cells. In some embodiments, the load, load component, and/or load expression product may remain in the region proximal to the cell after secretion. In some embodiments, the payload component, and/or the payload expression product may be basal secreted from the gastrointestinal cells and into the circulation. In some embodiments, the load, load components, and/or load expression products may be distributed systemically after entering the cycle.
In some embodiments, the therapeutic nucleic acid may encode a polypeptide or protein that also serves as a therapeutic. The nucleic acid may include DNA (e.g., plasmid DNA). In some embodiments, the nanoparticles may target gastrointestinal cells and transfect them with a nucleic acid load.
In some embodiments, the transfected gastrointestinal cells may express a polypeptide encoded by the nucleic acid cargo.
Cell signaling factors
In some embodiments, the nucleic acid may encode a cell signaling factor. The term "cell signaling factor" as used herein refers to any molecule that initiates a cellular response, including but not limited to cytokines, growth factors, and receptor ligands. Cell signaling factors encoded by nucleic acid nanoparticle loading may include, but are not limited to, interleukin (IL) -2, IL-2 mutein Fc fusion, IL-10 mutein, IL-22, granulocyte-macrophage colony-stimulating factor (GM-CSF), granulocyte colony-stimulating factor (G-CSF), adrenomedullin, glucagon-like peptide 1 (GLP-1), glucagon-like peptide 2 (GLP-2), GLP-2 analog Tidulutin (teduglutide), peroxisome proliferator-activated receptor gamma (PPARgamma), human Growth Hormone (HGH), parathyroid hormone (PTH), fibroblast growth factor 21 (FGF 21), and relaxin.
Antibodies to
In some embodiments, the nucleic acid encodes an antibody. The term "antibody" as used herein is used in its broadest sense and specifically covers various antibody forms, including but not limited to monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies formed from at least two intact antibodies), and antibody fragments (e.g., diabodies), so long as they exhibit the desired biological activity (e.g., are "functional" fragments). The encoded antibodies can bind to targets, including one or more of IL-18, IL-18 receptor 1 (IL 18R 1), IL-23, tumor necrosis factor alpha (TNF alpha), proprotein convertase subtilisin 9 (PCSK 9), and protein 19 (P19). The encoded antibody may comprise a bispecific antibody. Bispecific antibodies can bind to cluster of differentiation 3 (CD 3) for recruiting immune cells to the target of a second bispecific antibody epitope.
In some embodiments, transfected gastrointestinal cells may express a nucleic acid load encoding an antigen. The term "antigen" as used herein refers to an entity or structure that can be specifically bound or "recognized" by an antibody binding partner. Antigens that elicit an immune response in an organism are referred to herein as "immunogens". Nucleic acid cargo encoding an immunogen may be delivered to a subject to promote an immune response to the encoded immunogen. The encoded immunogen may be derived from a pathogenic organism or virus. Pathogens associated with the encoded immunogen may include, but are not limited to, influenza virus, SARS-CoV-2 virus, ebola virus, and poliovirus.
In some embodiments, the nucleic acid load encodes a tumor cell neoantigen. The term "neoantigen" as used herein refers to antigens expressed by tumor cells (e.g., due to mutations or other mechanisms) that distinguish them from non-tumor cells. Expression of the neoantigen may be used to promote an immune response in a subject against tumor cells. In some embodiments, the nucleic acid load encodes an antigen that can be used by a subject to develop tolerance to the antigen. Such antigens may include, but are not limited to, antigens associated with peanut allergy, celiac disease, rheumatoid arthritis, and IBD.
In some embodiments, the transfected gastrointestinal cells express a nucleic acid load encoding a clotting factor (e.g., factor VIII). In some embodiments, the transfected gastrointestinal cells express a nucleic acid load encoding an enzyme [ e.g., β -Glucocerebrosidase (GBA) ].
In some embodiments, gastrointestinal cells may be transfected with a nucleic acid load comprising non-coding RNA. The term "non-coding RNA" as used herein refers to RNA molecules having sequences that do not encode proteins but are generally of significance in certain other RNA functions. Non-coding RNAs can include, but are not limited to, interfering short RNAs (siRNA), micrornas (miRNA), long non-coding RNAs, RNAs that interact with piwi (piRNA), nucleolar micrornas (snoRNA), cajal body-specific micrornas (scaRNA), transfer RNAs (tRNA), ribosomal RNAs (rRNA), and intranuclear micrornas (snRNA).
In some embodiments, transfected gastrointestinal cells may express a nucleic acid load encoding an antimicrobial agent. The term "antimicrobial agent" as used herein refers to any substance capable of killing or otherwise slowing or stopping the growth, spread or reproduction of a microorganism or virus. Antimicrobial agents encoded by nucleic acid loading may include, but are not limited to, intestinal Alkaline Phosphatase (IAP) and defensins.
Additional load delivery method
In some embodiments, the present disclosure provides a method of delivering a load to a target cell, the method comprising contacting the target cell with a composition described herein (e.g., a load and nanoparticle composition). The target cells may include human cells. The target cells may include epithelial cells. The epithelial cells may include intestinal epithelial cells.
In some embodiments, the present disclosure provides a method of delivering a load to a target cell, wherein the target cell is part of a mucosal tissue, the method comprising contacting the mucosal tissue with a composition described above or herein. The mucosal tissue may be part of the gastrointestinal tract. The target cell may be a gastrointestinal cell. The gastrointestinal cells may include one or more of intestinal epithelial cells, lamina propria cells, intraepithelial lymphocytes, intestinal muscle cells, and intestinal neurons.
In some embodiments, the present disclosure provides a method of delivering a load to a subject, the method comprising introducing the composition described above or herein into the gastrointestinal tract of the subject. The composition may be introduced into the gastrointestinal tract of the subject by administering the composition to the subject by a route of administration selected from one or more of oral administration and intrarectal administration. The nanoparticle may target gastrointestinal cells. The gastrointestinal cells may be selected from one or more of intestinal epithelial cells, lamina propria cells, intraepithelial lymphocytes, intestinal muscle cells and intestinal neurons. The load may be delivered to gastrointestinal cells. The load may be delivered to the intracellular space of the gastrointestinal cells. The payload, the payload component or the expression product of the payload may be secreted from the gastrointestinal cell. Secretion of the payload, the payload component, or the expression product of the payload may include apical secretion or basal secretion. The load, the load component, or the expression product of the load may remain in the region proximal to the cell after secretion. The payload, the payload component or the expression product of the payload may be secreted from the gastrointestinal cell foundation and into the circulation. The load, load component or expression product of the load may be distributed systemically after entering the cycle. The load may include a therapeutic agent. The therapeutic agent may include one or more of nucleic acids, polypeptides, proteins, biologicals, antibodies, enzymes, hormones, cytokines, immunogens, and components of a gene or epigenetic editing system. The therapeutic agent may comprise a nucleic acid. The nucleic acid may encode at least one polypeptide. The nucleic acid may comprise DNA. The nucleic acid may comprise plasmid DNA. The nanoparticle may target a gastrointestinal cell and the gastrointestinal cell may be transfected with the nucleic acid. The gastrointestinal cell may express a polypeptide encoded by the nucleic acid. The nucleic acid may encode a cell signaling factor. The cell signaling factor may be selected from one or more of the following: interleukin (IL) -2, IL-2 mutein Fc-fusion, IL-10 mutein, IL-22, granulocyte-macrophage colony stimulating factor (GM-CSF), granulocyte colony stimulating factor (G-CSF), adrenomedullin, glucagon-like peptide 1 (GLP-1), glucagon-like peptide 2 (GLP-2), GLP-2 analog tiltuin, peroxisome proliferator-activated receptor gamma (PPARgamma), human Growth Hormone (HGH), parathyroid hormone (PTH), fibroblast growth factor 21 (FGF 21) and relaxin. The nucleic acid may encode an antibody. The antibody may bind to a target selected from one or more of IL-18, IL-18 receptor 1 (IL 18R 1), IL-23, tumor necrosis factor alpha (TNF alpha), proprotein convertase subtilisin 9 (PCSK 9), and protein 19 (P19). The antibody may be a bispecific antibody. Bispecific antibodies can bind to cluster of differentiation 3 (CD 3). The nucleic acid may encode an antimicrobial agent. The antimicrobial agent may be selected from one or more of Intestinal Alkaline Phosphatase (IAP) and defensin. The nucleic acid may encode a gene editing system component. The nucleic acid may encode an antigen as an immunogen to promote an immune response in the subject to the antigen. The antigen may be derived from one or more of influenza virus, SARS-CoV-2 virus, ebola virus and poliovirus. The antigen may comprise a tumor cell neoantigen. The immune response may include tolerance of the subject to the antigen. The antigen may be associated with one or more of peanut allergy, celiac disease, rheumatoid arthritis and IBD. The nucleic acid may encode a clotting factor. The clotting factor may comprise factor VIII. The nucleic acid may encode an enzyme. The enzyme may comprise beta-Glucocerebrosidase (GBA). The nucleic acid may be non-coding RNA. The non-coding RNAs may include one or more of interfering short RNAs (siRNA), micrornas (miRNA), long non-coding RNAs, piwi-interacting RNAs (piRNA), nucleolar micrornas (snoRNA), cajal body-specific micrornas (scaRNA), transfer RNAs (tRNA), ribosomal RNAs (rRNA), and intranuclear micrornas (snRNA).
Methods of treating indications
In some embodiments, the present disclosure provides methods of treating a therapeutic indication in a subject by administering a delivery vehicle and/or pharmaceutical composition (e.g., composition, nanoparticle, and/or payload) described herein. In some embodiments, the method of treating a therapeutic indication comprises at least one method of delivering a load to a subject as described herein. In some embodiments, the method of treating a subject comprises at least one method of delivering a load to the gastrointestinal tract of a subject disclosed herein. For clarity, "methods of treating therapeutic indications" may also be referred to herein simply as "methods of treatment.
In some embodiments, the method of treatment comprises delivering a load (e.g., any of the therapeutic agents described herein) to a target in need thereof. In some embodiments, the method of treatment comprises systemically delivering the load to a subject in need thereof. In some embodiments, the method of treatment comprises: (i) delivering the load to at least one cell of the subject; (ii) the cell expresses or produces a therapeutic agent; and optionally (iii) the cells secrete the therapeutic agent locally or systemically.
The term "therapeutic indication" as used herein refers to any disease, condition, disorder or symptom that can be ameliorated, healed, stabilized, alleviated, or otherwise addressed by medical treatment or other intervention. The delivery vehicle load for therapeutic indication treatment may include and/or encode a therapeutic agent.
Exemplary therapeutic indications (e.g., diseases) that can be treated with the subject delivery vehicles provided herein (particularly such delivery vehicles with therapeutic loads) can be cancerous or non-cancerous. Such diseases may be cardiovascular diseases, neurodegenerative diseases, ocular diseases, reproductive diseases, gastrointestinal diseases, brain diseases, skin diseases, bone diseases, musculoskeletal diseases, pulmonary diseases, thoracic diseases, etc. The disease may be a genetic disease, such as cystic fibrosis, familial amaurosis dementia, fragile X syndrome, huntington's disease, neurofibromatosis, sickle cell disease, thalassemia, progressive pseudohypertrophic muscular dystrophy, or a combination thereof.
In some embodiments, the method of treatment comprises screening the subject for the presence of a disease. In some embodiments, screening may be utilized to identify appropriate subjects. In some embodiments, the disease may be identified by genetic, phenotypic, molecular, or chromosomal screening. In some embodiments, the appropriate subject is positive for the diseases provided herein. For example, genetic screening can identify mutations in the APC gene that can lead to FAP. In some embodiments, screening may include analyzing genes, such as CDH1, STK11, SMAD4, MLH1, MSH2, EPCAM, MSH6, PMS2, MYO5B, APC, TP53, portions thereof, promoters thereof, and combinations thereof.
Gastrointestinal indications
In some embodiments, the disease is a gastrointestinal disease. In some embodiments, the gastrointestinal disease is a monogenic GI disease. In some embodiments, the gastrointestinal disorder is inherited. In some embodiments, the gastrointestinal disease is an epithelial disease. Exemplary gastrointestinal diseases may include Familial Adenomatous Polyposis (FAP), attenuated FAP, microvilli inclusion body disease (MVID), chronic inflammatory bowel disease, ileal crohn's disease, juvenile polyposis, hereditary diffuse gastric cancer syndrome (HDGC), peutz-Jeghers syndrome, lynch syndrome, gastric adenocarcinoma with proximal gastric polyposis (GAPPS), li-Fraumeni syndrome, familial gastric cancer, or a combination thereof. In some embodiments, the GI disease may produce polyps in the gastrointestinal tract. In some embodiments, the disease is FAP. In some embodiments, FAP may progress to cancer. In some embodiments, the gastrointestinal disease may be hereditary. For example, the hereditary gastrointestinal disease may be Gilbert syndrome, telangiectasia, mucopolysaccharidosis, osler-Weber-Rendu syndrome, pancreatitis, keratoacanthoma, biliary atresia, morquio syndrome, hurler's syndrome, hunter's syndrome, crigler-Najjar syndrome, rotator syndrome, peutz-Jeghers syndrome, dubin-Johnson syndrome, osteochondrosis, osteochondral dysplasia, polyposis, or a combination thereof.
Immune-related indications
In some embodiments, the therapeutic indication to be treated by the methods disclosed herein can include an immune-related indication. The term "immune-related indication" as used herein refers to any therapeutic indication associated with the immune system.
In some embodiments for treating immune-related indications, the methods of the present disclosure may include delivering (also referred to herein as "using") at least one nucleic acid load encoding one or more of IL-2, IL-2 mutein Fc-fusion, IL-10 mutein, IL-22, adrenomedullin, an antimicrobial agent, and an anti-inflammatory antibody. In some embodiments, the nucleic acid load may be delivered to a gastrointestinal cell. In some embodiments, the gastrointestinal cells may express a therapeutic agent from a nucleic acid load. In some embodiments, the gastrointestinal cells may secrete the therapeutic agent locally or systemically (e.g., by entering the circulation).
In some embodiments, the immune-related indications addressed by the methods of treatment of the present disclosure include gastrointestinal indications, which may include gastrointestinal diseases and any other conditions involving the gastrointestinal tract and related components. Gastrointestinal indications may include, but are not limited to, gastrointestinal infections, inflammatory Bowel Disease (IBD), ulcerative colitis, and crohn's disease. The gastrointestinal cells may express and locally secrete (e.g., into the intestinal lumen) a therapeutic agent encoded by the cargo nucleic acid for use in treating such gastrointestinal indications.
In some embodiments, the immune-related indications addressed by the methods of treatment of the present disclosure are systemic or not gastrointestinal-specific. In some embodiments, the method of treatment may comprise: (i) transfecting the gastrointestinal cells; (ii) The gastrointestinal cells may express the therapeutic agent and secrete it into the circulation. Non-limiting examples of indications addressed by the treatment methods comprising a secretion step may include Graft Versus Host Disease (GVHD), systemic Lupus Erythematosus (SLE), type I diabetes, rheumatoid arthritis, infection, wounds, and allergies.
Cancer of the human body
In some embodiments, therapeutic indications treated according to the methods of the present disclosure include cancer and related disorders, referred to herein as "cancer-related indications".
In some embodiments, the method of treating a cancer-related indication comprises secreting a therapeutic agent from a subject's cells. In some embodiments, the therapeutic agent encoded by the nucleic acid load associated with the method of treating an indication associated with cancer may comprise GM-CSF. In some embodiments, the gastrointestinal cells may locally express and secrete GM-CSF encoded by the nucleic acid load or into the circulation. Cancer-related indications treated according to such methods may include, but are not limited to, hodgkin's lymphoma, non-hodgkin's lymphoma, acute lymphoblastic leukemia, and acute myelogenous leukemia.
In some embodiments, the subject receiving the treatment method has previously received or is receiving concurrent chemotherapy treatment and/or stem cell transplantation treatment.
In some embodiments, GM-CSF is present in an amount sufficient to provide from about 10 to about 500 μg/m 2 Per day (e.g., about 50 to about 200, about 100 to about 250, or about 150 to about 400 μg/m) 2 Day) is secreted into the circulation.
Specific adaptability
In some embodiments, a therapeutic indication treated according to the methods of the present disclosure may include neutropenia, a condition characterized by low neutrophil blood levels. Nucleic acid loading associated with such methods can encode G-CSF, which facilitates granulocyte production and neutrophil regulation. In some embodiments, the gastrointestinal cells may express and secrete G-CSF locally and/or systemically for use in neutropenia treatment. In some embodiments, the G-CSF is secreted into the circulation at a level sufficient to provide the subject with a dose of G-CSF of about 1 to about 20 μg/kg/day (e.g., about 1 to about 10, about 5 to about 15, or about 10 to about 20 μg/kg/day). In some embodiments, the subject is treated until a neutrophil blood level of about 1000/μl is reached.
In some embodiments, therapeutic indications treated according to methods of the present disclosure may include microvilli inclusion body disease (MVID). Nucleic acid loads associated with such methods may encode a MYO5B gene product.
In some embodiments, therapeutic indications treated according to methods of the present disclosure may include cystic fibrosis. Nucleic acid loads associated with such methods may encode Cystic Fibrosis Transmembrane Regulator (CFTR).
In some embodiments, therapeutic indications treated according to methods of the present disclosure may include hemophilia. Nucleic acid loads associated with such methods may encode coagulation factors. The clotting factor may comprise factor VIII. In some embodiments, the hemophilia being treated can include hemophilia a.
In some embodiments, therapeutic indications treated according to methods of the present disclosure may include Gaucher's disease. Nucleic acid loads associated with such methods may encode GBA. The nucleic acid load encoding GBA may be delivered to gastrointestinal cells. In some embodiments, the gastrointestinal cells may secrete GBA into the circulation at a level sufficient to provide a steady state subject GBA plasma level of about 1ng/mL to about 10ng/mL (e.g., about 6 ng/mL).
In some embodiments, the therapeutic indications treated according to the methods of the present disclosure include Short Bowel Syndrome (SBS). Nucleic acid loads associated with such methods may encode GLP-2. In some embodiments, the nucleic acid load encoding GLP-2 may be delivered to and expressed by a gastrointestinal cell. GLP-2 may be secreted into the circulation at a level sufficient to provide a circulating GLP-2 concentration of about 10ng/mL to about 50ng/mL (e.g., about 36 ng/mL).
In some embodiments, therapeutic indications treated according to methods of the present disclosure may include hormone deficiency. Nucleic acid loads delivered according to such methods may encode deficient hormones. The deficient hormones may include, but are not limited to, HGH and PTH. The nucleic acid load may be delivered to and expressed by a gastrointestinal cell. In some embodiments, the expressed hormone may be secreted into the circulation. In some embodiments, HGH may be secreted into the circulation at a level sufficient to provide a circulating HGH concentration of about 0.1 to about 100 ng/mL. In some embodiments, the level in an adult is about 1 to about 10ng/mL. In some embodiments, the level in the child is about 10 to about 50ng/mL. In some embodiments, PTH may be secreted into the circulation at a level sufficient to provide a circulating PTH concentration of about 50 to about 300pg/mL (e.g., about 150 pg/mL).
In some embodiments, the therapeutic indications treated according to the methods of the present disclosure include non-alcoholic steatohepatitis (NASH). Nucleic acid payloads associated with such methods may encode GLP-1 or FGF21.
In some embodiments, the therapeutic indications treated according to the methods of the present disclosure include elevated circulating Low Density Lipoprotein (LDL) levels. Nucleic acid loads associated with such methods may encode anti-PCSK 9 antibodies. In some embodiments, the nucleic acid load encoding an anti-PCSK 9 antibody may be delivered to and expressed by a gastrointestinal cell. In some embodiments, the anti-PCSK 9 antibody may be secreted into the circulation at a level sufficient to provide a circulating antibody concentration of about 1 to about 50 μg/mL (e.g., about 1 to about 10, about 6 to about 18, about 12 to about 19, or about 15 to about 45 μg/mL).
Additional methods of treating indications
In some embodiments, the present disclosure provides a method of treating a therapeutic indication in a subject, the method comprising delivering a load to the subject according to any of the methods described above or herein. Therapeutic indications may include immune-related indications. The payload may include a nucleic acid encoding a therapeutic agent. The therapeutic agent is selected from IL-2, IL-2 mutein Fc fusion protein, IL-10 mutein, IL-22, kidney Upper medullasin, antimicrobial agents and anti-inflammatory antibodies. The load may be delivered to gastrointestinal cells. The gastrointestinal cells may express a therapeutic agent. The gastrointestinal cells may secrete the therapeutic agent locally. Immune-related indications may include gastrointestinal indications. The gastrointestinal indications may include one or more of gastrointestinal infections, inflammatory Bowel Disease (IBD), ulcerative colitis, and crohn's disease. The gastrointestinal cells may secrete the therapeutic agent into the circulation. Immune-related indications may include parenteral-specific indications and/or systemic indications. Immune-related indications may include one or more of Graft Versus Host Disease (GVHD), systemic Lupus Erythematosus (SLE), type I diabetes, rheumatoid arthritis, infection, wounds, and allergies. Therapeutic indications may include cancer-related indications. The payload may include a nucleic acid encoding a therapeutic agent. The therapeutic agent may comprise GM-CSF. The cancer-related indication may include one or more of hodgkin's lymphoma, non-hodgkin's lymphoma, acute lymphoblastic leukemia, and acute myelogenous leukemia. The subject may have received or may be receiving chemotherapy and/or stem cell transplantation. The payload may be delivered to gastrointestinal cells and the gastrointestinal cells may secrete GM-CSF into the circulation at a level sufficient to provide about 250 μg/m 2 Circulating GM-CSF concentration per day. Therapeutic indications may include neutropenia. The load may comprise a nucleic acid encoding G-CSF. The load may be delivered to gastrointestinal cells and the gastrointestinal cells may secrete G-CSF into the circulation at a level sufficient to provide about 5 μg/kg/day of G-CSF. The subject may be treated until the subject's neutrophil blood level reaches 1000/. Mu.l. The therapeutic indication may be microvilli inclusion body disease (MVID), and the load may comprise a nucleic acid encoding a MYO5B gene product. Therapeutic indications may include cystic fibrosis and the load may include a nucleic acid encoding a Cystic Fibrosis Transmembrane Regulator (CFTR). Therapeutic indications may include hemophilia, and loads may include nucleic acids encoding clotting factors. The clotting factor may comprise factor VIII. Hemophilia can include hemophilia a. Therapeutic indications may include gaucher's disease and loads may include nucleic acids encoding GBA. The payload may be delivered to gastrointestinal cells and the gastrointestinal cells may secrete GBA into the circulation at a level sufficient to provide steady state GBA plasma water of about 6ng/mLFlat. The therapeutic indication may comprise Short Bowel Syndrome (SBS) and the load may comprise a nucleic acid encoding GLP-2. The payload may be delivered to a gastrointestinal cell and the gastrointestinal cell may secrete GLP-2 into the circulation at a level sufficient to provide a circulating GLP-2 concentration of about 36 ng/mL. Therapeutic indications may include hormone deficiency, and the load may include nucleic acid encoding a deficient hormone. The deficient hormone may be selected from HGH and PTH. The hormone that is deficient may be HGH, the load may be delivered to gastrointestinal cells, and the gastrointestinal cells may secrete HGH into circulation at a level sufficient to provide a circulating HGH concentration of about 1 to about 10ng/mL in adults or about 10 to about 50ng/mL in children. The hormone that is absent may be PTH, the payload may be delivered to the gastrointestinal cells, and the gastrointestinal cells may secrete PTH into the circulation at a level sufficient to provide a circulating PTH concentration of about 150 pg/mL. Therapeutic indications may include non-alcoholic steatohepatitis (NASH), and the payload may include a nucleic acid encoding GLP-1 or FGF 21. Therapeutic indications may include elevated circulating Low Density Lipoprotein (LDL) levels, and the load may include nucleic acids encoding anti-PCSK 9 antibodies. The load may be delivered to a gastrointestinal cell and the gastrointestinal cell may secrete the anti-PCSK 9 antibody into the circulation at a level sufficient to provide a circulating anti-PCSK 9 antibody concentration of about 18 to about 19 μg/mL.
Method of prevention
In some embodiments, the methods described herein comprise administering the delivery vehicle or pharmaceutical composition as a prophylactic measure. For example, any of the methods described herein can include administering a delivery vehicle or pharmaceutical composition to a subject that may not have been diagnosed with a disease. In some embodiments of the method, the subject may appear to be susceptible to a disease. In some embodiments, the disease may be at least one cancer. In some embodiments, the cancer may be colon cancer.
In some embodiments, prophylactic treatment may prevent a disease, such as cancer. In some embodiments, prophylaxis may be used in connection with: conditions such as local recurrence (e.g., pain); diseases, such as cancer; syndrome (syndrome), such as heart failure; or any other medical condition.
In some embodiments, preventing may include administering a composition that reduces the frequency of symptoms of or delays onset of symptoms of a medical condition in a subject relative to a subject not receiving the composition. Thus, prevention of cancer includes, for example, a reduction in the number of detectable cancerous growths in a population of patients receiving prophylactic treatment relative to an untreated control population, and/or a delay in the appearance of detectable cancerous growths in a treated population relative to an untreated control population, e.g., a statistically and/or clinically significant amount.
In some embodiments, prevention of infection includes, for example, reducing the number of infection diagnoses in the treated population relative to an untreated control population, and/or delaying the onset of symptoms of infection in the treated population relative to an untreated control population.
In some embodiments, the prevention of pain includes, for example, reducing the intensity of or delaying the pain sensation experienced by the subject in the treated population relative to an untreated control population.
Assay, imaging and diagnosis
In some embodiments, the delivery vehicles herein carry a diagnostic load and are used to visualize or diagnose the state of a cell or tissue or to diagnose or monitor a condition or disease in a subject. For example, an effective amount of a delivery vehicle is administered to a subject, and a diagnostic method for FAP includes determining the level of APCs incorporated into the genome of cells, whereby a difference in APC levels before and during and/or after treatment of a patient will prove the effectiveness of a therapy in a patient, including whether the patient has completed the therapy or whether the disease state has been inhibited or eliminated.
In some embodiments, the methods described herein can include performing additional procedures on the subject receiving the delivery vehicle. In some embodiments, the subject may receive procedures such as blood transfusion, blood drawing, computed Tomography (CT), magnetic Resonance Imaging (MRI), X-ray, radiation therapy, organ transplantation, and any combination thereof. In some embodiments, an assessment of a lesion, such as a cancerous lesion, may be performed.
In some embodiments of the method, non-target lesions may be evaluated. In some embodiments, the complete response to a non-target lesion may be the disappearance and normalization of tumor marker levels. In some embodiments, the size of all lymph nodes must be non-pathological (minor axis less than 10 mm). In some embodiments, if tumor markers are initially above the upper normal limit, they must be normalized to the patient to be considered a complete clinical response. non-CR/non-PD is the persistent presence of one or more non-target lesions and/or tumor marker levels are maintained above normal limits. Progressive disease may be defined as the appearance of one or more new lesions and/or the definite progression of an existing non-target lesion. Definite progression should generally not outperform the target lesion state. In some embodiments, the optimal overall response may be the optimal response recorded from the beginning of treatment until disease progression/recurrence.
In some embodiments, the methods described herein comprise determining the therapeutic effectiveness of the delivery vehicle and the load. In some embodiments, an assay may be utilized to determine the therapeutic effectiveness of the delivery vehicles provided herein. In some embodiments, the assay may be performed before, during, and/or after administration of the subject delivery vehicle. In some embodiments, the determination may be made prior to or after administration, e.g., day-30, -15, -7, -3, 0, 3, 5, 7, 10, 14, 18, 20, 24, 30, 35, 40, 50, 55, 60, 80, 100, 150, 250, 360 days, 2 years, 5 years, or 10 years. Suitable assays may be in vivo or ex vivo. In some embodiments, the determining comprises scanning. Suitable scans may include CT, PET, MRI, or a combination thereof. In some embodiments, the assay comprises an in vitro assay, such as histology, serology, sequencing, ELISA, microscopy, and the like.
In some embodiments, additional procedures may be performed on the subject receiving the delivery vehicle. In some embodiments, the subject may receive procedures such as blood transfusion, blood drawing, computed Tomography (CT), magnetic Resonance Imaging (MRI), X-ray, radiation therapy, organ transplantation, and any combination thereof. In some embodiments, an assessment of a lesion, such as a cancerous lesion, may be performed.
In some embodiments, proteins and/or proteins encoded by nucleic acid compounds contained within a lipid structure may be measured and quantified. In some embodiments, the modified cells may be isolated and western blotted to determine the presence and relative amount of protein production as compared to the unmodified cells. In some embodiments, intracellular staining of proteins may be performed using flow cytometry to determine the presence and relative amounts of protein production. In some embodiments, additional assays may also be performed to determine whether a protein, such as an APC, is functional. In some embodiments, cytoplasmic β -catenin expression of modified cells expressing APC transgenes can be measured and compared to unmodified cells. In some embodiments, reduced expression of β -catenin in the cytosol of the modified cell as compared to the unmodified cell may be indicative of a functional APC transgene. In some embodiments, a murine model of FAP can be used to determine the function of a transgene encoding an APC protein. In some embodiments, mice with FAP can be treated with modified cells encoding APC, and the reduction in FAP disease measured relative to untreated mice.
Effective amount of
In some embodiments, an effective amount of a structure may mean an amount sufficient to increase the expression level of at least one gene, which may be reduced in a subject prior to treatment; or an amount sufficient to alleviate one or more symptoms of cancer. For example, the effective amount may be an amount sufficient to increase the expression level of at least one gene selected from the group consisting of a gastrointestinal differentiation gene, a cell cycle inhibitor gene, and a tumor inhibitor gene by at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 200%, 300%, 400%, 500%, 1000%, 1500% or more compared to a reference value or an expression level not treated with any compound.
In some embodiments, an effective amount may mean an amount sufficient to reduce the expression level of at least one gene, which expression level may be increased in a subject prior to treatment; or an amount sufficient to alleviate one or more symptoms of cancer. For example, an effective amount may be an amount sufficient to reduce the expression level of a gene by at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 200%, 300%, 400%, 500%, 1000%, 1500% or more compared to a reference value or an expression level not treated with any compound.
In some embodiments, the treatment comprises at least about a 1-fold, 5-fold, 10-fold, 20-fold, 40-fold, 80-fold, 100-fold, 300-fold, 600-fold, or 1000-fold reduction in disease in a subject in need thereof, as measured by an in vitro or in vivo assay, as compared to a similar subject not administered. In one aspect, the reduction in disease may be the result of an increase or decrease in the expression level of at least one gene in the subject. Various gene expression assays may be utilized, including but not limited to sequencing, PCR, RT-PCR, western blotting, northern blot, ELISA, protein quantification, mRNA quantification, FISH, RNA-Seq, SAGE, or combinations thereof. Additional assays that may be utilized include microscopy, histology, in vivo animal experiments, human experiments, or any combination thereof.
In some embodiments, an assay may be utilized to determine the therapeutic effectiveness of the delivery vehicles provided herein. In some embodiments, the assay may be performed before, during, and/or after administration of the subject delivery vehicle. In some embodiments, the determination may be made prior to or after administration, e.g., day-30, -15, -7, -3, 0, 3, 5, 7, 10, 14, 18, 20, 24, 30, 35, 40, 50, 55, 60, 80, 100, 150, 250, 360 days, 2 years, 5 years, or 10 years. In some embodiments, the appropriate assay may be in vivo or ex vivo. In some embodiments, the determining comprises scanning. Suitable scans may include CT, PET, MRI, or a combination thereof. In some embodiments, the assay comprises an in vitro assay, such as histology, serology, sequencing, ELISA, microscopy, and the like.
Exemplary delivery vehicles for use in methods
In some embodiments, the methods described herein can utilize any of the delivery vehicles or pharmaceutical compositions disclosed herein. For example, suitable delivery vehicles include part II of the present disclosure or all those described in table 1B.
In some embodiments of the method, the nanoparticle may include at least one cationic lipid; at least one structural lipid; at least one bile salt; and at least one conjugated lipid conjugated to a hydrophilic polymer (e.g., PEG). In some embodiments of the method, the bile salt may be selected from one or more of deoxycholate, lithocholate, isophthalate, allopsocholate, dehydrolithocholate, xiong Erchun, 5β -cholanic acid, chenodeoxycholate, cholate, taurodeoxycholate, tauxe deoxycholate, glycocholate, 3-oxo-cholanic acid, and porcine deoxycholate. In some embodiments of the method, bile salts may be included in the nanoparticle at a level of about 5 to about 40 mole percent of the total nanoparticle lipid (e.g., about 20 to about 40 or about 33 to about 37 mole percent of the total nanoparticle lipid). In some embodiments of the method, the nanoparticle bile salt may comprise deoxycholate and/or lithocholate. In some embodiments of the method, the nanoparticle may comprise two bile salts. In some embodiments of the method, the nanoparticle may include deoxycholate at a level of about 20 to about 30 mole% of the total nanoparticle lipid and lithocholate at a level of about 5 to about 10 mole% of the total nanoparticle lipid. In some embodiments of the method, the nanoparticle cationic lipid can comprise MVL5. In some embodiments of the method, MVL5 may be present at a level of about 5 to about 20 mole% of the total nanoparticle lipid. In some embodiments of the method, the nanoparticle cationic lipid may include one or more of MC2, CL1H6, and CL4H6 and each may be present at a level of about 5 to about 20 mole% of the total nanoparticle lipid. In some embodiments of the method, the nanoparticle structured lipid may comprise one or more of DSPC and DMPC and each may be present at a level of about 35 to about 45 mole% of the total nanoparticle lipid. In some embodiments of the method, the nanoparticle conjugated lipid may be conjugated to a hydrophilic polymer. In some embodiments of the method, the hydrophilic polymer may comprise PEG. In some embodiments of the method, the conjugated lipid may include one or more of DMG-PEG and DMPE-PEG and may be present at a level of about 0.5 to about 2.0 mole% of the total nanoparticle lipid.
VIII definition of
As used herein, the singular forms "a", "an" and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise. Furthermore, if the terms "include," have, "" with, "or variants thereof are used in the detailed description and/or claims, such terms are intended to be inclusive in a manner similar to the term" comprising. The term "about" or "approximately" may mean within an acceptable error range for a particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, e.g., limitations of the measurement system. For example, "about" may mean within ±10% of a given value. When a particular value is described in the application and claims, the term "about" should be assumed to mean an acceptable error range for the particular value unless otherwise specified.
Substituents or properties of the compounds of the present disclosure are disclosed in groups or ranges at different positions of the disclosure. It is expressly intended that the present disclosure includes each individual or subcombination of the members of these groups and ranges.
Unless otherwise indicated, the following terms and phrases have the meanings described below. These definitions are not meant to be limiting in nature and are intended to provide a clearer understanding of certain aspects of the present disclosure.
The term "about" and grammatical equivalents thereof as used herein in relation to a reference number and grammatical equivalents thereof may include a range of values plus or minus 10% from the value. For example, an amount of "about 10" includes an amount from 9 to 11. The term "about" in relation to a reference value may also include a range of values from plus or minus 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% of that value.
Active ingredients: the terms "active ingredient", "therapeutic agent" and "therapeutic ingredient" refer to components of a pharmaceutical composition having biological activity, such as cannabinoids.
And (3) application: the term "administering" and grammatical equivalents thereof may refer to any method by which a subject provides a structure described herein. Such methods are well known to those skilled in the art and include, but are not limited to, oral administration, transdermal administration, inhalation administration, nasal administration, topical administration, intravaginal administration, ocular administration, intra-aural administration, intra-brain administration, rectal administration, and parenteral administration, including injections, such as intravenous administration, intra-arterial administration, intramuscular administration, and subcutaneous administration. Administration may be continuous or intermittent. In various aspects, the structures disclosed herein can be administered therapeutically. In some cases, the structure may be administered to treat an existing disease or condition. In further various aspects, the structure may be administered prophylactically to prevent a disease or condition.
Adjuvants: the term "adjuvant" as used herein refers to any substance or combination of substances used to increase the efficacy or potency of another drug.
About: the term "about" or "approximately" as used herein, when applied to one or more target values, refers to values similar to the stated reference values. The term "about" as used herein refers to +/-10% of the value. In certain embodiments, the term "about" refers to a range of values that fall within 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or less in either direction (greater or less) of the stated reference value unless stated otherwise or apparent from the context (unless such numbers would exceed 100% of the possible values).
Biodegradable: the term "biodegradable" and grammatical equivalents thereof may refer to polymers, compositions, and formulations, such as those described herein that are intended to degrade during use. The term "biodegradable" is intended to encompass materials and processes also referred to as "bioerodible".
Cancer: the term "cancer" and grammatical equivalents thereof as used herein may refer to the hyperproliferation of cells whose unique characteristics (loss of normal control) result in unregulated growth, lack of differentiation, localized tissue invasion and metastasis. With respect to the methods of the invention, the cancer may be any cancer, including any of the following: acute lymphocytic carcinoma, acute myeloid leukemia, acinar rhabdomyosarcoma, bladder carcinoma, bone cancer, brain cancer, breast cancer, anal canal cancer, rectal cancer, eye cancer, intrahepatic bile duct cancer, joint cancer, neck cancer, gall bladder cancer or pleural cancer, nasal cancer or middle ear cancer, oral cancer, vulval cancer, chronic lymphocytic leukemia, chronic myeloid cancer, colon cancer, esophageal cancer, cervical cancer, fibrosarcoma, gastrointestinal carcinoid tumor, hodgkin's lymphoma, hypopharyngeal cancer, kidney cancer, laryngeal cancer, leukemia, liquid tumor, liver cancer, lung cancer, lymphoma, malignant mesothelioma, mast cell tumor, melanoma, multiple myeloma, nasopharyngeal cancer, non-hodgkin's lymphoma, ovarian cancer, pancreatic cancer, peritoneal cancer, omentum cancer, mesenteric cancer, pharyngeal cancer, prostate cancer, rectal cancer, renal cancer, skin cancer, small intestine cancer, soft tissue cancer, solid tumor, stomach cancer, testicular cancer, thyroid cancer, ureteral cancer and/or carcinoma. The term "tumor" as used herein refers to abnormal growth of cells or tissues, such as malignant or benign types.
Load: the term "load" as used herein may refer to one or more molecules or structures contained in a delivery vehicle for delivery to or into a cell or tissue. Non-limiting examples of the loading may include nucleic acids, dyes, drugs, proteins, liposomes, chemical small molecules, biological macromolecules, and any combination thereof.
And (3) cells: the term "cell" and grammatical equivalents thereof as used herein may refer to structural and functional units of an organism. The size of the cells may be microscopic and may consist of cytoplasm and nuclei encapsulated in a membrane. The cells may be referred to as intestinal crypt cells. Crypt cells may be referred to as Li Baqu Encrypts (crypts of Lieberk. U. Hn), which are pit-like structures surrounding the basal portion of villi in the intestine. The cells may be of human or non-human origin.
Conjugate: the term "conjugate" as used herein may refer to covalent or non-covalent binding of two or more molecules or structures, including but not limited to binding of a peptide, such as a Mucus Penetrating Peptide (MPP), to a delivery vehicle, polymer, surface modification, or any combination thereof.
The functions are as follows: the term "functional" and grammatical equivalents thereof as used herein may refer to the ability to operate, have, or serve an intended purpose. The function may include any percentage of 100% from baseline to the intended purpose. For example, the functionality may comprise or include about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or up to about 100% of the intended purpose. In some embodiments, the term functional may mean more than or more than about 100% of normal function, e.g., 125%, 150%, 175%, 200%, 250%, 300%, 400%, 500%, 600%, 700%, or up to about 1000% of the intended purpose.
Gastrointestinal disease: the term "gastrointestinal disease" as used herein may refer to diseases involving the gastrointestinal tract (including but not limited to the esophagus, stomach, small intestine, large intestine, and rectum), and digestive organs, liver, gall bladder, and pancreas, and any combination thereof.
Hydrophilicity: the term "hydrophilic" and grammatical equivalents thereof as used herein refers to substances or structures having polar groups that readily interact with water.
Hydrophobicity: the term "hydrophobic" and grammatical equivalents thereof as used herein refers to a substance or structure having polar groups that do not readily interact with water.
Mucus: the term "mucus" and grammatical equivalents thereof as used herein may refer to viscoelastic natural materials that contain primarily mucin glycoproteins and other materials that protect the epithelial surfaces of various organs/tissues, including but not limited to the respiratory system, nose, cervical vagina, gastrointestinal, rectal, visual and auditory systems.
Lipid structure: the term "lipid structure" as used herein refers to a lipid composition for delivery to a cell or tissue, e.g., for delivery of a therapeutic product, e.g., a nucleic acid. The term "lipid structure" and grammatical equivalents thereof as used herein may refer to nanoparticles or delivery vehicles. The structure may be a liposome structure. The structure may be a lipid nanoparticle. Lipid structure may also be referred to as particles. The lipid structure or particle may be a nanoparticle or a delivery vehicle. The lipid particle or lipid structure may be any shape having a diameter of about 1nm up to about 1 micron. The nanoparticle or nanostructure may be or may be about 100 to 200nm. Nanoparticles or nanostructures may also be up to 500nm. Nanoparticles or nanostructures having a spherical shape may be referred to as "nanospheres".
The structure is as follows: the term "structure" and grammatical equivalents thereof as used herein may refer to a nanoparticle or a delivery vehicle. The structure may be a liposome structure. The structure may also be referred to as particles. The structure or particle may be a nanoparticle or a delivery vehicle. The particles or structures may be any shape having a diameter of about 1nm up to about 1 micron. The nanoparticle or nanostructure may be or may be about 100 to 200nm. Nanoparticles or nanostructures may also be up to 500nm. Nanoparticles or nanostructures having a spherical shape may be referred to as "nanospheres".
Nucleic acid: the term "nucleic acid" refers to any compound comprising a nucleic acid. The terms "Nucleic acid", "polynucleotide" and "oligonucleotide" and grammatical equivalents thereof may be used interchangeably and may refer to polymers of deoxyribonucleotides and/or ribonucleotides in either linear or circular conformation and in either single-or double-stranded form. For the purposes of this disclosure, these terms should not be construed as limiting in length. The term may also encompass known analogues of natural nucleotides, as well as nucleotides that are modified in the base, sugar and/or phosphate moieties (e.g., phosphorothioate backbones). In general, analogs of a particular nucleotide can have the same base pairing specificity, i.e., analogs of adenine "A" can base pair with thymine "T".
Pharmaceutically acceptable: the term "pharmaceutically acceptable" as used herein refers to compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
A pharmaceutically acceptable carrier: the term "pharmaceutically acceptable carrier" and grammatical equivalents thereof may refer to sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, as well as sterile powders for reconstitution into sterile injectable solutions or dispersions immediately prior to use. For example, proper fluidity can be maintained, for example, by the use of a coating material such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants. These solutions, dispersions, suspensions or emulsions may also contain adjuvants such as preserving, wetting, emulsifying and dispersing agents. By containing various antibacterial and antifungal agents, such as parahydroxybenzoate, chlorobutanol, phenol, sorbic acid, and the like, the prevention of the action of microorganisms can be ensured. It may also be desirable to include isotonic agents, for example, sugars, sodium chloride, and the like. The absorption of injectable pharmaceutical forms may be prolonged by the inclusion of delayed absorbents, such as aluminum monostearate and gelatin. Injectable depot forms are prepared by forming a microencapsulated matrix of the drug in biodegradable polymers such as polylactide-polyglycolide, poly (orthoesters) and poly (anhydrides). The term "pharmaceutically acceptable carrier" may refer to any excipient (e.g., carrier), adjuvant, or diluent that is capable of suspending, dissolving, encapsulating, or otherwise carrying the active ingredient in a formulation. Pharmaceutically acceptable carriers can act to improve the selectivity, effectiveness, and/or delivery safety of the active ingredient.
Pharmaceutical composition: the term "pharmaceutical composition" as used herein refers to a composition (e.g., a formulation mixture) comprising at least one active ingredient (e.g., a cannabinoid) and at least one pharmaceutically acceptable carrier or excipient.
Susceptibility to: the term "susceptible" as used herein may be understood to mean an increase in the probability that a subject will have a disease or condition (e.g., an increase in probability of at least 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200% or more).
Purified, purified: the terms "purified," "purifying," and grammatical equivalents thereof as used herein are intended to mean substantially pure or free of unwanted components, material contamination, mixtures, or imperfections. "purified" refers to a pure state. "purification" refers to the process of becoming pure.
Subjects, patients and individuals: the term "subject," "patient," or "individual" as used herein refers to any organism to which a composition according to the present disclosure may be administered for example for experimental, diagnostic, prophylactic, and/or therapeutic purposes. Typical subjects include animals (e.g., mammals such as mice, rats, rabbits, non-human primates, and humans) and/or plants. The subject or patient may seek or need treatment for a particular disease or condition, require treatment, be receiving treatment, or be receiving the care of a trained professional. The terms "individual," "patient," or "subject" are used interchangeably. None of these terms require or are limited to cases characterized by supervision (e.g., continuous or intermittent) by a medical practitioner (e.g., doctor, registry nurse, practitioner assistant, care worker, or end care worker). The subject may be a mammal. The subject may be a human male or a human female. The subject may have any age. The subject may be an embryo. The subject may be a neonate or up to about 100 years old. The subject may need it. The subject may have a disease such as cancer.
Sequence: the term "sequence" and grammatical equivalents thereof as used herein may refer to a nucleotide sequence that may be DNA and/or RNA; may be linear, circular or branched; and may be single-stranded or double-stranded. The sequence may have any length, e.g., from 2 to 1,000,000 nucleotides or more in length (or any integer value therebetween or above), e.g., from about 100 to about 10,000 nucleotides or from about 200 to about 500 nucleotides. In some cases, the indicated "sequence" as used herein may refer to an amino acid sequence, such as a sequence of a protein, polypeptide, and/or peptide.
Stem cells: the term "stem cell" as used herein may refer to an undifferentiated cell of a multicellular organism that is capable of producing an unlimited number of cells of the same type. Stem cells can also be differentiated to produce other types of cells. Stem cells can be found in crypts. The stem cells may be progenitor cells of epithelial cells found on the intestinal villus surface. Stem cells may be cancerous. Stem cells may be totipotent, unipotent or pluripotent. The stem cells may be induced stem cells.
Therapeutically effective amount and effective amount: the terms "therapeutically effective amount" and "effective amount" as used herein refer to any amount of an active ingredient that, when administered to a subject, can cause a desired effect (e.g., clinical outcome). The effective amount may be determined based on considerations known in the art, and one skilled in the art will recognize that the effective amount may depend on a variety of factors including: in vivo profiles, various pharmacological parameters (e.g., in vivo half-life), undesirable side effects (if any), age and sex, and other factors, among others.
Treatment: the term "treatment" and grammatical equivalents thereof as used herein refers to the partial or complete alleviation, amelioration, alleviation of one or more symptoms or characteristics of a particular infection, disease, disorder, and/or condition, delay of its onset, inhibition of its progression, reduction of its severity, and/or reduction of its incidence. Examples of treatments may include, but are not limited to: improving undesired symptoms associated with the disease, preventing their manifestation before the occurrence of such symptoms, slowing the progression of the disease, slowing the worsening of the symptoms, enhancing the onset of remission, slowing the irreversible damage caused by the progressive chronic phase of the disease, slowing the onset of said progressive phase, lessening the severity of the disease or curing the disease, increasing survival or faster recovery, preventing the occurrence of the disease, or a combination thereof. Treatment may be administered to subjects that do not exhibit signs of a disease, disorder, and/or condition and/or subjects that exhibit only early signs of a disease, disorder, and/or condition to reduce the risk of developing pathology associated with the disease, disorder, and/or condition.
Transfection efficiency: in some embodiments, the delivery vehicle employed may contain a load that is delivered to the target cell, for example, for expression in the cell and/or genetic modification of the target cell. The efficiency of such delivery (e.g., transfection) with a load (polynucleic acid as described herein) may be, for example, or may be, about 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or more than 99.9% of the total number of cells contacted (in vivo or ex vivo) and/or present in a tissue or location. Such delivery (e.g., transfection) with a load (polynucleic acid as described herein) may be, for example, or may be, about 1-fold, 10-fold, 20-fold, 40-fold, 60-fold, 80-fold, 100-fold, 120-fold, 140-fold, 160-fold, 180-fold, 200-fold, 300-fold, 400-fold, 500-fold, or more than 1000-fold of the total number of cells contacted (in vivo or ex vivo) and/or present in a tissue or location.
And (3) a carrier: the term "carrier" as used herein refers to any substance that is combined with an active ingredient to facilitate administration.
"hydrogen" when used in the context of chemical groups means-H; "hydroxy" refers to-OH; "halogen" independently refers to-F, -Cl, -Br or-I;
for the structures provided herein, the following subscripts in parentheses further define the group as follows: "(C) n ) "defines the exact number of carbon atoms (n) in the group. For example, "(C) 2-10 ) Alkyl groups represent those alkyl groups having 2 to 10 carbon atoms (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10, or any range derivable therein (e.g., 3 to 10 carbon atoms).
"alkyl" may refer to an aliphatic hydrocarbon group. The alkyl moiety may be a "saturated alkyl" meaning that it does not contain any alkene or alkyne moieties. The alkyl moiety may also be an "unsaturated alkyl" moiety, meaning that it contains at least one alkene or alkyne moiety. "alkene" moiety refers to a group consisting of at least two carbon atoms and at least one carbon-carbon double bond, and "alkyne" moiety refers to a group consisting of at least two carbon atoms and at least one carbon-carbon triple bond. Alkyl baseThe components, whether saturated or unsaturated, may be branched, straight chain or cyclic. Furthermore, the alkyl moiety, whether saturated or unsaturated, may comprise branched, straight chain, and/or cyclic moieties. The alkyl group may be mono-or di-based (i.e., alkylene) depending on the structure. "heteroalkyl" is as described for "alkyl" wherein at least one C atom is replaced with a N, S or O atom. "heteroalkyl" may include straight, branched, and/or cyclic moieties. In certain embodiments, a "lower alkyl" is an alkyl group having 1 to 6 carbon atoms (i.e., C 1 -C 6 Alkyl). In particular instances, the "lower alkyl" may be straight or branched.
"aryl" refers to a group derived from an aromatic monocyclic or aromatic polycyclic hydrocarbon ring system by removal of a hydrogen atom from a ring carbon atom. An aromatic mono-or polycyclic hydrocarbon ring system contains only hydrogen and carbon and from 5 to 18 carbon atoms, wherein at least one ring of the ring system is aromatic, i.e. it comprises a cyclic delocalized (4n+2) pi-electron system according to Huckel's theory. Ring systems from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetrahydronaphthalene, and naphthalene. In some embodiments, the term "aryl" may refer to an aromatic ring in which each atom forming the ring is a carbon atom. The aryl ring may be formed from five, six, seven, eight, nine or more than nine carbon atoms. Aryl groups may be optionally substituted. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, phenanthryl, anthracyl, fluorenyl, and indenyl. Depending on the structure, the aryl group may be mono-or di-yl (i.e., arylene).
"heteroaryl" refers to a group derived from a 3 to 12 membered aromatic ring group containing twenty-one carbon atoms and at least one heteroatom, wherein each heteroatom may be selected from N, O and S. The heteroaryl ring as used herein may be selected from monocyclic or bicyclic and fused or bridged ring system rings, wherein at least one ring of the ring system is aromatic, i.e. it contains a cyclic, delocalized (4n+2) pi-electron system according to Huckel's theory. The heteroatoms in the heteroaryl group may optionally be oxidized. One or more nitrogen atoms, if present, are optionally quaternized. Heteroaryl groups may be substituted if the valency permits Any atom of the perheteroaryl group (e.g., a carbon or nitrogen atom of the heteroaryl group) is attached to the remainder of the molecule. Examples of heteroaryl groups include, but are not limited to, azetidinyl, acridinyl, benzimidazolyl, benzindolyl, 1, 3-benzobisexylOxazolyl, benzofuranyl, benzo +.>Azolyl and benzo [ d ]]Thiazolyl, benzothiadiazolyl, benzo [ b ]][1,4]Dioxepinyl and benzo [ b ]][1,4]/>Oxazinyl, 1, 4-benzodi->Alkyl, benzonaphthofuranyl, benzo +.>Oxazolyl, benzodioxolyl, benzodioxanyl, benzopyranyl, benzopyronyl, benzofuranyl, benzothienyl (benzothienyl (benzothiophenyl)), benzothieno [3,2-d ]]Pyrimidinyl, benzotriazolyl, benzo [4,6 ]]Imidazo [1,2-a]Pyridyl, carbazolyl, cinnolinyl, cyclopenta [ d ]]Pyrimidinyl, 6, 7-dihydro-5H-cyclopenta [4,5 ]]Thieno [2,3-d ]]Pyrimidinyl, 5, 6-dihydrobenzo [ h ]]Quinazolinyl, 5, 6-dihydrobenzo [ h ]]Cinnolinyl, 6, 7-dihydro-5H-benzo [6,7 ]]Cyclohepta [1,2-c ]]Pyridazinyl, dibenzofuranyl, dibenzothienyl, furyl, furanonyl, furo [3,2-c ]]Pyridyl, 5,6,7,8,9, 10-hexahydrocycloocta [ d ] ]Pyrimidinyl, 5,6,7,8,9, 10-hexahydrocycloocta [ d ]]Pyridazinyl, 5,6,7,8,9, 10-hexahydrocycloocta [ d ]]Pyridyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isojd>Oxazolyl, 5, 8-methylene-5, 6,7, 8-tetrahydroquinazolinyl, naphthyridinyl, 1, 6-naphthyridonyl,Diazolyl, 2-oxo-azetidinyl, < - > or->Oxazolyl, oxiranyl, 5, 6a,7,8,9,10 a-octahydrobenzo [ h ]]Quinazolinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, pheno +.>Oxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyrazolo [3,4-d ]]Pyrimidinyl, pyridinyl, pyrido [3,2-d ]]Pyrimidinyl, pyrido [3,4-d ]]Pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, 5,6,7, 8-tetrahydroquinazolinyl, 5,6,7, 8-tetrahydrobenzo [4,5 ]]Thieno [2,3-d ]]Pyrimidinyl, 6,7,8, 9-tetrahydro-5H-cyclohepta [4,5 ]]Thieno [2,3-d ]]Pyrimidinyl, 5,6,7, 8-tetrahydropyrido [4,5-c ]]Pyridazinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, thieno [2,3-d ] ]Pyrimidinyl, thieno [3,2-d]Pyrimidinyl, thieno [2,3-c]Pyridyl and thienyl (i.e., thienyl)). "X-membered heteroaryl" refers to the number of internal ring atoms in the ring, i.e., X. For example, a 5 membered heteroaryl ring or a 5 membered aromatic heterocycle has 5 inner ring atoms, such as triazole,/->Oxazole, thiophene and the like.
In some embodiments, the term "heteroaryl" when used without a "substituted" modifier refers to a monovalent group having an aromatic carbon atom or nitrogen atom as the point of attachment, said carbon atom or nitrogen atom forming part of an aromatic ring structure, wherein at least one ring atom is nitrogen, oxygen or sulfur, and wherein the monovalent group is not formed by a group other than carbon, hydrogen, aromatic nitrogen, aromatic oxygen and aromatic sulfurAtomic composition of (a). Non-limiting examples of heteroaryl groups include acridinyl, furyl, imidazoimidazolyl, imidazopyrazolyl, imidazopyridyl, imidazopyrimidinyl, indolyl, indazolyl, picolyl, pyrrolyl, and pyrrolyl,Oxazolyl, phenylimidazolyl, pyridinyl, pyrrolyl, pyrimidinyl, pyrazinyl, quinolinyl, quinazolinyl, quinoxalinyl, tetrahydroquinolinyl, thienyl, triazinyl, pyrrolopyridinyl, pyrrolopyrimidinyl, pyrrolopyrazinyl, pyrrolotriazinyl, pyrroloimidazolyl, chromene (wherein the point of attachment is one of the aromatic atoms) and chromen (wherein the point of attachment is one of the aromatic atoms). Substituted heteroaryl refers to a monovalent group having an aromatic carbon atom or nitrogen atom as a point of attachment that forms part of an aromatic ring structure, wherein at least one ring atom is nitrogen, oxygen, or sulfur, and wherein the monovalent group also has at least one atom independently selected from the group consisting of non-aromatic nitrogen, non-aromatic oxygen, non-aromatic sulfur, F, cl, br, I, si, and P.
Substituted: the term "substituted" refers to a moiety having a substituent that displaces hydrogen on one or more carbons of the structure or on a substitutable heteroatom (e.g., NH). It is to be understood that "substitution" or "substitution by … …" includes implicit conditions that such substitution is in accordance with the permissible valences of the atoms and substituents to be substituted, and that the substitution results in stable compounds, i.e., compounds that do not spontaneously undergo transformation, e.g., by rearrangement, cyclization, elimination, and the like. In certain embodiments, substituted refers to a moiety having a substituent that replaces two hydrogen atoms on the same carbon atom, such as replacing two hydrogen atoms on a single carbon with oxo, imino, or thio. The term "substituted" as used herein is intended to include all permissible substituents of organic compounds. In a broad aspect, permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. For suitable organic compounds, the permissible substituents can be one or more and the same or different. For the purposes of this disclosure, heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms.
In some embodiments, substituents may include any of the substituents described herein, for example: halogen, hydroxy, oxo (= O), thio (= S), cyano (-CN), nitro (-NO) 2 ) Imino (=n-H), oxime (=n-OH), hydrazine (=n-NH) 2 )、-R b -OR a 、-R b -OC(O)-R a 、-R b -OC(O)-OR a 、-R b -OC(O)-N(R a ) 2 、-R b -N(R a ) 2 、-R b -C(O)R a 、-R b -C(O)OR a 、-R b -C(O)N(R a ) 2 、-R b -O-R c -C(O)N(R a ) 2 、-R b -N(R a )C(O)OR a 、-R b -N(R a )C(O)R a 、-R b -N(R a )S(O) t R a (wherein t is 1 or 2), -R b -S(O) t R a (wherein t is 1 or 2), -R b -S(O) t OR a (wherein t is 1 or 2) and-R b -S(O) t N(R a ) 2 (wherein t is 1 or 2); and alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl, any of which may be optionally substituted with: alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (=o), thio (=s), cyano (-CN), nitro (-NO 2 ) Imino (=n-H), oxime (=n-OH), hydrazine (=n-NH) 2 )、-R b -OR a 、-R b -OC(O)-R a 、-R b -OC(O)-OR a 、-R b -OC(O)-N(R a ) 2 、-R b -N(R a ) 2 、-R b -C(O)R a 、-R b -C(O)OR a 、-R b -C(O)N(R a ) 2 、-R b -O-R c -C(O)N(R a ) 2 、-R b -N(R a )C(O)OR a 、-R b -N(R a )C(O)R a 、-R b -N(R a )S(O) t R a (wherein t is 1 or 2), -R b -S(O) t R a (wherein t is 1 or 2), -R b -S(O) t OR a (wherein t is 1 or 2) and-R b -S(O) t N(R a ) 2 (wherein t is 1 or 2); wherein each R is a Independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, wherein each R a Optionally substituted, where valence permits, with: alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (=o), thio (=s), cyano (-CN), nitro (-NO 2 ) Imino (=n-H), oxime (=n-OH), hydrazine (=n-H) 2 )、-R b -OR a 、-R b -OC(O)-R a 、-R b -OC(O)-OR a 、-R b -OC(O)-N(R a ) 2 、-R b -N(R a ) 2 、-R b -C(O)R a 、-R b -C(O)OR a 、-R b -C(O)N(R a ) 2 、-R b -O-R c -C(O)N(R a ) 2 、-R b -N(R a )C(O)OR a 、-R b -N(R a )C(O)R a 、-R b -N(R a )S(O) t R a (wherein t is 1 or 2), -R b -S(O) t R a (wherein t is 1 or 2), -R b -S(O) t OR a (wherein t is 1 or 2) and-R b -S(O) t N(R a ) 2 (wherein t is 1 or 2); and wherein each R b Independently selected from direct bond or straight or branched alkylene, alkenylene or alkynylene chain, and each R c Is a straight or branched alkylene, alkenylene or alkynylene chain.
IX. equivalents and scope
Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the disclosure described herein. The scope of the present disclosure is not intended to be limited to the above description, but rather is as set forth in the appended claims.
In the claims, articles such as "a," "an," and "the" may mean one or more than one, unless indicated to the contrary or otherwise apparent from the context. If one, more than one, or all members of a group are present in, used in, or otherwise associated with a given product or process, then the claim or description containing an "or" between one or more members of the group is deemed satisfied unless indicated to the contrary or otherwise apparent from the context. The present disclosure encompasses embodiments in which exactly one member of a group is present in, used in, or otherwise associated with a given product or process. The present disclosure encompasses embodiments in which more than one or all of the group members are present in, used in, or otherwise associated with a given product or process.
It should also be noted that the term "comprising" is intended to be open-ended and allows for, but does not require, the inclusion of additional elements or steps. When the term "comprising" is used herein, the term "consisting of … …" is also hereby encompassed and disclosed.
Where ranges are given, endpoints are included. Furthermore, it is to be understood that unless otherwise indicated or otherwise evident from the context and understanding of one of ordinary skill in the art, values expressed as ranges may employ any particular value or subrange within the ranges described in the various embodiments of the disclosure, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise.
Furthermore, it should be understood that any particular embodiment of the present disclosure that falls within the scope of the prior art may be explicitly excluded from any one or more of the claims. Since such embodiments are considered to be known to those of ordinary skill in the art, they may be excluded even if the exclusion is not set forth explicitly herein. Any particular embodiment of a composition of the present disclosure (e.g., any antibiotic, therapeutic or active ingredient, any method of manufacture, any method of use, etc.) may be excluded from any one or more claims for any reason, whether or not related to the presence of the prior art.
It is to be understood that the words which have been used are words of description rather than limitation, and that changes may be made within the scope of the appended claims without departing from the true scope and spirit of the disclosure in its broader aspects.
Although the present disclosure has been described with a certain length and some particularity with respect to several described embodiments, it is not intended to be limited to any such details or embodiments or any particular embodiment, but rather should be construed by reference to the appended claims in order to provide the broadest possible interpretation of such claims in light of the prior art and, therefore, to effectively cover the intended scope of the disclosure.
All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. In addition, the section headings, materials, methods, and examples are illustrative only and not intended to be limiting.
X. incorporated by reference
All publications, patents, and patent applications herein are incorporated by reference in their entirety to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. In the event that a term herein conflicts with a term in the incorporated reference, then the term herein controls.
XI. Exemplified embodiment
Embodiment 1. A composition comprising: a load; and a nanoparticle comprising: at least one bile salt; at least one cationic lipid; at least one structural lipid; and at least one conjugated lipid, wherein the conjugated lipid is conjugated to a hydrophilic polymer.
Embodiment 2. The composition of embodiment 1 wherein the at least one bile salt is selected from one or more of deoxycholate, lithocholate, isophthalate, allopsocholate, dehydrolithocholate, xiong Erchun, 5β -cholanic acid, chenodeoxycholate, cholate, taurodeoxycholate, taurochenodeoxycholate, glycocholate, 3-oxo-cholanic acid, and porcine deoxycholate.
Embodiment 3. The composition of embodiment 1 or 2, wherein the at least one bile salt is included in the nanoparticle at a level of about 5 to about 40 mole% of the total nanoparticle lipid.
Embodiment 4. The composition of embodiment 3, wherein the at least one bile salt is included in the nanoparticle at a level of about 20 to about 40 mole% of the total nanoparticle lipid.
Embodiment 5. The composition of embodiment 4, wherein the at least one bile salt is included in the nanoparticle at a level of about 33 to about 37 mole% of the total nanoparticle lipid.
Embodiment 6. The composition of any of embodiments 1-5, wherein the at least one bile salt comprises deoxycholate.
Embodiment 7. The composition of any of embodiments 1-6, comprising two bile salts.
Embodiment 8. The composition of embodiment 7 wherein at least one of the two bile salts comprises a lithocholic acid salt.
Embodiment 9. The composition of embodiment 8, comprising: deoxycholate at a level of about 20 to about 30 mole% of the total nanoparticle lipid; and a level of lithocholic acid salt of about 5 to about 10 mole% of the total nanoparticle lipids.
Embodiment 10. The composition of any of embodiments 1-9 wherein the at least one cationic lipid comprises N1- [2- ((1S) -1- [ (3-aminopropyl) amino ] -4- [ bis (3-amino-propyl) amino ] butylcarboxamido) ethyl ] -3, 4-bis [ oleyloxy ] -benzamide (MVL 5).
Embodiment 11. The composition of embodiment 10 wherein the MVL5 is present at a level of about 5 to about 20 mole% of the total nanoparticle lipid.
Embodiment 12. The composition of any of embodiments 1-11, wherein the at least one cationic lipid comprises (6 z,9z,28z,31 z) -seventeen carbon-6,9,28,31-tetraen-19-yl 3- (dimethylamino) propionate (MC 2); 7- (4- (dimethylamino) butyl) -7-hydroxytridecane-1, 13-diyldioleate (CL 1H 6); and 7- (4- (diisopropylamino) butyl) -7-hydroxytridecane-1, 13-diyldioleate (CL 4H 6).
Embodiment 13. The composition of embodiment 12, wherein each of the at least one cationic lipid is present at a level of about 5 to about 20 mole% of the total nanoparticle lipids.
Embodiment 14. The composition of any of embodiments 1-13 wherein the at least one structural lipid is selected from one or more of 1, 2-distearoyl-sn-glycero-3-phosphorylcholine (DSPC) and 1, 2-dimyristoyl-sn-glycero-3-phosphorylcholine (DMPC).
Embodiment 15. The composition of embodiment 14, wherein the at least one structural lipid is present at a level of about 35 to about 45 mole% of the total nanoparticle lipids.
Embodiment 16. The composition of any of embodiments 1-15 wherein the hydrophilic polymer comprises polyethylene glycol (PEG).
Embodiment 17 the composition of embodiment 16 wherein the at least one conjugated lipid is selected from one or more of 1, 2-dimyristoyl-rac-glycerol (DMG) -PEG and 1, 2-dimyristoyl-sn-glycero-3-phosphoethanolamine (DMPE) -PEG.
Embodiment 18. The composition of embodiment 17, wherein the at least one conjugated lipid is present at a level of about 0.5 to about 2.0 mole% of the total nanoparticle lipid.
Embodiment 19. The composition of embodiment 1, comprising, in molar ratios between the components: about 1 to about 5 of at least one bile salt, about 0.5 to about 3 of at least one cationic lipid, about 2 to about 10 of at least one structural lipid, and about 0.02 to about 0.10 of at least one conjugated lipid.
Embodiment 20. The composition of embodiment 19, wherein the at least one bile salt is selected from one or more of deoxycholate, xiong Erchun, lithocholate, isophthalate, allophanate, dehydrolithocholate, and 5 β -cholanic acid.
Embodiment 21. The composition of embodiments 19 or 20, wherein the at least one cationic lipid comprises MVL5.
Embodiment 22. The composition of any of embodiments 19-21 wherein the at least one cationic lipid comprises MC2.
Embodiment 23. The composition of any of embodiments 19-22 wherein the at least one structural lipid comprises DSPC.
Embodiment 24 the composition of any one of embodiments 19-23, wherein the at least one conjugated lipid comprises DMG-PEG.
Embodiment 25. The composition of any of embodiments 19-24 comprising at least one bile salt, MVL5, MC2, DSPC, and DMG-PEG in a molar ratio of about 2.592:0.96:0.96:3.168:0.768.
Embodiment 26 the composition of embodiment 25 wherein the at least one bile salt is deoxycholate.
Embodiment 27. The composition of embodiment 1 wherein the nanoparticle comprises: MVL5, MC2, DSPC, deoxycholate, and DMPE-PEG in a molar ratio of about 2.4:2.4:7.9:6.48:0.192; MVL5, CL1H6, DSPC, deoxycholate, and DMG-PEG at a molar ratio of about 2.4:2.4:7.9:6.48:0.192; MVL5, CL4H6, DSPC, deoxycholate, and DMG-PEG at a molar ratio of about 2.4:2.4:7.9:6.48:0.192; MVL5, MC2, DSPC, chenodeoxycholate, and DMG-PEG in a molar ratio of about 2.4:2.4:7.9:6.48:0.192; MVL5, MC2, DMPC, deoxycholate, and DMG-PEG in a molar ratio of about 2.4:2.4:7.9:6.48:0.192; MVL5, MC2, DMPC, deoxycholate, and DMPE-PEG in a molar ratio of about 2.4:2.4:7.9:6.48:0.192; MVL5, CL1H6, DMPC, deoxycholate, and DMG-PEG in a molar ratio of about 2.4:2.4:7.9:6.48:0.192; MVL5, MC2, DSPC, deoxycholate, lithocholate, and DMG-PEG in a molar ratio of about 2.4:2.4:7.9:5.2:1.3:0.192; MVL5, CL1H6, DSPC, deoxycholate, lithocholate, and DMG-PEG in a molar ratio of about 2.4:2.4:7.9:5.2:1.3:0.192; MVL5, MC2, DSPC, allophanate and DMG-PEG in a molar ratio of about 2.4:2.4:7.92:6.48:0.192; or MVL5, MC2, DSPC, dehydrolithocholic acid salt, and DMG-PEG in a molar ratio of about 2.4:2.4:7.92:6.48:0.192.
Embodiment 28. A composition as in embodiment 1 comprising 12.4 mole% MVL5, 12.4 mole% MC2, 40.8 mole% DSPC, 33.4 mole% of at least one bile salt, and 1 mole% of at least one conjugated lipid.
Embodiment 29. The composition of embodiment 28, wherein the at least one conjugated lipid is DMG-PEG or DMPE-PEG.
Embodiment 30 the composition of embodiment 28 or 29, wherein the at least one bile salt is selected from one or more of taurodeoxycholate, taurochenodeoxycholate, glycocholate, 3-oxo-cholanic acid, and deoxycholate.
Embodiment 31 the composition of any one of embodiments 1-30, wherein the cargo comprises one or more of a nucleic acid, a protein, an antibody, a peptide, a small molecule, a biologic, a peptidomimetic, a ribozyme, a chemical agent, a viral particle, a growth factor, a cytokine, an immunomodulator, and a fluorescent dye.
Embodiment 32. The composition of embodiment 31, wherein the load comprises a nucleic acid.
Embodiment 33. The composition of embodiment 32, wherein the nucleic acid comprises DNA.
Embodiment 34. The composition of embodiment 33, wherein the DNA comprises plasmid DNA.
Embodiment 35. A composition comprising: a load; and a nanoparticle comprising: a first cationic lipid comprising CL1H6 or CL4H6; optionally a second cationic lipid; at least one bile salt; at least one structural lipid; and at least one conjugated lipid, wherein the at least one conjugated lipid is conjugated to a hydrophilic polymer.
Embodiment 36 the composition of embodiment 35, wherein the at least one bile salt is selected from one or more of deoxycholate, lithocholic acid salt, isophthalate, allopsocholate, dehydrolithocholate, xiong Erchun, 5β -cholanic acid, chenodeoxycholate, cholate, taurodeoxycholate, taurochenodeoxycholate, glycocholate, 3-oxo-cholanic acid, and porcine deoxycholate.
Embodiment 37 the composition of embodiment 35 or 36, wherein the at least one bile salt is included in the nanoparticle at a level of about 5 to about 40 mole% of the total nanoparticle lipid.
Embodiment 38 the composition of embodiment 37, wherein the at least one bile salt is included in the nanoparticle at a level of about 20 to about 40 mole% of the total nanoparticle lipid.
Embodiment 39 the composition of any one of embodiments 35-38, wherein the at least one bile salt comprises deoxycholate.
Embodiment 40. The composition of any of embodiments 35-39 wherein the first cationic lipid comprises about 5 to about 40 mole% of the total nanoparticle lipid.
Embodiment 41 the composition of any one of embodiments 35-40, wherein the nanoparticle comprises a second cationic lipid comprising MVL5, MC2, or DODMA.
Embodiment 42 the composition of embodiment 41, wherein the second cationic lipid is present at a level of about 5 to about 20 mole% of the total nanoparticle lipid.
Embodiment 43 the composition of embodiment 41 or 42, wherein each of the first cationic lipid and the second cationic lipid is present at a level of about 5 to about 20 mole percent of the total nanoparticle lipid, and wherein each of the first cationic lipid and the second cationic lipid is present in equal amounts.
Embodiment 44 the composition of any of embodiments 35-43, wherein said at least one structural lipid is selected from one or more of DSPC, DMPC, and dioleoyl phosphatidylethanolamine (DOPE).
Embodiment 45 the composition of embodiment 44, wherein the at least one structural lipid is present at a level of about 10 to about 70 mole% of the total nanoparticle lipids.
Embodiment 46 the composition of embodiment 45, wherein the at least one structural lipid is present at a level of about 30 to about 50 mole% of the total nanoparticle lipids.
Embodiment 47 the composition of any one of embodiments 44-46, wherein said at least one structural lipid and said at least one bile salt are present at a combined level of about 50 to about 80 mole% of the total nanoparticle lipids.
Embodiment 48. The composition of any of embodiments 35-47, wherein the hydrophilic polymer comprises PEG.
Embodiment 49 the composition of any one of embodiments 35-48, wherein said at least one conjugated lipid comprises DMG-PEG.
Embodiment 50. The composition of any of embodiments 35-49, wherein the at least one conjugated lipid is present at a level of about 0.5 to about 2.0 mole% of the total nanoparticle lipid.
Embodiment 51 the composition of any one of embodiments 35-50, wherein the first cationic lipid comprises CL1H6.
Embodiment 52 the composition of any of embodiments 35-51 wherein the nanoparticle comprises a second cationic lipid comprising MVL5.
Embodiment 53 the composition of any one of embodiments 35-52 wherein said at least one bile salt comprises deoxycholate.
Embodiment 54 the composition of any of embodiments 35-53 wherein said at least one structural lipid comprises DSPC.
Embodiment 55 the composition of any one of embodiments 35-54, wherein the at least one conjugated lipid comprises DMG-PEG.
Embodiment 56 the composition of any one of embodiments 35-55, comprising CL1H6, MVL5, and DMG-PEG in a molar ratio of about 1:1:0.08; and deoxycholate and DSPC in a molar ratio of about 0.5 to about 5.0.
Embodiment 57 the composition of embodiment 56 wherein the molar ratio of deoxycholate to DSPC is about 2.0 to about 4.0.
Embodiment 58 the composition of embodiment 35, wherein the nanoparticle comprises: CL1H6 at a level of about 10 to about 20 mole% of the total nanoparticle lipids; MVL5 at a level of about 10 to about 20 mole% of the total nanoparticle lipid; deoxycholate at a level of about 10 to about 40 mole% of the total nanoparticle lipid; DSPC, DMPC or DOPE at a level of about 30 to about 60 mole% of the total nanoparticle lipid; and DMG-PEG at a level of about 0.5 to about 2.0 mole% of the total nanoparticle lipid.
Embodiment 59 the composition of embodiment 58, wherein the nanoparticle comprises: CL1H6 and MVL5 at a level of about 10 to about 15 mole% of the total nanoparticle lipid; deoxycholate at a level of about 20 to about 40 mole% of the total nanoparticle lipid; DSPC at a level of about 35 to about 50 mole% of the total nanoparticle lipid; and DMG-PEG at a level of about 0.75 to about 1.5 mole% of the total nanoparticle lipid.
Embodiment 60 the composition of embodiment 59, wherein the nanoparticle comprises: CL1H6 and MVL5 at a level of about 12 to about 14 mole% of the total nanoparticle lipid; deoxycholate at a level of about 27 to about 38 mole% of the total nanoparticle lipid; DSPC at a level of about 38 to about 45 mole% of the total nanoparticle lipid; and about 0.75 to about 1.5 mole% DMG-PEG of the total nanoparticle lipid.
Embodiment 61 the composition of embodiment 60 wherein the nanoparticle comprises: CL1H6 and MVL5 at a level of about 12 mole% of total nanoparticle lipids; deoxycholate at a level of about 33 mole% of the total nanoparticle lipid; DSPC at a level of about 41 mole% of total nanoparticle lipid; and DMG-PEG at a level of about 1 mole% of the total nanoparticle lipid.
Embodiment 62. The composition of any of embodiments 1-61, wherein the hydrophilic polymer is conjugated to a polypeptide.
Embodiment 63 the composition of embodiment 62, wherein the polypeptide is a Mucus Penetrating Polypeptide (MPP).
Embodiment 64 the composition of embodiment 63, wherein the MPP comprises an amino acid sequence according to SEQ ID NO. 17.
Embodiment 65 the composition of any of embodiments 62-64, wherein the hydrophilic polymer comprises PEG.
Embodiment 66. The composition of embodiment 65, wherein the at least one conjugated lipid comprises DMG-PEG.
Embodiment 67 the composition of embodiment 66, wherein the nanoparticle comprises: CL1H6 and MVL5 at a level of about 12 to about 14 mole% of the total nanoparticle lipid; deoxycholate at a level of about 27 to about 38 mole% of the total nanoparticle lipid; DSPC at a level of about 38 to about 45 mole% of the total nanoparticle lipid; and DMG-PEG at a level of about 0.75 to about 1.5 mole% of the total nanoparticle lipid.
Embodiment 68. The composition of any of embodiments 1-67, wherein the cargo comprises one or more of a nucleic acid, a protein, an antibody, a peptide, a small molecule, a biologic, a peptidomimetic, a ribozyme, a chemical agent, a viral particle, a growth factor, a cytokine, an immunomodulator, and a fluorescent dye.
Embodiment 69 the composition of embodiment 68 wherein the load comprises a nucleic acid.
Embodiment 70 the composition of embodiment 69 wherein the nucleic acid comprises DNA.
Embodiment 71 the composition of embodiment 70, wherein the DNA comprises plasmid DNA.
Embodiment 72 the composition of any one of embodiments 69-71 wherein the molar ratio of total nanoparticle cationic lipid to the total number of nucleotides comprised by the nucleic acid load is from about 2 to about 20.
Embodiment 73 the composition of embodiment 72, wherein the molar ratio of total nanoparticle cationic lipid to the total number of nucleotides comprised by the nucleic acid load is from about 14 to about 18.
Embodiment 74. The composition of embodiment 69, wherein the nucleic acid comprises RNA.
Embodiment 75. The composition of embodiment 74, wherein the molar ratio of total nanoparticle cationic lipid to the total number of nucleotides comprised by the nucleic acid loading is from about 2 to about 20.
Embodiment 76 the composition of embodiment 75, wherein the molar ratio of total nanoparticle cationic lipid to total number of nucleotides comprised by the nucleic acid cargo is from about 2 to about 4.
Embodiment 77. A method of delivering a load to a target cell, the method comprising contacting the target cell with the composition of any one of embodiments 1-76.
Embodiment 78. The method of embodiment 77, wherein the target cells comprise human cells.
Embodiment 79 the method of embodiment 77 or 78, wherein said target cells comprise epithelial cells.
Embodiment 80. The method of embodiment 79 wherein the epithelial cells comprise intestinal epithelial cells.
Embodiment 81. A method of delivering a cargo to a target cell, wherein the target cell is part of a mucosal tissue, the method comprising contacting the mucosal tissue with the composition of any of embodiments 1-76.
Embodiment 82. The method of embodiment 81 wherein the mucosal tissue is a portion of the gastrointestinal tract.
Embodiment 83. The method of embodiment 82, wherein the target cell is a gastrointestinal cell.
Embodiment 84 the method of embodiment 83, wherein the gastrointestinal cells are selected from one or more of intestinal epithelial cells, lamina propria cells, intraepithelial lymphocytes, intestinal muscle cells, and intestinal neurons.
Embodiment 85. A method of delivering a load to a subject, the method comprising introducing the composition of any one of embodiments 1-76 into the gastrointestinal tract of the subject.
Embodiment 86 the method of embodiment 85, wherein the composition is introduced into the gastrointestinal tract of the subject by administering the composition to the subject by a route of administration selected from one or more of oral administration and intrarectal administration.
Embodiment 87. The method of embodiment 85 or 86, wherein the nanoparticle targets a gastrointestinal cell.
Embodiment 88 the method of embodiment 87, wherein the gastrointestinal cells are selected from one or more of intestinal epithelial cells, lamina propria cells, intraepithelial lymphocytes, intestinal muscle cells, and intestinal neurons.
Embodiment 89. The method of embodiment 87 or 88, wherein the load is delivered to a gastrointestinal cell.
Embodiment 90. The method of embodiment 89, wherein the load is delivered to the intracellular space of a gastrointestinal cell.
Embodiment 91. The method of embodiment 90, wherein the payload, payload component, or expression product of the payload is secreted from a gastrointestinal cell.
Embodiment 92. The method of embodiment 91, wherein the secretion of the load, the load component, or the expression product of the load comprises apical secretion or basal secretion.
Embodiment 93 the method of embodiment 92, wherein the load, load component, or expression product of the load remains in a region proximal to the cell after secretion.
Embodiment 94. The method of embodiment 93, wherein the payload, payload component, or expression product of the payload is secreted from the gastrointestinal cell foundation and into the circulation.
Embodiment 95. The method of embodiment 94, wherein the load, load component, or expression product of the load is distributed systemically upon entry into the circulation.
The method of any one of embodiments 85-95, wherein the load comprises a therapeutic agent.
Embodiment 97 the method of embodiment 96, wherein the therapeutic agent comprises one or more of a nucleic acid, a polypeptide, a protein, a biologic, an antibody, an enzyme, a hormone, a cytokine, an immunogen, and a gene or epigenetic editing system component.
Embodiment 98 the method of embodiment 97, wherein the therapeutic agent comprises a nucleic acid.
Embodiment 99. The method of embodiment 98, wherein the nucleic acid encodes at least one polypeptide.
Embodiment 100. The method of embodiment 98 or 99, wherein the nucleic acid comprises DNA.
Embodiment 101. The method of embodiment 100, wherein the nucleic acid comprises plasmid DNA.
Embodiment 102. The method of any one of embodiments 98-101, wherein the nanoparticle targets a gastrointestinal cell and wherein the gastrointestinal cell is transfected with the nucleic acid.
Embodiment 103 the method of embodiment 102, wherein the gastrointestinal cell expresses a polypeptide encoded by the nucleic acid.
Embodiment 104. The method of embodiment 103, wherein the nucleic acid encodes a cell signaling factor.
The method of embodiment 104, wherein the cell signaling factor is selected from one or more of Interleukin (IL) -2, IL-2 mutein Fc-fusion, IL-10 mutein, IL-22, granulocyte-macrophage colony-stimulating factor (GM-CSF), granulocyte colony-stimulating factor (G-CSF), adrenomedullin, glucagon-like peptide 1 (GLP-1), glucagon-like peptide 2 (GLP-2), GLP-2 analog tiltuin, peroxisome proliferator-activated receptor gamma (PPARgamma), human Growth Hormone (HGH), parathyroid hormone (PTH), fibroblast growth factor 21 (FGF 21), and relaxin.
Embodiment 106. The method of embodiment 103, wherein the nucleic acid encodes an antibody.
Embodiment 107 the method of embodiment 106, wherein the antibody binds to a target selected from one or more of IL-18, IL-18 receptor 1 (IL 18R 1), IL-23, tumor necrosis factor alpha (tnfa), proprotein convertase subtilisin 9 (PCSK 9), and protein 19 (P19).
Embodiment 108. The method of embodiment 106, wherein the antibody is a bispecific antibody.
Embodiment 109. The method of embodiment 108, wherein the bispecific antibody binds to cluster of differentiation 3 (CD 3).
Embodiment 110. The method of embodiment 103, wherein the nucleic acid encodes an antimicrobial agent.
Embodiment 111 the method of embodiment 110 wherein the antimicrobial agent is selected from one or more of Intestinal Alkaline Phosphatase (IAP) and defensin.
Embodiment 112. The method of embodiment 103, wherein the nucleic acid encodes a gene editing system component.
Embodiment 113 the method of embodiment 103, wherein the nucleic acid encodes an antigen as an immunogen to promote an immune response in a subject to the antigen.
Embodiment 114. The method of embodiment 113, wherein the antigen is derived from one or more of influenza virus, SARS-CoV-2 virus, ebola virus, and poliovirus.
Embodiment 115 the method of embodiment 113, wherein the antigen comprises a tumor cell neoantigen.
Embodiment 116. The method of embodiment 113, wherein the immune response comprises tolerance of the subject to an antigen.
Embodiment 117 the method of embodiment 116, wherein the antigen is associated with one or more of peanut allergy, celiac disease, rheumatoid arthritis, and IBD.
Embodiment 118. The method of embodiment 103, wherein the nucleic acid encodes a clotting factor.
Embodiment 119. The method of embodiment 118 wherein the clotting factor comprises factor VIII.
Embodiment 120. The method of embodiment 103, wherein the nucleic acid encodes an enzyme.
Embodiment 121. The method of embodiment 120, wherein the enzyme comprises beta-Glucocerebrosidase (GBA).
Embodiment 122. The method of embodiment 102, wherein the nucleic acid comprises non-coding RNA.
Embodiment 123. The method of embodiment 122, wherein the non-coding RNAs comprise one or more of interfering short RNAs (siRNA), micrornas (miRNA), long-chain non-coding RNAs, piwi-interacting RNAs (piRNA), nucleolar micrornas (snoRNA), cajal body-specific micrornas (scaRNA), transfer RNAs (tRNA), ribosomal RNAs (rRNA), and intranuclear micrornas (snRNA).
Embodiment 124. A method of treating a therapeutic indication in a subject, the method comprising delivering a load to the subject according to the method of any one of embodiments 81-123.
Embodiment 125. The method of embodiment 124, wherein the therapeutic indication comprises an immune-related indication.
Embodiment 126 the method of embodiment 125 wherein the load comprises a nucleic acid encoding a therapeutic agent.
Embodiment 127 the method of embodiment 126, wherein the therapeutic agent is selected from the group consisting of IL-2, IL-2 mutein Fc-fusion, IL-10 mutein, IL-22, adrenomedullin, an antimicrobial agent, and an anti-inflammatory antibody.
Embodiment 128 the method of embodiment 127, wherein the load is delivered to a gastrointestinal cell.
Embodiment 129 the method of embodiment 128, wherein the gastrointestinal cells express the therapeutic agent.
Embodiment 130 the method of embodiment 129, wherein the gastrointestinal cells secrete the therapeutic agent locally.
Embodiment 131 the method of embodiment 130, wherein the immune-related indication comprises a gastrointestinal indication.
Embodiment 132 the method of embodiment 131, wherein the gastrointestinal indication comprises one or more of a gastrointestinal infection, inflammatory Bowel Disease (IBD), ulcerative colitis, and crohn's disease.
Embodiment 133 the method of embodiment 129, wherein the gastrointestinal cells secrete the therapeutic agent into the circulation.
Embodiment 134. The method of embodiment 133, wherein the immune-related indication comprises a parenteral-specific indication and/or a systemic indication.
Embodiment 135 the method of embodiment 133 or 134, wherein the immune-related indication comprises one or more of Graft Versus Host Disease (GVHD), systemic Lupus Erythematosus (SLE), type I diabetes, rheumatoid arthritis, infection, wound, and allergy.
Embodiment 136. The method of embodiment 124, wherein the therapeutic indication comprises a cancer-related indication.
Embodiment 137 the method of embodiment 136 wherein said loading comprises a nucleic acid encoding a therapeutic agent.
Embodiment 138 the method of embodiment 137, wherein said therapeutic agent comprises GM-CSF.
The method of embodiment 139, wherein the cancer-related indication comprises one or more of hodgkin's lymphoma, non-hodgkin's lymphoma, acute lymphoblastic leukemia, and acute myelogenous leukemia.
Embodiment 140 the method of embodiment 139, wherein the subject has received or is undergoing chemotherapy and/or stem cell transplantation.
Embodiment 141 the method of any one of embodiments 138-140, wherein the load is delivered to a gastrointestinal cell and wherein the gastrointestinal cell is present in an amount sufficient to provide about 250 μg/m 2 The level of circulating GM-CSF concentration per day secretes GM-CSF into the circulation.
Embodiment 142 the method of embodiment 124, wherein the therapeutic indication comprises neutropenia.
Embodiment 143 the method of embodiment 142, wherein the load comprises a nucleic acid encoding G-CSF.
The method of embodiment 144, wherein the load is delivered to gastrointestinal cells and wherein the gastrointestinal cells secrete G-CSF into the circulation at a level sufficient to provide about 5 μg/kg/day of G-CSF.
Embodiment 145 the method of embodiment 144, wherein the subject is treated until the subject's neutrophil blood level reaches 1000/. Mu.l.
Embodiment 146 the method of embodiment 124, wherein the therapeutic indication comprises microvilli inclusion body disease (MVID) and wherein the payload comprises a nucleic acid encoding a MYO5B gene product.
Embodiment 147 the method of embodiment 124, wherein the therapeutic indication comprises cystic fibrosis and wherein the load comprises a nucleic acid encoding a Cystic Fibrosis Transmembrane Regulator (CFTR).
The method of embodiment 124, wherein the therapeutic indication comprises hemophilia, and wherein the load comprises a nucleic acid encoding a clotting factor.
The method of embodiment 149, wherein the clotting factor comprises factor VIII.
Embodiment 150. The method of embodiment 149, wherein the hemophilia comprises hemophilia a.
Embodiment 151 the method of embodiment 124, wherein the therapeutic indication comprises gaucher's disease and wherein the load comprises a nucleic acid encoding GBA.
Embodiment 152 the method of embodiment 151 wherein the payload is delivered to a gastrointestinal cell and wherein the gastrointestinal cell secretes GBA into the circulation at a level sufficient to provide a steady state GBA plasma level of about 6 ng/mL.
Embodiment 153 the method of embodiment 124, wherein the therapeutic indication comprises Short Bowel Syndrome (SBS) and wherein the load comprises a nucleic acid encoding GLP-2.
Embodiment 154 the method of embodiment 153, wherein said payload is delivered to a gastrointestinal cell and wherein said gastrointestinal cell secretes GLP-2 into the circulation at a level sufficient to provide a circulating GLP-2 concentration of about 36 ng/mL.
Embodiment 155 the method of embodiment 124, wherein said therapeutic indication comprises a hormone deficiency and wherein said load comprises a nucleic acid encoding a deficient hormone.
Embodiment 156 the method of embodiment 155 wherein said deficient hormone is selected from HGH and PTH.
Embodiment 157 the method of embodiment 156, wherein the deficient hormone is HGH, wherein the payload is delivered to a gastrointestinal cell and wherein the gastrointestinal cell secretes HGH into the circulation at a level sufficient to provide a circulating HGH concentration of about 1 to about 10ng/mL in an adult or about 10 to about 50ng/mL in a pediatric.
The method of embodiment 158, wherein the deficient hormone is PTH, wherein the payload is delivered to a gastrointestinal cell and wherein the gastrointestinal cell secretes PTH into the circulation at a level sufficient to provide a circulating PTH concentration of about 150 pg/mL.
Embodiment 159 the method of embodiment 124, wherein said therapeutic indication comprises non-alcoholic steatohepatitis (NASH) and wherein said payload comprises a nucleic acid encoding GLP-1 or FGF 21.
The method of embodiment 124, wherein the therapeutic indication comprises elevated circulating Low Density Lipoprotein (LDL) levels and wherein the cargo comprises a nucleic acid encoding an anti-PCSK 9 antibody.
Embodiment 161 the method of embodiment 160, wherein the load is delivered to a gastrointestinal cell and wherein the gastrointestinal cell secretes an anti-PCSK 9 antibody into the circulation at a level sufficient to provide a circulating anti-PCSK 9 antibody concentration of about 18 to about 19 μg/mL.
Embodiment 162 a delivery vehicle comprising: at least one bile salt, at least one bile acid, or a combination thereof; at least one cationic lipid; at least one structural lipid; and optionally at least one conjugated lipid.
Embodiment 163 the delivery vehicle of embodiment 162 wherein the at least one bile salt comprises sulfobromophthalein disodium salt hydrate, taurine-3 beta, 5 alpha, 6 beta-Trihydroxycholanic acid, tauchenodeoxycholic acid sodium salt, taurocholate sodium salt hydrate, taurocholate sodium salt, taurodeoxycholic acid sodium salt, taurocholate deoxycholate, taurocholate sodium salt, taurocholate 3-sulfuric acid disodium salt, taurocholate sodium salt, tauro-beta-mous acid sodium salt, tauroursodeoxycholate sodium salt, tauro-alpha-mous acid sodium salt, tauro-gamma-mous acid sodium salt, tauro-omega-mous acid sodium salt, beta-estradiol 17- (beta-D-glucuronide) sodium salt, lithocholic acid 3-sulfate (disodium salt), chenodeoxycholic acid 3-sulfate (disodium salt) chenodeoxycholic acid 7-sulfate (disodium salt), cholic acid 3-sulfate (disodium salt), cholic acid 7-sulfate (disodium salt), cholic acid sodium salt, deoxycholic acid 3-sulfate (disodium salt), deoxycholic acid disulfate (trisodium salt), phenoxymethyl penicillin potassium salt, chenodeoxycholic acid disulfate (trisodium salt) sodium chenodeoxycholate, cholate, methylcholate, sodium taurocholate hydrate, 1-naphthyl isothiocyanate, deoxycholate, pig deoxycholate, glycocholate, sodium glycochenodeoxycholate, sodium cholate hydrate, taurocholate, taurodeoxycholate, sodium taurocholate, taurochenodeoxycholate, chenodeoxycholate, lithocholate, isophthalate, alloisophthalate, sodium deoxycholate monohydrate, dehydrolithocholate, sodium glycodeoxycholate, sodium glycocholate hydrate, sodium taurodeoxycholate hydrate, sodium chenodeoxycholate, glycocholate sulfate, glycinate, sodium taurocholate hydrate, sodium taurocholate, sodium tauroursodeoxycholate, sodium taurocholate, sodium glycodeoxycholate, and any combination thereof.
The delivery vehicle of embodiment 164 wherein the at least one bile salt comprises cholate, deoxycholate, chenodeoxycholate, lithocholate, and any combination thereof.
Embodiment 165 the delivery vehicle of embodiment 162, wherein the at least one bile acid comprises 3β,5α,6β -trihydroxy cholanic acid, 12-ketochenodeoxycholic acid, 12-ketodeoxycholic acid, 12-ketolithocholic acid, 3-oxo-chenodeoxycholic acid, 3-oxo-deoxycholic acid, 3α,6β,7α,12α -tetrahydroxy bile acid, 3α,6α,7α,12 a-tetrahydroxy bile acid, 4-bromobenzoic acid, 6, 7-diketo-lithocholic acid, 7-ketodeoxycholic acid, 7-ketolithocholic acid, allocholic acid, allo-iso-lithocholic acid, orthocholic acid (delta 14 isomer), arachidyl amidocholanic acid, chenodeoxycholic acid-D4, cholic acid, dehydrocholic acid, dehydrolithocholic acid, deoxycholic acid, dioxo-cholic acid, glyco-12-oxo Dan Danwan acid, glycochenodeoxycholic acid, glycocholic acid hydrate, glycodehydrocholic acid, glycodeoxycholic acid, glycohyodeoxycholic acid, glycolithocholic acid, glycoursodeoxycholic acid, glyco-gamma-murine cholic acid, hyodeoxycholic acid, obeticholic acid, pentadecanoic acid, bear deoxycholic acid, alpha-murine deoxycholic acid, beta-murine cholic acid, omega-murine cholic acid, and any combination thereof.
The delivery vehicle of embodiment 166 wherein the at least one bile acid comprises Xiong Erchun, 5 beta-cholanic acid, 3-oxo-cholanic acid, and any combination thereof.
Embodiment 167 the delivery vehicle of any of embodiments 162-166, wherein the delivery vehicle comprises about 5 to about 40 mole% of at least one bile salt or at least one bile acid.
Embodiment 168 the delivery vehicle of any of embodiments 162-167 wherein the delivery vehicle comprises from about 20 to about 40 mole% of at least one bile salt or at least one bile acid.
The delivery vehicle of any of embodiments 162-168, wherein the delivery vehicle comprises about 30 to about 40 mole% of at least one bile salt or at least one bile acid.
Embodiment 170 the delivery vehicle of any one of embodiments 162-169, wherein said at least one bile salt comprises deoxycholate.
The delivery vehicle of any of embodiments 162-169, wherein the at least one bile salt comprises chenodeoxycholate.
The delivery vehicle of any of embodiments 162-169, wherein the at least one bile salt comprises lithocholic acid salt.
Embodiment 173 the delivery vehicle of any one of embodiments 162-169, wherein said at least one bile allo-cholate.
Embodiment 174 the delivery vehicle of any of embodiments 162-169, wherein the at least one bile comprises dehydrolithocholate.
Embodiment 175 the delivery vehicle of any of embodiments 162-169, wherein the at least one bile acid comprises bear glycol.
The delivery vehicle of any of embodiments 162-169, wherein the at least one bile salt comprises isophthalate.
The delivery vehicle of any of embodiments 162-169, wherein the at least one bile salt comprises dehydrolithocholate.
The delivery vehicle of any of embodiments 162-169, wherein the at least one bile acid comprises 5- β -cholanic acid.
The delivery vehicle of any of embodiments 162-169, wherein the at least one bile salt comprises taurodeoxycholate.
Embodiment 180 the delivery vehicle of any one of embodiments 162-169, wherein the at least one bile comprises tauxe deoxycholate.
Embodiment 181 the delivery vehicle of any of embodiments 162-169 wherein said at least one bile salt glycocholate.
Embodiment 182 the delivery vehicle of any of embodiments 162-169, wherein said at least one bile acid comprises 3-oxo-cholanic acid.
Embodiment 183 the delivery vehicle of any of embodiments 162-169, wherein said delivery vehicle comprises deoxycholate and lithocholate.
The delivery vehicle of embodiment 184, wherein the delivery vehicle comprises about 20 to about 30 mole% deoxycholate and about 5 to about 10 mole% lithocholate.
Embodiment 185 the delivery vehicle of any one of embodiments 162-183, wherein said delivery vehicle comprises at least one bile salt and at least one bile acid.
The delivery vehicle of embodiment 162 wherein the at least one cationic lipid comprises N1- [2- ((1S) -1- [ (3-aminopropyl) amino ] -4- [ bis (3-amino-propyl) amino ] butylcarboxamido) ethyl ] -3, 4-bis [ oleyloxy ] -benzamide (MVL 5), N4-cholesteryl-spermine HCl (GL 67), 1, 2-dioleyloxy-3-dimethylaminopropane (DODMA), N- [1- (2, 3-dioleyloxy) propyl ] -N, N-trimethylammonium chloride (DOTMA), [1, 2-bis (oleoyloxy) -3- (trimethylammonium) propane ] (DOTAP), dimethyldioctadecyl ammonium (DDA), 3β [ N- (N ', N' -dimethylaminoethane) -carbamoyl ] cholesterol (DC-Chol) and dioctadecyl amidoglycinamide (dots), 1, 2-dialkyl-sn-3-dimethylamino-ethyl-3-trimethylammonium chloride (DOTMA), [1, 2-bis (oleoyloxy) -3- (trimethylammonium) propane ] (DOTAP), dimethyldioleyl-cholesterol (DC-Chol) and dioleyl amidoglycinamide (dots), 1, 2-dialkyl-3-dimethyl-aminopropane, 1, 2-dimethyl-3-N-trimethyl-ammonium chloride (DOTAP) N, N-dialkyl-N, N-dimethylammonium, N- (4-carboxybenzyl) -N, N-dimethyl-2, 3-bis (alkoxy) propan-1-ammonium, 1, 2-dialkyl-sn-glycero-3- [ (N- (5-amino-1-carboxypentyl) iminodiacetic acid) succinyl ], N1- [2- ((1S) -1- [ (3-aminopropyl) amino ] -4- [ bis (3-amino-propyl) amino ] butylcarboxamido) ethyl ] -3, 4-bis [ alkyl ] -benzamide, 1, 2-dialkoxy-N, N-dimethylaminopropane, 4- (2, 2-dioctyl-9, 12-dienyl- [1,3] dioxolan-4-ylmethyl) -dimethylamine, O-alkyl ethyl phosphorylcholine, (6Z, 9Z,28Z, 31Z) -tricdec-6,9,28,31-tetraen-19-yl 4- (dimethylamino) butyrate (MC 3), (6Z, 9Z, 28Z) -tricdec-35-tetraen-19- (dimethylamino) butanoate, N- (2-dimethyl-2-dienyl) 2- (N-dimethy-amino) -2-cholest-3- (N-methylcholest-3-yl) 2-methyl-N-3-cholest-yl) 2- (3-dimethyl-N-3-cholest-yl) propanoate, 1, 2-dialkyl-sn-glycero-3-ethylphosphocholine, 1, 2-dialkyl-3-dimethylammonium-propane, 1, 2-dialkyl-3-trimethylammonium-propane, 1, 2-di-O-alkyl-3-trimethylammonium propane, 1, 2-dialkoxy-3-dimethylaminopropane, N-dialkyl-N, N-dimethylammonium, N- (4-carboxybenzyl) -N, N-dimethyl-2, 3-bis (alkoxy) propan-1-ammonium, 1, 2-dialkyl-sn-glycero-3- [ (N- (5-amino-1-carboxypentyl) iminodiacetic acid) succinyl ], N1- [2- ((1S) -1- [ (3-aminopropyl) amino ] -4- [ di (3-amino-propyl) amino ] butylcarboxamido) ethyl ] -3, 4-di [ alkyl ] -benzamide, 7- (4- (dimethylamino) butyl) -7-hydroxytridecyl-1, 13-dioleate (1, 6H- (4-carboxybenzyl) -2, 3-bis (alkoxy) propan-1-ammonium, 1-2-dialkyl-3-dioleate, 7- (4-di-hydroxy-butyl) -CL (4-3-aminopropyl) iminodiacetic acid, 7- (4-hydroxy-3-carboxamido) propan-3-e, 7-di (dsl) 3-hydroxy-3-mercaptoethyl) oleate 1, 2-dipalmitoyl-3-trimethylammonium-propane (DPTAP), 1, 2-distearoyl-3-dimethylammonium-propane (DSDAP), or any combination thereof. In some embodiments, the saturated cationic lipid may include at least one of the following: 1, 2-dialkyl-sn-glycero-3-ethylphosphocholine, 1, 2-dialkyl-3-dimethylammonium-propane, 1, 2-dialkyl-3-trimethylammonium-propane, 1, 2-di-O-alkyl-3-trimethylammonium propane, 1, 2-dialkoxy-3-dimethylaminopropane, N-dialkyl-N, N-dimethylammonium, N- (4-carboxybenzyl) -N, N-dimethyl-2, 3-bis (alkoxy) propan-1-ammonium, 1, 2-dialkyl-sn-glycero-3- [ (N- (5-amino-1-carboxypentyl) iminodiacetic acid) succinyl ], N1- [2- ((1S) -1- [ (3-aminopropyl) amino ] -4- [ bis (3-amino-propyl) amino ] butylcarboxamido) ethyl ] -3, 4-bis [ alkyl ] -benzamide, and any combination thereof.
Embodiment 187 the delivery vehicle of embodiment 162 wherein the at least one cationic lipid comprises MVL5; MC2; CL1H6; CL4H6; DODMA, and any combination thereof.
Embodiment 188. The delivery vehicle of any of embodiment 1 or embodiment 25 or embodiment 26, wherein the delivery vehicle comprises from about 5 to about 90 mole% of the at least one cationic lipid.
Embodiment 189 the delivery vehicle of any one of embodiments 162 or embodiments 186-188, wherein the delivery vehicle comprises about 5 to about 60 mole% of at least one cationic lipid.
Embodiment 190 the delivery vehicle of any one of embodiment 162 or embodiments 186-189, wherein the delivery vehicle comprises about 10 to about 60 mole% of at least one cationic lipid.
Embodiment 191 the delivery vehicle of any of embodiments 162 or embodiments 186-190, wherein the delivery vehicle comprises about 10 to about 50 mole% of at least one cationic lipid.
Embodiment 192 the delivery vehicle of any of embodiments 162 or embodiments 186-191, wherein the delivery vehicle comprises from about 10 to about 30 mole% of at least one cationic lipid.
The delivery vehicle of embodiment 193, wherein the at least one cationic lipid comprises at least one multivalent cationic lipid and at least one ionizable cationic lipid.
Embodiment 194 the delivery vehicle of embodiment 193, wherein the at least one multivalent cationic lipid comprises MVL5.
Embodiment 195 the delivery vehicle of any of embodiments 193 or 194, wherein the delivery vehicle comprises about 5 to about 90 mole percent of at least one multivalent cationic lipid.
Embodiment 196. The delivery vehicle of any of embodiments 162 or embodiments 193-195, wherein the delivery vehicle comprises about 5 to about 60 mole% of at least one multivalent cationic lipid.
The delivery vehicle of any of embodiments 162 or 193-196, wherein the delivery vehicle comprises about 5 to about 30 mole% of at least one multivalent cationic lipid.
Embodiment 198 the delivery vehicle of any one of embodiment 162 or embodiments 193-197, wherein the delivery vehicle comprises about 5 to about 15 mole% of at least one multivalent cationic lipid.
The delivery vehicle of any of embodiments 193-198, wherein the at least one multivalent cationic lipid comprises up to about 100 mole% of the at least one cationic lipid.
Embodiment 200 the delivery vehicle of any of embodiments 193-199, wherein the at least one multivalent cationic lipid comprises about 5-75 mole% of the at least one cationic lipid.
Embodiment 201 the delivery vehicle of any one of embodiments 193-200, wherein the at least one multivalent cationic lipid comprises about 40-60 mole% of the at least one cationic lipid.
Embodiment 202 the delivery vehicle of any of embodiments 193-201, wherein the at least one multivalent cationic lipid comprises about 50 mole% of the at least one cationic lipid.
The delivery vehicle of embodiment 203 wherein the at least one ionizable cationic lipid comprises at least one of MC2, CL1H6, CL4H6, DODMA, and any combination thereof.
Embodiment 204 the delivery vehicle of any of embodiment 193 or embodiment 203, wherein said at least one ionizable cationic lipid comprises MC2.
Embodiment 205 the delivery vehicle of any of embodiments 193 or 203, wherein the at least one ionizable cationic lipid comprises CL1H6.
Embodiment 206 the delivery vehicle of embodiment 193 or embodiment 203 wherein the at least one ionizable cationic lipid comprises CL4H6.
Embodiment 207 the delivery vehicle of embodiment 193 or embodiment 203, wherein the at least one ionizable cationic lipid comprises DODMA.
Embodiment 208 the delivery vehicle of any of embodiments 162 or embodiments 193-207, wherein the delivery vehicle comprises about 5 to about 90 mole percent of at least one ionizable cationic lipid.
Embodiment 209 the delivery vehicle of any of embodiments 162 or embodiments 193-208, wherein the delivery vehicle comprises about 5 to about 60 mole percent of at least one ionizable cationic lipid.
Embodiment 210 the delivery vehicle of any of embodiments 162 or embodiments 193-209, wherein the delivery vehicle comprises about 5 to about 30 mole percent of at least one ionizable cationic lipid.
Embodiment 211 the delivery vehicle of any of embodiments 162 or embodiments 193-210, wherein the delivery vehicle comprises about 5 to about 15 mole% of at least one ionizable cationic lipid.
Embodiment 212 the delivery vehicle of any of embodiments 162 or embodiments 193-211, wherein the ionizable cationic lipid comprises up to about 100 mole% of the at least one cationic lipid.
Embodiment 213 the delivery vehicle of any of embodiments 162 or embodiments 193-212, wherein the ionizable cationic lipid comprises about 5-75 mole% of the at least one cationic lipid.
Embodiment 214 the delivery vehicle of any of embodiments 162 or embodiments 193-213, wherein the ionizable cationic lipid comprises about 40-60 mole% of the at least one cationic lipid.
Embodiment 215 the delivery vehicle of any of embodiments 162 or embodiments 193-214, wherein the ionizable cationic lipid comprises about 50 mole% of the at least one cationic lipid.
Embodiment 216 the delivery vehicle of embodiment 162, wherein the delivery vehicle comprises about the same amount of at least one multivalent cationic lipid and at least one ionizable cationic lipid.
The delivery vehicle of embodiment 217, wherein the at least one structural lipid comprises at least one neutral lipid, at least one anionic lipid, at least one phospholipid, and any combination thereof.
The delivery vehicle of any of embodiments 162 or 217, wherein the at least one structural lipid comprises Glycerol Monooleate (GMO), dioleoyl phosphatidylethanolamine (DOPE), 1, 2-dimyristoyl-sn-glycero-3-phosphorylcholine (DMPC), short chain bis-N-heptadecanoyl phosphatidylcholine (DHPC), di (hexadecanoyl) phosphoethanolamine (DHPE), 1, 2-dioleoyl-sn-glycero-3-phosphorylcholine (DLPC), dimyristoyl phosphoethanolamine (DMPE), dimyristoyl phosphatidylglycerol (DMPG), dioleoyl phosphatidylcholine (DOPC), dioleoyl-phosphatidylethanolamine 4- (N-maleimidomethyl) -cyclohexane-1-carboxylate (DOPE-mal), dioleoyl phosphatidylglycerol (DOPG), 1, 2-dioleoyl-sn-glycero-3- (phospho-L-serine) (DOPS), cell-free phosphatidylethanolamine (dopps), dimyristoyl phosphatidylethanolamine (dpp), stearoyl phosphatidylethanolamine (dpp), dioleoyl phosphatidylethanolamine (dpp), stearoyl phosphatidylethanolamine (dpp), ditolyphosphatidylethanolamine (dpp), ditolyl (dpp), and the like Distearoyl phosphoethanolamine imidazole (DSPEI), 1, 2-di (undecanoyl) -sn-glycero-phosphocholine (DUPC), lecithin phosphatidylcholine (EPC), hydrogenated Soybean Phosphatidylcholine (HSPC), mannosylated dipalmitoyl phosphatidylethanolamine (ManDOG), 1, 2-dioleoyl-sn-glycero-3-phosphoethanolamine-N- [4- (p-maleimidomethyl) cyclohexane-carboxamide ] (MCC-PE), 1, 2-di-phytoyl-sn-glycero-3-phosphoethanolamine (ME 16.0 PE), 1-myristoyl-2-hydroxy-sn-glycero-phosphocholine (MHPC), 1-oleoyl-2-cholesteryl hemisuccinyl-sn-glycero-3-phosphocholine (ochem pc), phosphatidic Acid (PA), phosphatidylethanolamine lipid (PE), phosphatidylglycerol (PG), partially hydrogenated soybean phosphatidylcholine (phsphos-inositol lipid (PI), phosphatidylinositol (p-maleimidomethyl) cyclohexane-carboxamide ] (MCC-PE), 1, 2-di-phytoyl-sn-glycero-3-phosphoethanolamine (ME 16.0 PE), 1-myristoyl-2-hydroxy-sn-glycero-Phosphoethanolamine (PE), palmitoyl phosphatidylethanolamine (PE-18), palmitoyl Phosphatidylethanolamine (PE), phosphatidylethanolamine (PE-18-Phosphatidylethanolamine (PS), trans-phosphatidylethanolamine (poacyl-phosphatidyl-18), 1-stearoyl-2-oleoyl-phosphatidylethanolamine (SOPE), soybean Phosphatidylcholine (SPC), 1, 2-di-arachidonoyl-sn-glycero-3-phosphocholine, 1, 2-di-arachidonoyl-sn-glycero-3-phosphoethanolamine, 1, 2-di (docosahexaenoic acid) -sn-glycero-3-phosphoethanolamine, 1, 2-di-linolenoyl-sn-glycero-3-phosphocholine, 1, 2-di-linolenoyl-sn-glycero-3-phosphoethanolamine, 1, 2-dioleoyl-sn-glycero-3-phosphoethanolamine, 1, 2-di-stearoyl-sn-glycero-3-phosphoethanolamine, and any combination thereof.
Embodiment 219 the delivery vehicle of any of embodiments 162 or 217 or 218, wherein the at least one structural lipid comprises DSPC, DMPC, DOPE, GMO, and any combination thereof.
Embodiment 220 the delivery vehicle of any of embodiments 162 or embodiments 217-219, wherein the delivery vehicle comprises about 5 to about 75 mole% of at least one structural lipid.
The delivery vehicle of any of embodiments 162 or embodiments 218-220, wherein the delivery vehicle comprises about 30 to about 50 mole% of at least one structural lipid.
Embodiment 222. The delivery vehicle of embodiment 162 or embodiments 218-221, wherein the delivery vehicle comprises about 35 to about 45 mole% of at least one structural lipid.
Embodiment 223 the delivery vehicle of embodiment 162, wherein said delivery vehicle does not comprise cholesterol.
The delivery vehicle of embodiment 224, wherein the at least one conjugated lipid comprises at least one conjugated lipid and at least one hydrophilic polymer.
Embodiment 225 the delivery vehicle of any one of embodiment 162 or embodiment 214, wherein the at least one hydrophilic polymer comprises polyethylene glycol (PEG).
The delivery vehicle of any of embodiments 162 or 224, wherein the at least one conjugated lipid comprises at least one phospholipid, at least one neutral lipid, at least one glyceride, at least one diglyceride, at least one anionic lipid, at least one cationic lipid, and any combination thereof.
Embodiment 227 the delivery vehicle of any one of embodiment 162 or embodiment 224 or embodiment 226, wherein the at least one conjugated lipid comprises 1, 2-dimyristoyl-rac-glycerol (DMG), 1, 2-dimyristoyl-sn-glycero-3-phosphoethanolamine (DMPE), 1, 2-distearoyl-rac-glycerol (DSG), 1, 2-dipalmitoyl-rac-glycerol (DPG), 1, 2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE), diacylglycerol (DAG), 1, 2-dipalmitoyl-sn-glycero-3-phosphoethanolamine (DPPE), and any combination thereof.
The delivery vehicle of embodiment 228 or any of embodiments 225-227, wherein the at least one conjugated lipid comprises at least one of: DMG-PEG, DMPE-PEG, DSG-PEG, DPG-PEG, DSPE-PEG, DAG-PEG, DPPE-PEG, PEG-S-DSG, PEG-S-DMG, PEG-PE, PEG-PAA, PEG-OH DSPE C18, PEG-DSPE, PEG-DSG, PEG-DPG, PEG-DOMG, PEG-DMPE Na, PEG-DMPE, PEG-DMG2000, PEG-DMG C14, PEG-DMG2000, PEG-DMG, PEG-DMA, PEG-ceramide C16, PEG-C-DOMG, PEG-C-DMG, PEG-C-DMA, PEG-cDMA, PEGA, PEG-C-DMA, PEG400, PEG2K-DMG, PEG2K-C11, PEG2000-PE, PEG2000-DOMG, PEG2000-DMG, PEG2000-DOMG, PEG2000, PEG200, PEG (2K) -DMG, DSG 18-DMG, PEG-C-DMG PEG DMPE C14, PEG DLPE C12, mPEG-PLA, MPEG-DSPE, mPEG3000-DMPE, MPEG-2000-DSPE, MPEG2000-DSPE, mPEG2000-DPPE, mPEG2000-DMPE, mPEG2000-DMG, mPPE-PEG 2000, HPEG-2K-LIPD, folic acid PEG-DSPE, DSPE-PEGMA 500, DSPE-PEGMA, DSPE-PEG6000, DSPE-PEG5000, DSPE-PEG2K-NAG, DSPE-PEG2K, DSPE-PEG2000 maleimide, DSPE-PEG2000, DSG-PEGMA, DSG-PEG5000, DPPE-PEG-2K, DPPE-mPEG2000, DPG-PEGMA, DOPE-PEG2000, DMPE-PEGMA, DMPE-2000, DMPE-mPEG2000, DMG-PEGMA, DMG-2000, DMG-750 PEG2000, cl8PEG, CI8PEG, CI8PEG3000, CI8PEG2000, CI6PEG2000, CI4PEG2000, C18-PEG5000, C18PEG, C16PEG, C14-PEG-DSPE200, C14-PEG2000, C14-PEG, C14PEG, (PEG) -C-DOMG, PEG-C-DMA, and any combination thereof.
Embodiment 229 the delivery vehicle of embodiment 162 or any of embodiments 224-228 wherein said at least one conjugated lipid comprises DMG-PEG.
Embodiment 230 the delivery vehicle of any of embodiments 162 or embodiments 224-228, wherein said at least one conjugated lipid comprises DMPE-PEG.
Embodiment 231 the delivery vehicle of any of embodiments 162 or embodiments 224-230, wherein the delivery vehicle comprises about 0.5 to about 2.0 mole% of at least one conjugated lipid.
Embodiment 232 the delivery vehicle of embodiment 162 wherein the delivery vehicle does not comprise at least one conjugated lipid.
Embodiment 233 the delivery vehicle of any one of embodiments 162-230, wherein the delivery vehicle comprises: at least one bile salt or at least one bile acid; at least one multivalent cationic lipid; at least one ionizable cationic lipid; at least one structural lipid; and at least one conjugated lipid.
The delivery vehicle of embodiment 234, wherein the delivery vehicle comprises: about 5-40 mole% of at least one bile salt or at least one bile acid; about 5 to 90 mole% of at least one multivalent cationic lipid; about 5 to 90 mole% of at least one ionizable cationic lipid; about 5 to 75 mole% of at least one structural lipid component; and about 0.5 to about 2.0 mole% of at least one conjugated lipid component.
Embodiment 235 the delivery vehicle of any one of embodiments 233 or 234, wherein the delivery vehicle comprises: about 5-40 mole% of at least one bile salt or at least one bile acid; about 5 to 60 mole% of at least one multivalent cationic lipid; about 5 to 60 mole% of at least one ionizable cationic lipid; about 5-75 mole% of at least one structural lipid; and about 0.5 to about 2.0 mole% of at least one conjugated lipid.
The delivery vehicle of any of embodiments 233-235, wherein the delivery vehicle comprises: about 20-40 mole% of at least one bile salt or at least one bile acid; about 5 to 30 mole% of at least one multivalent cationic lipid; about 5 to 30 mole% of at least one ionizable cationic lipid; about 30-50 mole% of at least one structural lipid; and about 0.5 to about 2.0 mole% of at least one conjugated lipid.
The delivery vehicle of any of embodiments 233-236, wherein the delivery vehicle comprises: about 30-40 mole% of at least one bile salt or at least one bile acid; about 5 to 15 mole% of at least one multivalent cationic lipid; about 5 to 15 mole% of at least one ionizable cationic lipid; about 35 to 45 mole% of at least one structural lipid; and about 0.5 to about 2.0 mole% of at least one conjugated lipid.
The delivery vehicle of any of embodiments 233-237, wherein the delivery vehicle comprises: about 33 mole% of at least one bile salt or at least one bile acid; about 12.5 mole% of at least one multivalent cationic lipid; about 12.5 mole% of at least one ionizable cationic lipid; about 41 mole% of at least one structural lipid; and about 1 mole% of at least one conjugated lipid.
Embodiment 239 the delivery vehicle of any of embodiments 162-238, wherein the delivery vehicle comprises any of the compositions disclosed in table 1B.
The delivery vehicle of any of embodiments 162-239, wherein the at least one conjugated lipid is conjugated to at least one polypeptide.
Embodiment 241 the delivery vehicle of embodiment 240 wherein the at least one polypeptide comprises at least one mucus penetrating polypeptide.
Embodiment 242 the delivery vehicle of any of embodiment 240 or embodiment 241, wherein said at least one mucus penetrating polypeptide comprises an amino acid sequence according to SEQ ID No. 17.
The delivery vehicle of any of embodiments 243, wherein said delivery vehicle comprises a payload.
The delivery vehicle of embodiment 244, wherein the cargo comprises a nucleic acid, a protein, an antibody, a peptide, a small molecule, a biologic, a peptidomimetic, a ribozyme, a chemical agent, a viral particle, a growth factor, a cytokine, an immunomodulator, a fluorescent dye, and any combination thereof.
Embodiment 245 the delivery vehicle of embodiment 244 wherein the load comprises a nucleic acid.
Embodiment 246 the delivery vector of embodiment 245 wherein the nucleic acid comprises DNA.
The delivery vehicle of embodiment 247, wherein the DNA comprises plasmid DNA.
The delivery vehicle of any of embodiments 245-247, wherein the molar ratio of total nanoparticle cationic lipid to total number of nucleotides contained by the nucleic acid load is about 2 to about 20.
Embodiment 249 the delivery vehicle of embodiment 248, wherein the molar ratio of total nanoparticle cationic lipid to the total number of nucleotides comprised by the nucleic acid load is from about 14 to about 18.
Embodiment 250 the delivery vector of embodiment 249, wherein the nucleic acid comprises RNA.
Embodiment 251. The delivery vehicle of embodiment 250, wherein the molar ratio of total nanoparticle cationic lipid to the total number of nucleotides comprised by the nucleic acid cargo is from about 2 to about 20.
Embodiment 252 the delivery vehicle of embodiment 251, wherein the molar ratio of total nanoparticle cationic lipid to the total number of nucleotides comprised by the nucleic acid cargo is from about 2 to about 4.
Embodiment 253. A pharmaceutical composition comprising at least one delivery vehicle as described in embodiments 162-252 and optionally a pharmaceutically acceptable excipient.
Embodiment 254 the pharmaceutical composition of embodiment 253 wherein the pharmaceutically acceptable excipient comprises excipients, adjuvants, solutions, stabilizers, additives, surfactants, lyophilized ingredients, diluents, and any combination thereof.
Embodiment 255 the pharmaceutical composition of embodiment 253 or 254, wherein the pharmaceutical composition is formulated for enteral delivery.
Embodiment 256. A method of delivering at least one load to a subject, the method comprising introducing the delivery vehicle of any one of at least one embodiments 162-252 or the pharmaceutical composition of any one of at least one embodiments 253-255 into the gastrointestinal tract of a subject.
Embodiment 257 the method of embodiment 256, wherein the at least one delivery vehicle or the at least one pharmaceutical composition is introduced to the Gastrointestinal (GI) tract of the subject by at least one route of administration.
The method of embodiment 258, wherein the at least one route comprises intravenous administration, intraperitoneal administration, intramuscular administration, transdermal administration, ocular administration, oral administration, intrarectal administration, direct injection into the GI tract, and any combination thereof.
The method of any one of embodiments 256-258, wherein the at least one delivery vehicle or at least one pharmaceutical composition targets at least one gastrointestinal cell.
The method of embodiment 260, wherein the at least one gastrointestinal cell comprises at least one of an intestinal epithelial cell, a lamina propria cell, an intraepithelial lymphocyte, an intestinal muscle cell, an intestinal neuron, or any combination thereof.
Embodiment 261. The method of embodiment 259 or 260, wherein at least one load is delivered to a gastrointestinal cell.
Embodiment 262 the method of embodiment 261, wherein the at least one payload is delivered to the intracellular space of a gastrointestinal cell.
The method of any one of embodiments 261 or 262, wherein the at least one payload, at least one payload component, or at least one expression product of a payload is secreted from a gastrointestinal cell.
The method of embodiment 264, wherein secretion of the at least one load, the at least one load component, or the at least one expression product of the load comprises apical secretion or basal secretion.
The method of embodiment 265, wherein the at least one cargo, the at least one cargo component, or at least one expression product of the cargo remains in a region proximal to a cell after secretion.
The method of embodiment 266, wherein the at least one cargo, the at least one cargo component, or at least one expression product of the cargo is secreted from the gastrointestinal cell foundation and into the circulation.
The method of embodiment 267, wherein said at least one load, said at least one load component, or at least one expression product of said load is distributed systemically upon entry into the circulation.
The method of any one of embodiments 256-267, wherein the at least one load comprises at least one therapeutic agent.
The method of embodiment 269, wherein the at least one therapeutic agent comprises one or more of a nucleic acid, a polypeptide, a protein, a biologic, an antibody, an enzyme, a hormone, a cytokine, an immunogen, and a gene or epigenetic editing system component.
The method of embodiment 270, wherein the at least one therapeutic agent comprises at least one nucleic acid.
Embodiment 271 the method of embodiment 270, wherein said at least one nucleic acid encodes at least one polypeptide.
Embodiment 272 the method of any of embodiments 270 or 271, wherein said at least one nucleic acid comprises DNA.
Embodiment 273. The method of embodiment 272, wherein the at least one nucleic acid comprises plasmid DNA.
Embodiment 274. The method of any of embodiments 270 or 271, wherein said at least one nucleic acid comprises RNA.
Embodiment 275 the method of embodiment 274, wherein the at least one nucleic acid comprises mRNA, circRNA, saRNA, and any combination thereof.
The method of any one of embodiments 269-275, comprising transfecting the at least one gastrointestinal cell with at least one nucleic acid.
Embodiment 278 the method of embodiment 276, wherein the at least one gastrointestinal cell expresses at least one polypeptide encoded by at least one nucleic acid.
The method of any one of embodiment 276 or embodiment 277, wherein the polypeptide comprises granulocyte spleen stimulating factor (G-CSF), green Fluorescent Protein (GFP), and any combination thereof.
Embodiment 280 the method of embodiment 270, wherein said at least one nucleic acid comprises at least one non-coding RNA.
Embodiment 281 the method of embodiment 271, wherein the at least one non-coding RNA comprises one or more of: interfering short RNAs (siRNA), micrornas (mirnas), long non-coding RNAs, piwi-interacting RNAs (pirnas), nucleolar micrornas (snornas), cajal body-specific micrornas (scarnas), transfer RNAs (trnas), ribosomal RNAs (rrnas), and intranuclear micrornas (snrnas).
Embodiment 282 a method of treating at least one therapeutic indication in a subject in need thereof, comprising delivering to the subject at least one delivery vehicle described herein or at least one pharmaceutical composition described herein by at least one method for delivering a load described herein.
Embodiment 283 the method of embodiment 282, wherein the at least one therapeutic indication comprises at least one of: neurodegenerative diseases, ocular diseases, reproductive diseases, gastrointestinal diseases, brain diseases, skin diseases, skeletal diseases, musculoskeletal diseases, pulmonary diseases, thoracic diseases, cystic fibrosis, familial amaurosis dementia, fragile X syndrome, huntington's disease, neurofibromatosis, sickle cell disease, thalassemia, progressive pseudohypertrophic muscular dystrophy, familial Adenomatous Polyposis (FAP), attenuated FAP, microvilli inclusion body disease (MVID), chronic inflammatory bowel disease, ileal Crohn's disease, juvenile polyposis, hereditary diffuse gastric cancer syndrome (HDGC), peutz-Jeghers syndrome, lynch syndrome, gastric adenocarcinoma with gastric proximal polyposis (GAPPS), li-Fraomeni syndrome familial gastric cancer, gilbert syndrome, telangiectasia, mucopolysaccharidosis, osler-Weber-Rendu syndrome, pancreatitis, keratoacanthoma, biliary tract occlusion, morquio syndrome, hurler's syndrome, hunter's syndrome, crigler-Najjar syndrome, rotor syndrome, peutz-Jeghers syndrome, dubin-Johnson syndrome, osteochondrosis, osteomalacia, polyposis, gastrointestinal infection, inflammatory Bowel Disease (IBD), ulcerative colitis, crohn's disease, hemophilia, short Bowel Syndrome (SBS), diabetes, non-alcoholic steatohepatitis (NASH), hodgkin's lymphoma, non-Hodgkin's lymphoma, acute lymphoblastic leukemia or Acute Myelogenous Leukemia (AML), neutropenia, or any combination thereof.
Embodiment 284 the method of embodiment 283 wherein said at least one therapeutic indication comprises at least one immune-related indication.
Embodiment 285 the method of embodiment 284, wherein said at least one immune-related indication comprises at least one gastrointestinal indication.
Embodiment 286 the method of embodiment 285, wherein the at least one therapeutic indication comprises at least one cancer-related indication.
XII. Examples
Example 1: preparation of exemplary delivery vehicles of the present disclosure
This example provides an exemplary method of preparing a delivery vehicle of the present disclosure. The lipid components 1, 2-dioleyloxy-3-dimethylaminopropane (DODMA) (Sigma Aldrich), deoxycholate (Sigma Aldrich), MVL5 (Avanti Polar Lipids), DSPC (Avanti Polar Lipids), DMG-PEG 2000 (Avanti Polar Lipids), DOPC (Avanti Polar Lipids), diI (ThermoFisher Scientific), diO (ThermoFisher Scientific) of the delivery vehicle were dissolved in ethanol and heated above their phase transition temperature, for example when the phase transition temperature was above 37 ℃. For example, when using DSPC, the lipid and aqueous phases are heated to 70 ℃. When DOPC is used, the lipid and aqueous phases are not heated and used at room temperature. The nucleic acid is dissolved in an aqueous buffer heated to a temperature above the phase transition temperature of the lipid.
The aqueous buffer pH is set below the pKa of the bile salts and the cationic lipids. Thus, lipids are strongly cationic when formulated with nucleic acids. To form a loaded delivery vehicle, the lipids and nucleic acids are mixed using microfluidic channels, and then the ethanol is removed by dialysis. Other suitable methods may be used for this step. For example, lipid structures such as liposomes can be formed by thin film hydration methods, where the lipids can be dissolved in an organic phase and dried under rotation using a rotary evaporator. The film formed can be hydrated in water. The hydrated lipid may be heated to 70 ℃ for DSPC, for example, or used at room temperature for DOPC, for example, and extruded through a suitable extruder aperture. The nucleic acid load may be mixed with a lipid to form a lipid complex.
Another suitable alternative method for preparing the exemplary delivery vehicle is to use a thin film hydration process. The lipids are dissolved and mixed in an organic solvent. The solvent is removed and the film formed is hydrated in an aqueous solution. Ultrasonic treatment or extrusion is used to properly size the lipids. The nucleic acid may be complexed by mixing the lipid mixture and the nucleic acid together.
Formulation of exemplary delivery vehicles
To prepare an exemplary delivery vector containing encapsulated nucleic acid, 300 μg of plasmid DNA encoding Gaussia luciferase under the Cytomegalovirus (CMV) promoter was dissolved in a final volume of 3mL of 50mM sodium acetate buffer (pH 4.8). Appropriate moles of MVL5, DODMA, deoxycholate, MVL5, DSPC, DMG-PEG2000 and/or DOPC were mixed in ethanol according to their mole and cationic lipid to nucleotide ratios (see Table 2 for mole% of lipid in each formulation prepared). The molar ratio of cationic lipid to nucleotide was maintained at about 16. In use, fluorescently labeled lipids (e.g., diI and DiO) are added to the mixture at 0.5% of the total lipid moles. The ethanol volume was increased to 1mL.
The nucleic acid was present in the aqueous sodium acetate buffer phase in a 3mL syringe. The lipid was present in ethanol in a 1mL syringe. Two syringes were mounted on NanoAssemblr (Precision Nanosystems) and then two samples were mixed using a microfluidic chip on nanoAssembler.
For this study, samples were mounted into syringes on NanoAssemblr Benchtop (nucleic acid in 3mL syringe and lipid in 1mL syringe as described above) and preheated to 65 ℃ (for DSPC formulation) or at room temperature (about 25 ℃) for DOPC formulation. Samples were mixed using a NanoAssemblr Benchtop microfluidic chip system at a flow rate of 6 mL/min. The pH was neutralized with 300mM HEPES buffer pH 7.5. Ethanol was removed using dialysis overnight. The sample was concentrated using Amicon Ultra-4 with a molecular weight cut-off of 100 kDa.
Table 2: prepared example formulation
Example 2: transfection of exemplary delivery vehicles of the present disclosure
In this study, transfection efficiencies of exemplary delivery vehicles (as prepared using the method described in example 1 above) were evaluated. HEK cells cultured to 50-80% confluence were used for transfection. 1 μg of plasmid DNA expressing Gaussia luciferase encapsulated in lipid nanoparticles (as listed in Table 2 above) was used in each well of a 24-well plate. Transfection efficiency was assessed by taking 30 μl of medium after 24 hours and performing a flash luciferase assay (Pierce Gaussia luciferase assay kit). The increased Relative Light Unit (RLU) value corresponds to a higher transfection efficiency.
The presence of the multivalent cationic lipid MVL5 was observed to significantly increase transfection, possibly by imposing a positive or neutral character on the bile salt stabilization system. This may be due to increased inclusion body escape. MVL5 and other multivalent lipids may be most suitable for this system due to its multivalent nature (+3 at physiological pH and +5 at lysosomal pH) and the high molar ratio of negatively charged bile salts required for stability. The data are shown in figure 1.
Example 3: stability of exemplary delivery vehicles of the present disclosure
In this study, stability of exemplary delivery vehicles in high bile salt environments was evaluated. To determine the stability of the delivery vehicle, the delivery vehicle used in this assay incorporates 0.5mol% of each of DiI and DiO. DiI and DiO are fluorescent dyes and are FRET pairs. Bile salts (in fig. 2-4) were simulated by using equal amounts of mixtures of cholic acid and deoxycholate at the indicated concentrations. It is expected that if the delivery vehicle is susceptible to damage by bile salts, a decrease in FRET strength will result. The Relative Fluorescence Units (RFU) were determined by excitation at 465nm and reading the emission at 501nm and 570 nm. RFU readings at 570nm divided by readings at 501 nm. Without any treatment, the reading was normalized to the FRET intensity of the system. The data are shown in fig. 2, 3 and 4.
This study showed that DSPC/deoxycholate (as in formulation number 10) but not DOPC/deoxycholate (as in formulation number 11) was stable to bile salts. It should be noted that DOPC/deoxycholate is similar to elastic liposomes that were found to be highly sensitive to bile salts. In contrast, DSPC/deoxycholate was found to be highly resistant to bile salt attack. In addition, DSPC/cholesterol (as in formulation No. 13) was found to be non-resistant to bile salts. This suggests that the presence of saturated lipid tails is insufficient to provide stability to bile salts, and that bile salts (e.g., deoxycholate) must be incorporated into lipid nanoparticles to provide stability.
Furthermore, as shown in fig. 4, it was observed that pegylation (as in formulation number 16) was not necessary for stability, but that omitting the high phase transition temperature lipid (as in formulation number 15) or omitting the bile salt (as in formulation number 14) resulted in a loss of bile salt stability of the delivery vehicle.
Example 4: encapsulation of nucleic acids in exemplary delivery vehicles of the present disclosure
For this study, a delivery vehicle containing 1 μg of dna encapsulated by lipid nanoparticles (formulation No. 5 in table 2) was loaded into lanes of agarose gel, which were untreated (lane 2 in fig. 5), (ii) treated with 7% triton-X100 (lane 3 in fig. 5), (iii) treated with 7% triton-X100 plus 70 ℃ for 30 minutes (lane 4 in fig. 5), and then subjected to electrophoresis. The DNA was detected by UV light using SYBR Safe. No DNA band was found for any bile salt stabilization system containing cationic lipids (lane 2, untreated), indicating encapsulation, and DNA was not released from the delivery vehicle; however, when the system was destroyed using detergent and heat (lanes 3 and 4), a DNA band was seen, indicating that the vector was unstable in this environment and that DNA was released after treatment. The data are shown in fig. 5. This demonstrates the benefit of encapsulation of a load (e.g. DNA) within a delivery vehicle that is stable in a bile salt environment, particularly effective protection in a high bile salt environment (e.g. gastrointestinal tract).
Example 5: preparation of a delivery vehicle with a load
Encapsulation of the nucleic acid load proceeds as follows: the lipids are dissolved in ethanol and heated above their phase transition temperature. The nucleic acid is dissolved in an aqueous buffer heated to a temperature above the phase transition temperature of the lipid. The aqueous buffer pH is set below the pKa of the bile salts and the cationic lipids. Thus, lipids are strongly cationic when formulated with nucleic acids. Microfluidic channels were used to mix lipids and nucleic acids. The pH was raised to neutral, the samples concentrated, and ethanol was removed using dialysis.
Materials: DODMA (Sigma Aldrich), deoxycholate (Sigma Aldrich), MVL5 (Avanti Polar Lipids), DSPC (Avanti Polar Lipids), DMG-PEG 2000 (Avanti Polar Lipids), DSG-PEG 2000 (Avanti Polar Lipids), DOPC (Avanti Polar Lipids), diI (ThermoFisher Scientific), diO (ThermoFisher Scientific) and Glycerol Monooleate (GMO) (MP Biomedicals).
Formulations
375ug of plasmid DNA encoding gaussia luciferase under CMV promoter was dissolved in a final volume of 3mL of 50mM sodium acetate buffer (pH 4.8). Appropriate moles of MVL5, DODMA, deoxycholate, MVL5, DSPC, GMO, DMG-PEG 2000, DSG-PEG 2000 and/or DOPC were mixed in ethanol according to their molar and cationic lipid to nucleotide ratios. The cationic lipid to nucleotide molar ratio was kept constant at 16. When lipids were fluorescently labeled with di and DiO, di and DiO were each added to the mixture at 0.5 mole% of the total lipid moles. The ethanol volume was increased to 1mL. Samples were mounted into syringes on Nanoassemblr Benchtop (Precision NanoSystems, CA) and preheated to 65 ℃ (for DSPC formulations) or at room temperature (for DOPC formulations). Samples were mixed using a NanoAssemblr Benchtop microfluidic chip system at a flow rate of 6 mL/min. The pH was neutralized and then ethanol was removed using dialysis overnight. The sample was concentrated using Amicon Ultra-4 (Merck Millipore Ltd, ireland) with a molecular weight cut-off of 100 kDa.
The following formulations were prepared as shown in table 3.
Table 3: prepared example formulation
In summary, the particles with DMG-PEG were stable even at 1% DMG-PEG and did not form aggregates. DSG has a stearic acid lipid tail which is present in the gel phase at 37 ℃. DMG has a myristic acid lipid tail, which is in the liquid phase at 37 ℃. DMG-PEG is present in the liquid phase portion of the carrier, thus stabilizing the cationic lipid against aggregation, whereas DSG-PEG is in the gel phase portion and does not provide the same stabilizing effect.
Example 6: in vivo administration of delivery vehicles
Mice were administered intrarectally with approximately 30 micrograms of DNA encapsulated in di and DiO-labeled nanoparticles. 4 hours after dosing, mice were sacrificed, the intestines were embedded in OCT, frozen in dry ice, and stored at-80 ℃. The tissues were frozen into 30 micrometer sections and imaged using BioTek rotation 1. DiI fluorescence was measured in the RFP channel.
Pegylated particles fail to reach intestinal epithelial cells
MVL 5/DODMA/DSPC/deoxycholate/DMG-PEG (particles 5-9) particles were formed with increased amounts of DMG-PEG and the behavior of the particles was studied in vivo. Increased amounts of DMG-PEG lead to a reduced distribution in intestinal tissue. This is in contradiction to the current teaching of increasing pegylation to increase intestinal epithelial arrival. It is believed that increasing pegylation reduces exposure of the surface positive charge by its shielding properties. This reduces the dual nature of the particles as shown in fig. 6 (particle 5), fig. 7 (particle 6), fig. 8 (particle 7), fig. 9 (particle 8) and fig. 10 (particle 9).
Example 7: in vivo delivery vehicle testing
Delivery vehicles were prepared as described previously, except that the ratio of MVL5/DODMA was changed in DSPC/deoxycholate/DMG-PEG/DiI/DiO nanoparticles, in order to investigate the effect of increasing positive charge. The following MVL5/DODMA ratios were formed in the particles: (0%/25%), (6.25%/18.75%), (12.5%/12.5%), (18.75%, 6.25%), (25%/0%). Since DODMA is primarily neutral and monovalent at neutral pH, the negative charge of deoxycholate and the multivalent charge of MVL5 dominate the behavior of the particle. The MVL5 is increased, thereby increasing the charge.
The administration, tissue collection and analysis were performed as described in example 6. The data shown in fig. 11A, 11B, 12A, 12B, 13A, 13B, 14A, 14B, 15A and 15B show that the 12.5%/12.5% mvl5/DODMA ratio is optimal for the intestinal epithelial distribution of the particles in vivo. Too much MVL5 provides too strong cationic character, resulting in adhesion to negatively charged mucus. Too low MVL5 may result in negatively charged particles that may repel mucus or have no interaction. In addition, MVL5/DODMA/DSPC/Chol/DMG-PEG particles were prepared and found not to reach intestinal epithelial cells. In summary, dual charges are required to reach intestinal epithelial cells with carefully balanced charges, as shown in fig. 11A, 11B, 12A, 12B, 13A, 13B, 14A, 14B, 15A, and 15B.
Example 8: zwitterionic delivery vehicles vs. biphasic delivery vehicles
Delivery vehicles were generated as described in example 6 and tested in vivo as described in example 7. Zwitterionic has previously been shown to increase mucus penetration in the absence of PEG. To investigate whether zwitterionic, rather than biphasic, properties are sufficient, particles were formulated, wherein the particles were designed as monophasic. To prepare single phase particles, DSPC (table 3, particle 5) was replaced with low phase transition temperature lipids [ i.e., containing DOPC (table 3, particle 11) or GMO (table 3, particle 12) ]. The charge remains the same between the particles. Particles that were only in the liquid phase (containing DOPC or GMO instead of DSPC) were found to have significantly reduced or very little intestinal epithelial cell arrival, as shown in fig. 16A, 16B, 16C and 16D for the DOPC particles (particle 11, table 3); for GMO particles (particle 12, table 3), as shown in fig. 17A, 17B, 17C, and 17D; for DSPC particles (particle 5, table 3), as shown in fig. 18A, 18B, 18C, and 18D. The results of PBS control particles are shown in fig. 19A, 19B, 19C, and 19D.
In summary, the data show that the presence of only zwitterionic ions is insufficient to achieve intestinal epithelial cell arrival.
Example 9: stability of delivery vehicles with bile salts
The following formulation was prepared using the method previously described in example 1: MVL5: MC2 (Biofine International LLC, vancouver BC Canada) bile salt: DSPC: DMG-PEG2000: diI: diO in a molar ratio of 0.96:0.96:2.592:3.168:0.0768:0.0384:0.0384, wherein the bile salt component is Xiong Erchun, deoxycholate, lithocholate, isophthalate, allophanate, dehydrolithocholate or 5 beta-cholanic acid. No nucleic acid was incorporated into the lipid nanoparticle. Alternative formulations, such as those provided in table 4, may also be generated.
Table 4: suitable alternative bile salt formulations
The stability of the lipid nanoparticle in bile salts was measured as previously discussed, up to 10g/L. FRET signals from DiI and DiO were normalized for no treatment. The stability level of the carrier in salt form is shown in figure 20.
Nanoparticles incorporating various bile salts according to the formulations listed in table 5 were prepared using the methods previously described in example 1. The mole% values shown are based on the percentage of total lipid. The indicated bile salts were included in an amount of 33.4% and the indicated PEG conjugated lipids were included in an amount of 1%. The nucleic acid was not incorporated into the lipid nanoparticle N001-N004. Lipid nanoparticles D001 and D002 were prepared with plasmid DNA at a cationic lipid to nucleotide ratio of 16.
Table 5: nanoparticle formulations
ID# | MVL5 | MC2 | DSPC | Bile salts | PEG-lipids |
N001 | 12.4% | 12.4% | 40.8% | Taurodeoxycholate salt | DMG-PEG |
N002 | 12.4% | 12.4% | 40.8% | Taurochenon deoxycholate | DMG-PEG |
N003 | 12.4% | 12.4% | 40.8% | Glycocholic acid salt | DMPE-PEG |
N004 | 12.4% | 12.4% | 40.8% | 3-oxo-cholanic acid | DMG-PEG |
D001 | 12.4% | 12.4% | 40.8% | Deoxycholate | DMG-PEG |
D002 | 12.4% | 12.4% | 40.8% | Deoxycholate | DMPE-PEG |
The stability of nucleic acid-free lipid nanoparticles in bile salts at different levels was measured as described previously. FRET signals from DiI and DiO were normalized to samples assayed in solutions without bile salts. The results showing the level of carrier stability are shown in table 6. Standard deviation values are shown in brackets.
Table 6: nanoparticle stability level
Of those samples tested, N003 and N004 exhibited the highest levels of stability.
The stability of lipid nanoparticles prepared with plasmid DNA loading was also evaluated at different bile salt levels as described previously. FRET signals from DiI and DiO were normalized to samples assayed in solutions without bile salts. The results showing the level of carrier stability are shown in table 7. Standard deviation values are shown in brackets.
Table 7: DNA nanoparticle stability level
Both formulations tested exhibited similar stability levels.
EXAMPLE 10 nanoparticle therapy
Nanoparticles according to those described in example 9 are prepared for therapeutic loading and oral administration (or by other routes of introducing the nanoparticles into the gastrointestinal tract, such as intrarectal) for local (gastrointestinal) or systemic delivery of the loading or loaded expression product. The cargo is selected from nucleic acids, polypeptides, protein biologicals (e.g., mAbs, enzymes, etc.), short half-life biologicals (e.g., hormones), immunogens, and gene or epigenetic editing system components. Local gastrointestinal delivery includes nanoparticles targeting intestinal epithelial cells, lamina propria cells, intestinal muscle cells, intestinal neurons, and/or other cell types present in intestinal tissue. Systemic delivery includes nanoparticle targeting of gastrointestinal epithelial cells and basal secretion of nanoparticle-loaded or expression products into the circulation.
EXAMPLE 11 nanoparticle-mediated delivery of cell signaling factors
Nanoparticles according to those described in example 9 were prepared with a nucleic acid load encoding a cell signaling factor (e.g., a cytokine). The nanoparticle is introduced orally or rectally into the gastrointestinal tract of a subject to transfect and induce expression of the factor in the gastrointestinal cells. The expressed factors are secreted locally or into the circulation to treat systemic disorders. Nanoparticles with nucleic acid encoding Interleukin (IL) -2 or IL-2 mutein Fc fusion (AMG 592,Amgen,Thousand Oaks,CA) were administered to provide low doses of either factor: (1) Systemic treatment of immune related disorders including Graft Versus Host Disease (GVHD), systemic Lupus Erythematosus (SLE), and type I diabetes; (2) The topical treatment of gastrointestinal immune related disorders, including Irritable Bowel Disease (IBD), ulcerative colitis and crohn's disease.
Example 12 nanoparticle mediated antibody delivery
Nanoparticles according to those described in example 9 were prepared with a nucleic acid load encoding an anti-IL 18 receptor 1 (IL-18R 1) antibody. The nanoparticle is introduced orally or rectally into the gastrointestinal tract of a subject to transfect and induce antibody expression in gastrointestinal cells. The expressed antibodies are secreted locally or into the circulation to treat systemic disorders. Antibodies block IL-18 cell signaling activity and inflammation associated with the immune-related disorder that occurs. Local secretion of antibodies treats or prevents gastrointestinal immune-related disorders, including IBD, ulcerative colitis, and crohn's disease.
EXAMPLE 13 nanoparticle treatment of gastrointestinal disorders
Nanoparticles according to those described in example 9 were prepared with a nucleic acid load encoding IL-10, IL-22 or muteins thereof. The nanoparticle is introduced orally or rectally into the gastrointestinal tract of a subject to transfect and induce expression of the factor in the gastrointestinal cells. The expressed factors are secreted locally to treat gastrointestinal immune-related disorders, including IBD, ulcerative colitis and crohn's disease.
EXAMPLE 14 nanoparticle-mediated delivery of granulocyte-macrophage colony stimulating factor (GM-CSF)
Nanoparticles according to those described in example 9 were prepared with a nucleic acid load encoding GM-CSF. The nanoparticle is introduced orally or rectally into the gastrointestinal tract of a subject to transfect and induce expression of the factor in the gastrointestinal cells. The expressed factors are secreted locally or into the circulation to promote bone marrow recovery. Subjects receiving treatment include patients with hodgkin's lymphoma, non-hodgkin's lymphoma, acute lymphoblastic leukemia, or Acute Myelogenous Leukemia (AML). Including subjects that have received or are undergoing other forms of therapy, such as chemotherapy or stem cell transplantation (e.g., autologous or allogeneic stem cell transplantation from an HLA-matched donor). In some subjects, leukopenia is used to collect hematopoietic progenitor cells mobilized by treatment. In some subjects receiving neutrophil recovery therapy, in an amount sufficient to provide about 250 μg/m 2 Dose and regimen of GM-CSF at daily level nanoparticles anduntil the neutrophil blood level reached 1000/. Mu.L.
EXAMPLE 15 nanoparticle-mediated delivery of granulocyte colony-stimulating factor (G-CSF)
Nanoparticles according to those described in example 9 were prepared with a nucleic acid load encoding G-CSF. The nanoparticle is introduced orally or rectally into the gastrointestinal tract of a subject to transfect and induce expression of the factor in the gastrointestinal cells. The expressed factors are secreted locally or into the circulation to promote granulocyte production and neutrophil regulation. Subjects receiving treatment include patients with neutropenia (e.g., chemotherapy-induced febrile neutropenia in non-myeloid malignancies or congenital or acquired severe chronic neutropenia). In subjects receiving neutrophil recovery treatment, nanoparticles are administered at a dose and regimen sufficient to provide a level of G-CSF of 5 μg/kg/day, and until neutrophil blood levels reach 1000/μl. Other subjects receiving treatment include subjects undergoing bone marrow transplant therapy, subjects undergoing peripheral blood progenitor cell collection and transplantation, and subjects previously receiving AML treatment.
EXAMPLE 16 nanoparticle mediated delivery of adrenomedullin
Nanoparticles according to those described in example 9 were prepared with a nucleic acid payload encoding adrenomedullin. Adrenomedullin reduces endothelial cell barrier dysfunction associated with inflammation or other conditions. The nanoparticle is introduced orally or rectally into the gastrointestinal tract of a subject to transfect and induce adrenomedullin expression in and local secretion from the gastrointestinal cells.
EXAMPLE 17 nanoparticle-mediated factor secretion into the gastrointestinal lumen
Nanoparticles according to those described in example 9 were prepared with a nucleic acid load encoding an antimicrobial agent. In some embodiments, intestinal Alkaline Phosphatase (IAP) or defensin. The nanoparticle is introduced orally or rectally into the gastrointestinal tract of a subject to transfect and induce expression in gastrointestinal cells. The expression product is secreted apical into the gastrointestinal lumen to target the infectious agent.
EXAMPLE 18 nanoparticles for transient gastrointestinal protein expression
Nanoparticles according to those described in example 9 were prepared with a nucleic acid load encoding a protein associated with gastrointestinal disease or systemic disease with gastrointestinal axis interactions. Nanoparticles are introduced orally or rectally into the gastrointestinal tract of a subject to transfect and induce transient protein expression in gastrointestinal epithelial cells. In some subjects, gastrointestinal epithelial cells are transfected with nucleic acid encoding a MYO5B gene product to treat microvilli inclusion body disease (MVID). In some subjects, gastrointestinal epithelial cells are transfected with a nucleic acid encoding a Cystic Fibrosis Transmembrane Regulator (CFTR) to treat cystic fibrosis.
Example 19 nanoparticle-mediated delivery of non-coding RNA to gastrointestinal cells
Nanoparticles according to those described in example 9 were prepared with non-coding RNA loading (e.g., siRNA, miRNA, long-chain ncRNA, piRNA, snoRNA, scaRNA, tRNA, rRNA, and/or snRNA). The nanoparticle is introduced orally or rectally into the gastrointestinal tract of a subject to alter gene expression in gastrointestinal cells. In some subjects, nanoparticles are introduced to treat gastrointestinal disorders. In some subjects, nanoparticles are introduced to treat systemic disorders through gastrointestinal interactions. In some subjects, the non-coding RNA load inhibits SMAD7 gene expression to treat IBD.
Example 20 nanoparticle-mediated delivery of Gene editing System
Nanoparticles according to those described in example 9 were prepared with genetic or epigenetic editing system components. Nanoparticles are used to contact stem cells in vitro or introduced orally or rectally into the gastrointestinal tract of a subject to edit cellular genes (e.g., by CRISPR base editing) or modify expression of cellular genes (e.g., by a modified Cas system). In some subjects, the nanoparticles are used to correct mutations in epithelial cell genes, including CFTR gene mutations, GPR35 gene mutations, RNF186 a64T germline mutations associated with increased risk of ulcerative colitis (see beaudein, m.et al. Plos genetics.2013.9 (9): e 1003723), mutations associated with very early IBD (see Leung, g. And muse, a.m., physiolog.2018.33:360-9, including genes listed in table 1 thereof), and/or somatic mutations in genes that affect IL-17 signaling (e.g., NFKBIZ, ZC3H12A and PIGR; see Nanki, k.et al. Nature.2020.577 (7789): 254-9). In some subjects, the nanoparticles are used to delete genes encoding IL-18 and/or IL-18R1 in gastrointestinal stem cells to treat or prevent IBD. In some subjects, the nanoparticles are used to generate RNF186 (179X) mutations in gastrointestinal stem cells to provide protection against IBD. In some subjects, the nanoparticle is used to insert a transgene into gastrointestinal cell DNA (e.g., via CRISPR or RNA-mediated retrotransposons) to provide a permanent source for factor expression, including anti-TNF, anti-P19, or anti-IL-23 to treat or prevent IBD; or GLP-1 or FGF21 for treatment or prevention of metabolic disorders.
EXAMPLE 21 nanoparticle-mediated delivery of antigen
Nanoparticles according to those described in example 9 were prepared with a nucleic acid load encoding an antigen as an immunogen for generating a local or systemic immune response. The nanoparticle is introduced orally or rectally into the gastrointestinal tract of a subject to transfect and induce antigen expression in gastrointestinal cells. The expressed antigen is secreted locally or into the circulation to promote an immune response. Some subjects receive nanoparticles with a load encoding antigens from different infectious agents, including influenza virus, SARS-CoV-2, ebola virus, poliovirus, or others (e.g., any of those described in pattetti, m.f., et al immunol rev.2011.239 (1): 125-48), to immunize the subject against these infectious agents.
EXAMPLE 22 nanoparticle-mediated delivery of neoantigens
Nanoparticles according to those described in example 9 were prepared with a nucleic acid load encoding a neoantigen for use in generating a local or systemic immune response against oncology applications. The nanoparticle is introduced orally or rectally into the gastrointestinal tract of a subject to transfect and induce expression of the neoantigen in gastrointestinal cells. The expressed antigen is secreted locally or into the circulation to promote an immune response. Some subjects receive nanoparticles with a payload encoding neoantigens capable of generating an immune response against colorectal and/or parenteral cancers.
Example 23 nanoparticle-mediated tolerance facilitates delivery of antigen
Nanoparticles according to those described in example 9 were prepared with a nucleic acid load encoding antigens associated with allergic and/or autoimmune diseases. The nanoparticle is introduced orally or rectally into the gastrointestinal tract of a subject to transfect and induce antigen expression in gastrointestinal cells. The expressed antigen is secreted locally or into the circulation to promote tolerance of the immune system to the antigen and to prevent associated immune-related indications (e.g., peanut allergy, celiac disease, rheumatoid arthritis, and IBD).
EXAMPLE 24 nanoparticle-mediated delivery of nucleic acids to intestinal immune cells
Nanoparticles according to those described in example 9 were prepared with nucleic acid loading encoding factors for intestinal immune cell expression (e.g., lamina propria monocytes or intraepithelial lymphocytes) either exclusively or non-exclusively. The nanoparticle is introduced orally or rectally into the gastrointestinal tract of a subject to transfect and induce expression of the factor in intestinal immune cells. In some subjects, nanoparticles with a nucleic acid load encoding IL-10 are administered for delivery to gastrointestinal monocytes/macrophages to promote induction of suppressor T regulatory (Treg) cells. In some subjects, nanoparticles loaded with nucleic acids encoding IL-22 are administered for delivery to gastrointestinal monocytes/macrophages to promote wound healing. In some subjects, nanoparticles having a nucleic acid load encoding a transcription factor are administered for delivery to gastrointestinal monocytes/macrophages to modulate cellular activity, including a nucleic acid load encoding peroxisome proliferator-activated receptor gamma (ppary) for M2 macrophage polarization.
EXAMPLE 25 nanoparticle-mediated delivery of nucleic acids to enteric neurons
Nanoparticles according to those described in example 9 were prepared with nucleic acid payloads encoding factors for expression in enteric neurons either exclusively or non-exclusively. Nanoparticles are introduced orally or rectally into the gastrointestinal tract of a subject to transfect and induce expression of factors in enteric neurons. The expressed factors act intracellularly to affect cellular activity, or are secreted to act locally or systemically.
EXAMPLE 26 nanoparticles for intestinal organoids
Nanoparticles according to those described in example 9 were prepared for ex vivo delivery of loads to intestinal organoids. Some nanoparticle payloads include nucleic acids encoding factors for expression in intestinal organoids. These nanoparticles were introduced into organoid ex vivo cultures for transfection and induction of factor expression. Some nanoparticle payloads include genetic or epigenetic editing system components. These nanoparticles are introduced into organoid cultures to edit genes in organoid cells (e.g., by CRISPR base editing) or to modify expression of genes in organoid cells (e.g., by a modified Cas system). In some embodiments, exosomes from nanoparticle treated cells are isolated. In some cases, exosomes are used (in vivo or ex vivo) to deliver therapeutic loads to other cells or tissues.
Example 27 nanoparticles for use in animal models
Nanoparticles according to those described in example 9 were prepared for delivery of a load to a study animal subject (e.g., a mouse or other species). Some nanoparticle payloads include nucleic acids encoding factors for expression in the gastrointestinal tract of a subject following oral or intrarectal administration. Some nanoparticle payloads include genetic or epigenetic editing system components. These nanoparticles are introduced orally or rectally into the gastrointestinal tract of a subject to edit genes in gastrointestinal cells (e.g., by CRISPR base editing) or to modify expression of genes in gastrointestinal cells (e.g., by a modified Cas system). In some embodiments, nanoparticle delivery is used to create animal models, for example, to study specific diseases or effects associated with nanoparticle treatment. In some embodiments, exosomes from the nanoparticle treated study animal subjects are isolated. In some cases, exosomes are used to deliver therapeutic loads to other cells, tissues and/or subjects, including other animal or human subjects.
EXAMPLE 28 nanoparticle-mediated treatment of hemophilia A
Nanoparticles according to those described in example 9 were prepared with a nucleic acid load encoding a factor VIII clotting factor. The nanoparticles are administered to patients with hemophilia a to provide or replace factor VIII clotting factors that are deleted or defective due to mutations or other mechanisms. The nanoparticles are administered orally or rectally to transfect and induce expression of factor VIII in gastrointestinal cells. Factor VIII is secreted locally or into the circulation to restore clotting ability. In some subjects, circulating levels of factor VIII reach about 10ng/mL to about 300ng/mL after nanoparticle administration.
EXAMPLE 29 nanoparticle-mediated treatment of Gaucher's disease
Nanoparticles according to those described in example 9 were prepared with a nucleic acid load encoding beta-Glucocerebrosidase (GBA). The nanoparticles are administered to a subject suffering from gaucher's disease to provide or replace GBA that is deleted or defective due to mutation or other mechanism. The nanoparticles are orally or rectally administered to reach the gastrointestinal tract of a subject for transfection and induction of GBA expression in gastrointestinal cells. GBA is secreted locally or into the circulation to restore GBA enzyme activity. In some subjects, steady state GBA levels of about 6ng/mL are achieved in nanoparticle treated plasma.
EXAMPLE 30 nanoparticle mediated short bowel heddleTreatment of syndrome
Nanoparticles according to those described in example 9 were prepared with a nucleic acid load encoding glucagon-like peptide 2 (GLP-2) or an analog thereof (e.g., tidolutetin). Nanoparticles are administered to a subject with Short Bowel Syndrome (SBS) to improve intestinal absorption. The nanoparticles are orally or rectally administered to reach the gastrointestinal tract of a subject for transfection and induction of local GLP-2 expression in gastrointestinal cells. In some subjects, nanoparticle administration provided a maximum circulating GLP-2 concentration of about 36 ng/mL.
Example 31 nanoparticle mediated adalimumab treatment
Nanoparticles according to those described in example 9 were prepared with a nucleic acid load encoding adalimumab, an antibody that binds Tumor Necrosis Factor (TNF) alpha and prevents binding of the TNF alpha receptor. The nanoparticle is administered to a subject suffering from immune-related disorders, including rheumatoid arthritis, IBD, and ankylosing spondylitis. The nanoparticles are administered orally or intrarectally for transfection and induction of adalimumab expression in gastrointestinal cells. The expressed antibodies are secreted locally and/or into the circulation for systemic treatment. In some subjects, the maximum circulating antibody concentration reaches about 4-5 μg/mL after nanoparticle administration.
EXAMPLE 32 nanoparticle-mediated human growth hormone therapy
Nanoparticles according to those described in example 9 were prepared with a nucleic acid load encoding Human Growth Hormone (HGH). Nanoparticles are administered to subjects suffering from HGH deficiency or wastage (wastage). The nanoparticles are administered orally or intrarectally for transfection and induction of HGH expression in gastrointestinal cells. The expressed HGH is secreted locally and/or into the circulation for systemic treatment. In some subjects, the circulating HGH level achieved after administration of the nanoparticles is about 1 to about 10ng/mL in normal adults, or about 10 to about 50ng/mL in children.
EXAMPLE 33 nanoparticle-mediated GLP-1 treatment
Nanoparticles according to those described in example 9 were prepared with a nucleic acid load encoding glucagon-like peptide 1 (GLP-1), which is a peptide hormone agonist of the GLP-1 receptor. The nanoparticle is administered to a subject suffering from diabetes, cardiovascular disease, and/or nonalcoholic steatohepatitis (NASH). The nanoparticles will be administered orally or rectally for transfection and induction of GLP-1 expression in gastrointestinal cells. Expressed GLP-1 is secreted locally and/or into the circulation for systemic treatment.
EXAMPLE 34 nanoparticle-mediated treatment of hypoparathyroidism
Nanoparticles according to those described in example 9 were prepared with a nucleic acid load encoding parathyroid hormone (PTH). The nanoparticles are administered to a subject suffering from hypoparathyroidism to increase circulating PTH concentrations to normal levels. Nanoparticles are administered orally or intrarectally for transfection and induction of PTH expression in gastrointestinal cells. Expressed PTH is secreted locally and/or into the circulation. In some subjects, the maximum circulating PTH concentration reaches about 150 pg/mL after nanoparticle administration.
EXAMPLE 35 nanoparticle-mediated anti-PCSK 9 treatment
Nanoparticles according to those described in example 9 were prepared with nucleic acid loading encoding an antibody inhibitor of proprotein convertase subtilisin 9 (PCSK 9). The nanoparticles are administered to a subject to block PCSK 9-dependent degradation of Low Density Lipoprotein (LDL) receptors, thereby reducing circulating LDL cholesterol levels and reducing the risk of cardiovascular disease. The nanoparticles are administered orally or intrarectally for transfection and induction of antibody expression in gastrointestinal cells. The expressed antibodies (e.g., allo You Shan antibody (evolocumab) and al Li Xiyou mab (alirocumab)) are secreted locally and/or into the circulation. In some subjects, a maximum circulating antibody concentration of about 18-19 μg/mL is reached after administration of the nanoparticles.
Example 36 nanoparticle-mediated T cell redirection
Nanoparticles according to those described in example 9 were prepared with a nucleic acid load encoding an anti-CD 3 bispecific antibody. The nanoparticle is administered to a subject to direct T cells to tumor cells. Nanoparticles are administered orally or intrarectally for transfection and induction of antibody expression in gastrointestinal cells. The expressed antibodies are secreted locally and/or into the circulation. In some subjects, antibodies are secreted locally to target gastrointestinal tumor cells (e.g., those associated with colon cancer). In some subjects, antibodies are secreted into the circulation to target parenteral tumor cells and/or parenteral specific tumor cells.
EXAMPLE 37 nanoparticle-mediated delivery of fibroblast growth factor 21
Nanoparticles according to those described in example 9 were prepared with a nucleic acid payload encoding Fibroblast Growth Factor (FGF) 21. The nanoparticles are administered to a subject to promote metabolic balance, including subjects with NASH. The nanoparticle is introduced orally or rectally into the gastrointestinal tract of a subject for transfection and factor expression in gastrointestinal cells. The expressed factors are secreted locally and/or into the circulation to promote metabolic balance.
EXAMPLE 38 nanoparticle-mediated delivery of relaxin
Nanoparticles according to those described in example 9 were prepared with a nucleic acid load encoding relaxin. The nanoparticles are administered to a subject to promote relaxin-dependent anti-fibrotic activity, including administration to a subject suffering from cardiovascular disease and/or liver fibrosis. The nanoparticle is introduced orally or rectally into the gastrointestinal tract of a subject for transfection and relaxin expression in gastrointestinal cells. The expressed factors are secreted locally and/or into the circulation to promote systemic activity.
EXAMPLE 39 CL1H6 formulation
LNP with mRNA loading was prepared according to the methods previously described in examples 1, 4 and 5. The lipid component of the formulation is shown in table 8, wherein the lipid component levels are provided in mole percent units relative to the total nanoparticle lipid. The molar ratio of total LNP cationic lipid to total LNP nucleotide is expressed as CL: N.
Table 8: other nanoparticle formulations
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In addition to the above components, a Mucus Penetrating Peptide (MPP) having the amino acid sequence TVDNDAPTKRASKLFAV (SEQ ID NO: 17) was also incorporated by conjugation to the nanoparticle PEG in an amount of about 0.2 to about 0.3 mole% of the total nanoparticle lipid. The nanoparticles were further fluorescently labeled with Dil and DiO. Using Precision Nanosystems LNP with mRNA was prepared by microfluidic mixing. The lipids were dissolved in ethanol and the mRNA was dissolved in sodium acetate. The assembled particles were then dialyzed in HEPES buffer to reduce the percentage of ethanol and spin-concentrated using a 100kDa Amicon filter.
Nanoparticle characteristics were determined, including size (diameter in nanometers), polydispersity index (PDI), and stability in bile salts at various concentrations (see table 9). The size and PDI were determined by Dynamic Light Scattering (DLS) via Malvern Zetasizer Nano ZS-90. For PDI, a value of 1 indicates maximum heterogeneity. Stability in bile salts (or triton x 100 buffered control solutions) at different concentrations was assessed by measuring FRET intensity signals from Dil and DiO as previously described in example 3. The average values of the size, PDI and FRET signals (relative light units) are reported in the table, with standard deviation values shown in brackets.
Table 9: nanoparticle Properties
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The LNPs tested showed relative uniformity (PDI of about 2 or less for most formulations) and an average diameter of about 30 to about 100nm (typical gastrointestinal tract mucus pore size of less than about 200 nm) within each population.
In general, all formulations tested were stable in a low bile salt environment (0.625 g/L). LNP D110-D112, having about 27 to about 38 mole% deoxycholate and about 38 to about 45 mole% DSPC, exhibited the greatest stability in high bile salts (10 g/L). LNP lacking DSPC or replacing DSPC with DMPC or DOPE is less stable under high bile salt conditions.
For LNP D107-D112, transfection efficiency was assessed with mRNA load encoding G-CSF. Human Embryonic Kidney (HEK) and Caco 2 intestinal epithelial cell lines were seeded at a density of 10,000 cells/well in 96-well plates in G-CSF free medium. After 24 hours, cells were transfected in triplicate with LNP and incubated at 37 ℃ for 24 hours. The G-CSF protein level in the medium is then determined by standard immunological assays. The average concentration (pg/mL) of the detected G-CSF protein is shown in Table 10, and the standard deviation is shown in brackets.
Table 10: G-CSF concentration in transfected cell culture media
Except D107 (which does not include deoxycholate), all LNPs demonstrated efficient transfection of both cell lines.
Further transfection efficiency assays were performed generally according to the procedure described in example 2 and using mRNA loading encoding luciferase. HEK and Caco 2 cell lines were transfected with LNP and cultured for 24 hours, then lysed with RIPA buffer and assayed for luciferase activity. The average luciferase activity (relative light units) associated with transfected cells is shown in table 11. Standard deviation values are shown in brackets.
Table 11: luciferase Activity in transfected cells
All LNPs were successfully transfected with treated cells, with formulations including DOPE yielding the highest transfection efficiency values. LNP (D180 and D181) with a higher cationic lipid to nucleotide ratio resulted in lower transfection efficiency than the corresponding preparation with a standard ratio of 2.5.
Example 40 LNP storage
Glycerol preparation
As described above at 12.4 mol% MVL5, 12.4 mol% CL1H6, 33.4 mol% deoxycholic acid, 40.8 mol% DSPC and 1 mol% DMG-PEG (GI-LNP); or 50 mole% MC3, 38.5 mole% cholesterol, 10 mole% DSPC and 1.5 mole% DMG-PEG (liver 0 LNP) preparation LNP with nano-luciferase mRNA was prepared. The nano-luciferase mRNA expression construct was synthesized from template DNA plasmid accession # JQ437372 (Genescript Biotech).
LNP was formulated in 10mM HEPES buffer containing 0 or 20% glycerol and each pellet was then aliquoted. 0% glycerol LNP was stored at 4 ℃ and 20% glycerol particles were stored at-20 ℃. During the course of one week, size, PDI and in vitro transfection efficiency were determined. 0% glycerol, 4 ℃ showed a 21% increase in size after 1 week, and a 95.6% decrease in expression. 20% glycerol, -20 ℃ showed a 62% increase in size after 1 week with a 52% decrease in expression. In vitro transfection was accomplished by transfecting mRNA in 96-well plates of HEK293 cells and evaluating luminescence 24 hours post-transfection normalized to control for lipofectamine mRNA transfection.
Phosphate and Tris-sucrose formulations
Lipid nanoparticles were prepared as described above and formulated in phosphate or Tris-sucrose buffers. The phosphate buffer contained 0.0mg of potassium dihydrogen phosphate, 0.07mg of disodium hydrogen phosphate dihydrate, 0.01mg of potassium chloride, 0.36mg of sodium chloride and 6mg of sucrose; tris-sucrose buffer contained 20mM Tris (hydroxymethyl) aminomethane (Tris) from Sigma Aldrich and 10% w/v sucrose.
Nanoparticle size and PDI were tested before and after storage as described previously. After storage, HEK cell lines were then transfected with LNP as described above.
To determine the optimal storage conditions, the storage procedure with and without cryoprotectants listed in table 12 was tested. The dimensions in nm and the PDI results are shown in table 13A, with standard deviation in brackets. Table 13B lists the concentrations (pg/ml) of secreted mRNA for transfection before and after freezing.
Table 12: LNP storage Condition
ID | Cryoprotectant | Temperature (. Degree. C.) | Freezing method |
ID | Cryoprotectant | Temperature (. Degree. C.) | Freezing method |
G1 | 0% glycerol | 4 | NA |
G2 | 20% | -20 | NA |
NA1 | None (HEPES buffer) | -20 | Slowly freezing |
NA2 | None (HEPES buffer) | -20 | Quick freezing |
NA3 | None (HEPES buffer) | -20 | Directly in the freezer |
NB1 | None (HEPES buffer) | Room temperature | NA |
NB2 | None (HEPES buffer) | 4 | NA |
PA1 | Phosphate buffer | -80 | Slowly freezing |
PA2 | Phosphate buffer | -80 | Quick freezing |
PA3 | Phosphate buffer | -80 | Directly in the freezer |
PB1 | Phosphate buffer | Room temperature | NA |
PB2 | Phosphate buffer | 4 | NA |
TA1 | Tris-sucrose buffer | -80 | Slowly freezing |
TA2 | Tris-sucrose buffer | -80 | Quick freezing |
TA3 | Tris-sucrose buffer | -80 | Directly in the freezer |
TB1 | Tris-sucrose buffer | Room temperature | NA |
Table 13A: LNP stores results
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Table 13B: transfection results before and after storage
LNP ID | Store ID | Storage Pre-mRNA transfection (RFU) | Post-storage mRNA transfection (RFU) |
GI-LNP | G1 | 370334(193283) | 101903(64039) |
GI-LNP | G2 | 181018(1932) | 59486(14493) |
GI-LNP | TA2 | 1171171.67(112435.95) | 1433495.67(165577.51) |
These results show that HEPES buffer (without cryoprotectant) is not protected from freezing for CL1H6 particles, whereas phosphate buffer results in high PDI. In addition, 20mM Tris 10% sucrose buffer was most effective with little change in size, PDI and in vitro transfection.
Sequence listing
<110> DNALite therapeutic Co (DNALITE THERAPEUTICS, INC.)
<120> biological delivery System
<130> 2214.1006PCT
<140> PCT/US2021/XXXXXX
<141> 2021-12-14
<150> 63/125,075
<151> 2020-12-14
<150> 63/194,315
<151> 2021-05-28
<150> PCT/US2021/037011
<151> 2021-06-11
<150> 63/282,421
<151> 2021-11-23
<160> 17
<170> PatentIn version 3.5
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<213> Simian Virus 40 (Simian Virus 40)
<400> 1
Pro Lys Lys Lys Arg Lys Val
1 5
<210> 2
<211> 16
<212> PRT
<213> unknown
<220>
<223> unknown description:
nuclear protein bipartite NLS sequence
<400> 2
Lys Arg Pro Ala Ala Thr Lys Lys Ala Gly Gln Ala Lys Lys Lys Lys
1 5 10 15
<210> 3
<211> 9
<212> PRT
<213> unknown
<220>
<223> unknown description:
c-myc NLS sequence
<400> 3
Pro Ala Ala Lys Arg Val Lys Leu Asp
1 5
<210> 4
<211> 11
<212> PRT
<213> unknown
<220>
<223> unknown description:
c-myc NLS sequence
<400> 4
Arg Gln Arg Arg Asn Glu Leu Lys Arg Ser Pro
1 5 10
<210> 5
<211> 38
<212> PRT
<213> Homo sapiens (Homo sapiens)
<400> 5
Asn Gln Ser Ser Asn Phe Gly Pro Met Lys Gly Gly Asn Phe Gly Gly
1 5 10 15
Arg Ser Ser Gly Pro Tyr Gly Gly Gly Gly Gln Tyr Phe Ala Lys Pro
20 25 30
Arg Asn Gln Gly Gly Tyr
35
<210> 6
<211> 42
<212> PRT
<213> unknown
<220>
<223> unknown description:
IBB domains from the input protein-alpha sequence
<400> 6
Arg Met Arg Ile Glx Phe Lys Asn Lys Gly Lys Asp Thr Ala Glu Leu
1 5 10 15
Arg Arg Arg Arg Val Glu Val Ser Val Glu Leu Arg Lys Ala Lys Lys
20 25 30
Asp Glu Gln Ile Leu Lys Arg Arg Asn Val
35 40
<210> 7
<211> 8
<212> PRT
<213> unknown
<220>
<223> unknown description:
myoma T protein sequence
<400> 7
Val Ser Arg Lys Arg Pro Arg Pro
1 5
<210> 8
<211> 8
<212> PRT
<213> unknown
<220>
<223> unknown description:
myoma T protein sequence
<400> 8
Pro Pro Lys Lys Ala Arg Glu Asp
1 5
<210> 9
<211> 8
<212> PRT
<213> Homo sapiens (Homo sapiens)
<400> 9
Pro Gln Pro Lys Lys Lys Pro Leu
1 5
<210> 10
<211> 12
<212> PRT
<213> mice (Mus musculus)
<400> 10
Ser Ala Leu Ile Lys Lys Lys Lys Lys Met Ala Pro
1 5 10
<210> 11
<211> 5
<212> PRT
<213> Influenza Virus (Influenza Virus)
<400> 11
Asp Arg Leu Arg Arg
1 5
<210> 12
<211> 7
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<213> Influenza Virus (Influenza Virus)
<400> 12
Pro Lys Gln Lys Lys Arg Lys
1 5
<210> 13
<211> 10
<212> PRT
<213> delta hepatitis Virus (Hepatitis delta virus)
<400> 13
Arg Lys Leu Lys Lys Lys Ile Lys Lys Leu
1 5 10
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Arg Glu Lys Lys Lys Phe Leu Lys Arg Arg
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Lys Ser Lys Lys
20
<210> 16
<211> 17
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<213> Homo sapiens (Homo sapiens)
<400> 16
Arg Lys Cys Leu Gln Ala Gly Met Asn Leu Glu Ala Arg Lys Thr Lys
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Lys
<210> 17
<211> 17
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<223> type 2
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Thr Val Asp Asn Asp Ala Pro Thr Lys Arg Ala Ser Lys Leu Phe Ala
1 5 10 15
Val
Claims (124)
1. A delivery vehicle comprising:
at least one bile salt, at least one bile acid, or a combination thereof;
at least one cationic lipid;
at least one structural lipid; and
optionally at least one conjugated lipid.
2. The delivery vehicle of claim 1 wherein the at least one bile salt comprises sulfobromophthalein disodium salt hydrate, taurine-3 beta, 5 alpha, 6 beta-Trihydroxycholanic acid, tauchenodeoxycholic acid sodium salt, taurocholate sodium salt hydrate, taurocholate sodium salt, taurodeoxycholic acid sodium salt, taurocholate deoxycholate, taurocholate sodium salt, taurocholate 3-sulfuric acid disodium salt, taurocholate sodium salt, tauro-beta-mous acid sodium salt, tauroursodeoxycholate sodium salt, tauro-alpha-mous acid sodium salt, tauro-gamma-mous acid sodium salt, tauro-omega-mous acid sodium salt, beta-estradiol 17- (beta-D-glucuronide) sodium salt, lithocholic acid 3-sulfate (disodium salt), chenodeoxycholic acid 3-sulfate (disodium salt) chenodeoxycholic acid 7-sulfate (disodium salt), cholic acid 3-sulfate (disodium salt), cholic acid 7-sulfate (disodium salt), cholic acid sodium salt, deoxycholic acid 3-sulfate (disodium salt), deoxycholic acid disulfate (trisodium salt), phenoxymethyl penicillin potassium salt, chenodeoxycholic acid disulfate (trisodium salt) sodium chenodeoxycholate, cholate, methylcholate, sodium taurocholate hydrate, 1-naphthyl isothiocyanate, deoxycholate, pig deoxycholate, glycocholate, sodium glycochenodeoxycholate, sodium cholate hydrate, taurocholate, taurodeoxycholate, sodium taurocholate, taurochenodeoxycholate, chenodeoxycholate, lithocholate, isophthalate, alloisophthalate, sodium deoxycholate monohydrate, dehydrolithocholate, sodium glycodeoxycholate, sodium glycocholate hydrate, sodium taurodeoxycholate hydrate, sodium chenodeoxycholate, glycocholate sulfate, glycinate, sodium taurocholate hydrate, sodium taurocholate, sodium tauroursodeoxycholate, sodium taurocholate, sodium glycodeoxycholate, and any combination thereof.
3. The delivery vehicle of claim 1, wherein the at least one bile salt comprises cholate, deoxycholate, chenodeoxycholate, lithocholate, and any combination thereof.
4. The delivery vehicle of claim 1, wherein the at least one bile acid comprises 3 beta, 5 alpha, 6 beta-trihydroxy cholanic acid, 12-ketochenodeoxycholic acid, 12-ketodeoxycholic acid, 12-ketolithocholic acid, 3-oxochenodeoxycholic acid, 3-oxodeoxycholic acid, 3-oxo cholic acid, 3 alpha, 6 beta, 7 alpha, 12 alpha-tetrahydroxy bile acid, 3 alpha, 6 alpha, 7 alpha, 12 a-tetrahydroxy bile acid, 4-bromobenzoic acid, 6, 7-diketo-lithocholic acid, 7-ketodeoxycholic acid, 7-ketolithocholic acid, allocholic acid, allo-iso-lithocholic acid, orthocholic acid (delta 14 isomer), arachidyl amidocholanic acid, chenodeoxycholic acid-D4, cholic acid, dehydrocholic acid, dehydrolithocholic acid, deoxycholic acid, dioxo-cholic acid, glyco-12-oxo Dan Danwan acid, glycochenodeoxycholic acid, glycocholic acid hydrate, glycodehydrocholic acid, glycodeoxycholic acid, glycohyodeoxycholic acid, glycolithocholic acid, glycoursodeoxycholic acid, glyco-gamma-murine cholic acid, hyodeoxycholic acid, obeticholic acid, pentadecanoic acid, bear deoxycholic acid, alpha-murine deoxycholic acid, beta-murine cholic acid, omega-murine cholic acid, and any combination thereof.
5. The delivery vehicle of claim 1 wherein the at least one bile acid comprises Xiong Erchun, 5 beta-cholanic acid, 3-oxo-cholanic acid, and any combination thereof.
6. The delivery vehicle of any one of claims 1-5, wherein the delivery vehicle comprises about 5 to about 40 mole% of at least one bile salt or at least one bile acid.
7. The delivery vehicle of any one of claims 1-6, wherein the delivery vehicle comprises about 20 to about 40 mole% of at least one bile salt or at least one bile acid.
8. The delivery vehicle of any one of claims 1-7, wherein the delivery vehicle comprises about 30 to about 40 mole% of at least one bile salt or at least one bile acid.
9. The delivery vehicle of any one of claims 1-8 wherein the at least one bile salt comprises deoxycholate.
10. The delivery vehicle of any one of claims 1-8, wherein the at least one bile salt comprises chenodeoxycholate.
11. The delivery vehicle of any one of claims 1-8 wherein the at least one bile salt comprises lithocholic acid salt.
12. The delivery vehicle of any one of claims 1-8, wherein the at least one bile salt comprises allo-isophthalate.
13. The delivery vehicle of any one of claims 1-8 wherein the at least one bile comprises dehydrolithocholate.
14. The delivery vehicle of any one of claims 1-8 wherein the at least one bile acid comprises bear diol.
15. The delivery vehicle of any one of claims 1-8 wherein the at least one bile salt comprises isophthalate.
16. The delivery vehicle of any one of claims 1-8, wherein the at least one bile salt comprises dehydrolithocholate.
17. The delivery vehicle of any one of claims 1-8, wherein the at least one bile acid comprises 5- β -cholanic acid.
18. The delivery vehicle of any one of claims 1-8 wherein the at least one bile salt comprises taurodeoxycholate.
19. The delivery vehicle of any one of claims 1-8, wherein the at least one bile salt comprises tauxe deoxycholate.
20. The delivery vehicle of any one of claims 1-8 wherein the at least one bile salt comprises glycocholate.
21. The delivery vehicle of any one of claims 1-8 wherein the at least one bile acid comprises 3-oxo-cholanic acid.
22. The delivery vehicle of any one of claims 1-8, wherein the delivery vehicle comprises deoxycholate and lithocholate.
23. The delivery vehicle of claim 22, wherein the delivery vehicle comprises from about 20 to about 30 mole% deoxycholate and from about 5 to about 10 mole% lithocholate.
24. The delivery vehicle of any one of claims 1-21, wherein the delivery vehicle comprises at least one bile salt and at least one bile acid.
25. The delivery vehicle of claim 1 wherein the at least one cationic lipid comprises N1- [2- ((1S) -1- [ (3-aminopropyl) amino ] -4- [ bis (3-amino-propyl) amino ] butylcarboxamido) ethyl ] -3, 4-bis [ oleyloxy ] -benzamide (MVL 5), N4-cholesteryl-spermine HCl (GL 67), 1, 2-dioleyloxy-3-dimethylaminopropane (DODMA), N- [1- (2, 3-dioleyloxy) propyl ] -N, N-trimethylammonium chloride (DOTMA), [1, 2-bis (oleoyloxy) -3- (trimethylammonio) propane ] (DOTAP), dimethyl Dioctadecyl Ammonium (DDA), 3 beta [ N- (N ', N' -dimethylaminoethane) -carbamoyl ] cholesterol (DC-Chol) and dioctadecyl amidoglycinamide (DOGS), 1, 2-dialkyl-sn-glycero-3-ethyl phosphorylcholine, 1, 2-dialkyl-3-dimethylammonium-propane, 1, 2-dialkyl-3-trimethylammonio-propane, 1, 2-di-O-alkyl-3-trimethylammonio-propane, 1, 2-dialkoxy-3-dimethylaminopropane, N, N-dialkyl-N, N-dimethylammonium, N- (4-carboxybenzyl) -N, N-dimethyl-2, 3-bis (alkoxy) propan-1-ammonium, 1, 2-dialkyl-sn-glycero-3- [ (N- (5-amino-1-carboxypentyl) iminodiacetic acid) succinyl ], N1- [2- ((1S) -1- [ (3-aminopropyl) amino ] -4- [ bis (3-amino-propyl) amino ] butylcarboxamido) ethyl ] -3, 4-bis [ alkyl ] -benzamide, 1, 2-dialkoxy-N, N-dimethylaminopropane, 4- (2, 2-dioctyl-9, 12-dienyl- [1,3] dioxolan-4-ylmethyl) -dimethylamine, O-alkyl ethyl phosphorylcholine, (6Z, 9Z,28Z, 31Z) -trideca-6,9,28,31-tetraen-19-yl 3- (dimethylamino) propionate (MC 2), 3 beta- [ N- (N ', N' -dimethylamino) -ethane ] amino-4-dicarboxamide, 4-dimethyl-glycero-2, 2-dicarboxy-ethyl-1, 3-dimethy lamino-N-4-methyl-glycero-1, 3-dimethy lamino-N-4-methyl-phosphorylcholine, 3-dimethy lamino-ethyl-2-cholest-1-2-dimethy-ethyl choline, 1, 2-dialkyl-3-trimethylammonium-propane, 1, 2-di-O-alkyl-3-trimethylammonium propane, 1, 2-dialkoxy-3-dimethylaminopropane, N-dialkyl-N, N-dimethylammonium, N- (4-carboxybenzyl) -N, N-dimethyl-2, 3-bis (alkoxy) propan-1-ammonium, 1, 2-dialkyl-sn-glycero-3- [ (N- (5-amino-1-carboxypentyl) iminodiacetic acid) succinyl, N1- [2- ((1S) -1- [ (3-aminopropyl) amino ] -4- [ di (3-amino-propyl) amino ] butylcarboxamido) ethyl ] -3, 4-di [ alkyl ] -benzamide, 7- (4- (dimethylamino) butyl) -7-hydroxytridecyl-1, 13-dioleate (CL 1H 6), 7- (4- (diisopropylamino) butyl) -7-hydroxytridecyl-1, 13-dioleate (CL) 1,2- [ (2S) -1, 3-stearoyl-propan-3-dicarboxamide, 4-dioleate (CL) 2-dimethyl-1, 3-palmitoyl-propan-3-dicarboxamide 1, 2-distearoyl-3-dimethylammonium-propane (DSDAP), or any combination thereof. In some embodiments, the saturated cationic lipid may include at least one of the following: 1, 2-dialkyl-sn-glycero-3-ethylphosphocholine, 1, 2-dialkyl-3-dimethylammonium-propane, 1, 2-dialkyl-3-trimethylammonium-propane, 1, 2-di-O-alkyl-3-trimethylammonium propane, 1, 2-dialkoxy-3-dimethylaminopropane, N-dialkyl-N, N-dimethylammonium, N- (4-carboxybenzyl) -N, N-dimethyl-2, 3-bis (alkoxy) propan-1-ammonium, 1, 2-dialkyl-sn-glycero-3- [ (N- (5-amino-1-carboxypentyl) iminodiacetic acid) succinyl ], N1- [2- ((1S) -1- [ (3-aminopropyl) amino ] -4- [ bis (3-amino-propyl) amino ] butylcarboxamido) ethyl ] -3, 4-bis [ alkyl ] -benzamide, and any combination thereof.
26. The delivery vehicle of claim 1 wherein the at least one cationic lipid comprises MVL5; MC2; CL1H6; CL4H6; DODMA, and any combination thereof.
27. The delivery vehicle of any one of claim 1 or claim 25 or claim 26, wherein the delivery vehicle comprises from about 5 to about 90 mole% of at least one cationic lipid.
28. The delivery vehicle of claim 1 or any one of claims 25-27, wherein the delivery vehicle comprises about 5 to about 60 mole% of at least one cationic lipid.
29. The delivery vehicle of claim 1 or any one of claims 25-28, wherein the delivery vehicle comprises about 10 to about 60 mole% of at least one cationic lipid.
30. The delivery vehicle of claim 1 or any one of claims 25-29, wherein the delivery vehicle comprises about 10 to about 50 mole% of at least one cationic lipid.
31. The delivery vehicle of claim 1 or any one of claims 25-30, wherein the delivery vehicle comprises about 10 to about 30 mole% of at least one cationic lipid.
32. The delivery vehicle of claim 1 or any one of claims 25-31 wherein the at least one cationic lipid comprises at least one multivalent cationic lipid and at least one ionizable cationic lipid.
33. The delivery vehicle of claim 32 wherein the at least one multivalent cationic lipid comprises MVL5.
34. The delivery vehicle of any one of claim 32 or claim 33, wherein the delivery vehicle comprises from about 5 to about 90 mole% of at least one multivalent cationic lipid.
35. The delivery vehicle of claim 1 or any one of claims 32-34, wherein the delivery vehicle comprises from about 5 to about 60 mole% of at least one multivalent cationic lipid.
36. The delivery vehicle of claim 1 or any one of claims 32-35, wherein the delivery vehicle comprises from about 5 to about 30 mole% of at least one multivalent cationic lipid.
37. The delivery vehicle of claim 1 or any one of claims 32-36, wherein the delivery vehicle comprises from about 5 to about 15 mole% of at least one multivalent cationic lipid.
38. The delivery vehicle of claim 1 or any one of claims 32-37 wherein the at least one multivalent cationic lipid comprises up to about 100 mole percent of the at least one cationic lipid.
39. The delivery vehicle of any one of claims 32-38 wherein the at least one multivalent cationic lipid comprises about 5-75 mole% of the at least one cationic lipid.
40. The delivery vehicle of any one of claims 32-39 wherein the at least one multivalent cationic lipid comprises about 40-60 mole% of the at least one cationic lipid.
41. The delivery vehicle of any one of claims 32-40, wherein the at least one multivalent cationic lipid comprises about 50 mole% of the at least one cationic lipid.
42. The delivery vehicle of any one of claims 32, wherein the at least one ionizable cationic lipid comprises at least one of MC2, CL1H6, CL4H6, DODMA, and any combination thereof.
43. The delivery vehicle of any one of claim 32 or claim 42, wherein the at least one ionizable cationic lipid comprises MC2.
44. The delivery vehicle of any one of claim 32 or claim 42, wherein the at least one ionizable cationic lipid comprises CL1H6.
45. The delivery vehicle of any one of claim 32 or claim 42, wherein the at least one ionizable cationic lipid comprises CL4H6.
46. The delivery vehicle of any one of claim 32 or claim 42 wherein the at least one ionizable cationic lipid comprises DODMA.
47. The delivery vehicle of claim 1 or any of claims 32-46, wherein the delivery vehicle comprises about 5 to about 90 mole% of at least one ionizable cationic lipid.
48. The delivery vehicle of claim 1 or any of claims 32-47, wherein the delivery vehicle comprises about 5 to about 60 mole% of at least one ionizable cationic lipid.
49. The delivery vehicle of claim 1 or any of claims 32-48, wherein the delivery vehicle comprises about 5 to about 30 mole% of at least one ionizable cationic lipid.
50. The delivery vehicle of claim 1 or any of claims 32-49, wherein the delivery vehicle comprises about 5 to about 15 mole% of at least one ionizable cationic lipid.
51. The delivery vehicle of claim 1 or any of claims 32-50 wherein the ionizable cationic lipid comprises up to about 100 mole% of the at least one cationic lipid.
52. The delivery vehicle of claim 1 or any of claims 32-51, wherein the ionizable cationic lipid comprises about 5-75 mole% of the at least one cationic lipid.
53. The delivery vehicle of claim 1 or any one of claims 32-52, wherein the ionizable cationic lipid comprises about 40-60 mole% of the at least one cationic lipid.
54. The delivery vehicle of claim 1 or any of claims 32-53 wherein the ionizable cationic lipid comprises about 50 mole% of the at least one cationic lipid.
55. The delivery vehicle of claim 32 wherein the delivery vehicle comprises about the same amount of at least one multivalent cationic lipid and at least one ionizable cationic lipid.
56. The delivery vehicle of claim 1, wherein the at least one structural lipid comprises at least one neutral lipid, at least one anionic lipid, at least one phospholipid, and any combination thereof.
57. The delivery vehicle of claim 1 or claim 56, wherein the at least one structural lipid is a delivery vehicle comprising Glycerol Monooleate (GMO), dioleoyl phosphatidylethanolamine (DOPE), 1, 2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC), short chain bis-N-heptadecanoyl phosphatidylcholine (DHPC), di (hexadecanoyl) phosphoethanolamine (DHPE), 1, 2-dioleoyl-sn-glycero-3-phosphocholine (DLPC), dimyristoyl phosphoethanolamine (DMPE), dimyristoyl phosphatidylglycerol (DMPG), dioleoyl phosphatidylcholine (DOPC), dioleoyl-phosphatidylethanolamine 4- (N-maleimidomethyl) -cyclohexane-1-carboxylate (DOPE-mal), dioleoyl phosphatidylethanolamine (DOPG), 1, 2-dioleoyl-sn-glycero-3- (phospho-L-serine) (dopps), cell-free fusogenic phosphatidylethanolamine (dpp), dimyristoyl phosphatidylethanolamine (DPPE), dimyristoyl phosphatidylethanolamine (dpp), distearoyl phosphatidylethanolamine (dpp-pe), distearoyl phosphatidylethanolamine (dpp-pc) Distearoyl phosphoethanolamine imidazole (DSPEI), 1, 2-di (undecanoyl) -sn-glycero-phosphocholine (DUPC), lecithin phosphatidylcholine (EPC), hydrogenated Soybean Phosphatidylcholine (HSPC), mannosylated dipalmitoyl phosphatidylethanolamine (ManDOG), 1, 2-dioleoyl-sn-glycero-3-phosphoethanolamine-N- [4- (p-maleimidomethyl) cyclohexane-carboxamide ] (MCC-PE), 1, 2-di-phytoyl-sn-glycero-3-phosphoethanolamine (ME 16.0 PE), 1-myristoyl-2-hydroxy-sn-glycero-phosphocholine (MHPC), 1-oleoyl-2-cholesteryl hemisuccinyl-sn-glycero-3-phosphocholine (ochem pc), phosphatidic Acid (PA), phosphatidylethanolamine lipid (PE), phosphatidylglycerol (PG), partially hydrogenated soybean phosphatidylcholine (phsphos-inositol lipid (PI), phosphatidylinositol (p-maleimidomethyl) cyclohexane-carboxamide ] (MCC-PE), 1, 2-di-phytoyl-sn-glycero-3-phosphoethanolamine (ME 16.0 PE), 1-myristoyl-2-hydroxy-sn-glycero-Phosphoethanolamine (PE), palmitoyl phosphatidylethanolamine (PE-18), palmitoyl Phosphatidylethanolamine (PE), phosphatidylethanolamine (PE-18-Phosphatidylethanolamine (PS), trans-phosphatidylethanolamine (poacyl-phosphatidyl-18), 1-stearoyl-2-oleoyl-phosphatidylethanolamine (SOPE), soybean Phosphatidylcholine (SPC), 1, 2-di-arachidonoyl-sn-glycero-3-phosphocholine, 1, 2-di-arachidonoyl-sn-glycero-3-phosphoethanolamine, 1, 2-di (docosahexaenoic acid) -sn-glycero-3-phosphoethanolamine, 1, 2-di-linolenoyl-sn-glycero-3-phosphocholine, 1, 2-di-linolenoyl-sn-glycero-3-phosphoethanolamine, 1, 2-dioleoyl-sn-glycero-3-phosphoethanolamine, 1, 2-di-stearoyl-sn-glycero-3-phosphoethanolamine, and any combination thereof.
58. The delivery vehicle of any one of claim 1 or claim 56 or claim 57, wherein the at least one structural lipid comprises DSPC, DMPC, DOPE, GMO, and any combination thereof.
59. The delivery vehicle of claim 1 or claims 56-58, wherein the delivery vehicle comprises about 5 to about 75 mole% of at least one structural lipid.
60. The delivery vehicle of claim 1 or claims 57-59, wherein the delivery vehicle comprises about 30 to about 50 mole% of at least one structural lipid.
61. The delivery vehicle of claim 1 or claims 57-60 wherein the delivery vehicle comprises about 35 to about 45 mole% of at least one structural lipid.
62. The delivery vehicle of claim 1 wherein the delivery vehicle does not comprise cholesterol.
63. The delivery vehicle of claim 1 wherein the at least one conjugated lipid comprises at least one conjugated lipid and at least one hydrophilic polymer.
64. The delivery vehicle of any of claim 1 or claim 63, wherein the at least one hydrophilic polymer comprises polyethylene glycol (PEG).
65. The delivery vehicle of any one of claim 1 or claim 63, wherein the at least one conjugated lipid comprises at least one phospholipid, at least one neutral lipid, at least one glyceride, at least one diglyceride, at least one anionic lipid, at least one cationic lipid, and any combination thereof.
66. The delivery vehicle of any one of claim 1 or claim 63 or claim 65, wherein the at least one conjugated lipid comprises 1, 2-dimyristoyl-rac-glycerol (DMG), 1, 2-dimyristoyl-sn-glycero-3-phosphoethanolamine (DMPE), 1, 2-distearoyl-rac-glycerol (DSG), 1, 2-dipalmitoyl-rac-glycerol (dpp), 1, 2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE), diacylglycerol (DAG), 1, 2-dipalmitoyl-sn-glycero-3-phosphoethanolamine (DPPE), and any combination thereof.
67. The delivery vehicle of claim 1 or any of claims 64-66, wherein the at least one conjugated lipid comprises at least one of: DMG-PEG, DMPE-PEG, DSG-PEG, DPG-PEG, DSPE-PEG, DAG-PEG, DPPE-PEG, PEG-S-DSG, PEG-S-DMG, PEG-PE, PEG-PAA, PEG-OH DSPE C18, PEG-DSPE, PEG-DSG, PEG-DPG, PEG-DOMG, PEG-DMPE Na, PEG-DMPE, PEG-DMG2000, PEG-DMG C14, PEG-DMG2000, PEG-DMG, PEG-DMA, PEG-ceramide C16, PEG-C-DOMG, PEG-C-DMG, PEG-C-DMA, PEG-cDMA, PEGA, PEG-C-DMA, PEG400, PEG2K-DMG, PEG2K-C11, PEG2000-PE, PEG2000-DOMG, PEG2000-DMG, PEG2000-DOMG, PEG2000, PEG200, PEG (2K) -DMG, DSG 18-DMG, PEG-C-DMG PEG DMPE C14, PEG DLPE C12, mPEG-PLA, MPEG-DSPE, mPEG3000-DMPE, MPEG-2000-DSPE, MPEG2000-DSPE, mPEG2000-DPPE, mPEG2000-DMPE, mPEG2000-DMG, mPPE-PEG 2000, HPEG-2K-LIPD, folic acid PEG-DSPE, DSPE-PEGMA 500, DSPE-PEGMA, DSPE-PEG6000, DSPE-PEG5000, DSPE-PEG2K-NAG, DSPE-PEG2K, DSPE-PEG2000 maleimide, DSPE-PEG2000, DSG-PEGMA, DSG-PEG5000, DPPE-PEG-2K, DPPE-mPEG2000, DPG-PEGMA, DOPE-PEG2000, DMPE-PEGMA, DMPE-2000, DMPE-mPEG2000, DMG-PEGMA, DMG-2000, DMG-750 PEG2000, cl8PEG, CI8PEG, CI8PEG3000, CI8PEG2000, CI6PEG2000, CI4PEG2000, C18-PEG5000, C18PEG, C16PEG, C14-PEG-DSPE200, C14-PEG2000, C14-PEG, C14PEG, (PEG) -C-DOMG, PEG-C-DMA, and any combination thereof.
68. The delivery vehicle of claim 1 or any of claims 63-67, wherein the at least one conjugated lipid comprises DMG-PEG.
69. The delivery vehicle of claim 1 or any of claims 63-67, wherein the at least one conjugated lipid comprises DMPE-PEG.
70. The delivery vehicle of claim 1 or any of claims 63-69, wherein the delivery vehicle comprises about 0.5 to about 2.0 mole% of at least one conjugated lipid.
71. The delivery vehicle of claim 1, wherein the delivery vehicle does not comprise at least one conjugated lipid.
72. The delivery vehicle of any one of claims 1-70, wherein the delivery vehicle comprises:
the at least one bile salt or at least one bile acid;
the at least one multivalent cationic lipid;
the at least one ionizable cationic lipid;
the at least one structural lipid; and
the at least one conjugated lipid.
73. The delivery vehicle of claim 72, wherein the delivery vehicle comprises:
about 5-40 mole% of at least one bile salt or at least one bile acid;
about 5 to 90 mole% of at least one multivalent cationic lipid;
About 5 to 90 mole% of at least one ionizable cationic lipid;
about 5 to 75 mole% of at least one structural lipid component; and
about 0.5 to about 2.0 mole% of at least one conjugated lipid component.
74. The delivery vehicle of any of claims 72 or 73, wherein the delivery vehicle comprises:
about 5-40 mole% of at least one bile salt or at least one bile acid;
about 5 to 60 mole% of at least one multivalent cationic lipid;
about 5 to 60 mole% of at least one ionizable cationic lipid;
about 5-75 mole% of at least one structural lipid; and
about 0.5 to about 2.0 mole% of at least one conjugated lipid.
75. The delivery vehicle of any of claims 72-74, wherein the delivery vehicle comprises:
about 20-40 mole% of at least one bile salt or at least one bile acid;
about 5 to 30 mole% of at least one multivalent cationic lipid;
about 5 to 30 mole% of at least one ionizable cationic lipid;
about 30-50 mole% of at least one structural lipid; and
about 0.5 to about 2.0 mole% of at least one conjugated lipid.
76. The delivery vehicle of any of claims 72-75, wherein the delivery vehicle comprises:
About 30-40 mole% of at least one bile salt or at least one bile acid;
about 5 to 15 mole% of at least one multivalent cationic lipid;
about 5 to 15 mole% of at least one ionizable cationic lipid;
about 35 to 45 mole% of at least one structural lipid; and
about 0.5 to about 2.0 mole% of at least one conjugated lipid.
77. The delivery vehicle of any of claims 72-76, wherein the delivery vehicle comprises:
about 33 mole% of at least one bile salt or at least one bile acid;
about 12.5 mole% of at least one multivalent cationic lipid;
about 12.5 mole% of at least one ionizable cationic lipid;
about 41 mole% of at least one structural lipid; and
about 1 mole% of at least one conjugated lipid.
78. The delivery vehicle of any of claims 1-77, wherein the delivery vehicle comprises any of the compositions disclosed in table 1B.
79. The delivery vehicle of any one of claims 1-78, wherein the at least one conjugated lipid is conjugated to at least one polypeptide.
80. The delivery vehicle of claim 79 wherein the at least one polypeptide comprises at least one mucus penetrating polypeptide.
81. The delivery vehicle of any one of claim 79 or claim 80, wherein the at least one mucus penetrating polypeptide comprises an amino acid sequence according to SEQ ID No. 17.
82. The delivery vehicle of any one of claims 1-81, wherein the delivery vehicle comprises a payload.
83. The delivery vehicle of claim 82, wherein the cargo comprises a nucleic acid, a protein, an antibody, a peptide, a small molecule, a biologic, a peptidomimetic, a ribozyme, a chemical agent, a viral particle, a growth factor, a cytokine, an immunomodulator, a fluorescent dye, and any combination thereof.
84. The delivery vehicle of claim 83, wherein the cargo comprises a nucleic acid.
85. The delivery vehicle of claim 84, wherein the nucleic acid comprises DNA.
86. The delivery vehicle of claim 85, wherein the DNA comprises plasmid DNA.
87. The delivery vehicle of any of claims 84-86, wherein the molar ratio of total nanoparticle cationic lipid to total number of nucleotides contained in the nucleic acid load is about 2 to about 20.
88. The delivery vehicle of claim 87, wherein the molar ratio of total nanoparticle cationic lipid to total number of nucleotides comprised by the nucleic acid cargo is about 14 to about 18.
89. The delivery vector of claim 84, wherein the nucleic acid comprises RNA.
90. The delivery vehicle of claim 89, wherein the molar ratio of total nanoparticle cationic lipid to total number of nucleotides comprised by the nucleic acid cargo is about 2 to about 20.
91. The delivery vehicle of claim 90 wherein the molar ratio of total nanoparticle cationic lipid to total number of nucleotides comprised by the nucleic acid cargo is from about 2 to about 4.
92. A pharmaceutical composition comprising at least one delivery vehicle of claims 1-91 and optionally a pharmaceutically acceptable excipient.
93. The pharmaceutical composition of claim 92, wherein the pharmaceutically acceptable excipient comprises an excipient, adjuvant, solution, stabilizer, additive, surfactant, lyophilized component, diluent, and any combination thereof.
94. The pharmaceutical composition of claim 92 or 93, wherein the pharmaceutical composition is formulated for enteral delivery.
95. A method of delivering to a subject at least one load, the method comprising introducing at least one delivery vehicle of any one of claims 1-91 or at least one pharmaceutical composition of any one of claims 92-94 to the gastrointestinal tract of a subject.
96. The method of claim 95, wherein the at least one delivery vehicle or the at least one pharmaceutical composition is introduced into the Gastrointestinal (GI) tract of the subject by at least one route of administration.
97. The method of claim 96, wherein the at least one route comprises intravenous administration, intraperitoneal administration, intramuscular administration, transdermal administration, ocular administration, oral administration, intrarectal administration, direct injection into the GI tract, and any combination thereof.
98. The method of any one of claims 95-97, wherein at least one delivery vehicle or at least one pharmaceutical composition targets at least one gastrointestinal cell.
99. The method of claim 98, wherein the at least one gastrointestinal cell comprises at least one of an intestinal epithelial cell, a lamina propria cell, an intraepithelial lymphocyte, an intestinal muscle cell, an intestinal neuron, or any combination thereof.
100. The method of claim 98 or 99, wherein the at least one payload is delivered to the gastrointestinal cells.
101. The method of claim 100, wherein the at least one payload is delivered to an intracellular space of the gastrointestinal cell.
102. The method of any one of claims 100 or 101, wherein the at least one payload, at least one payload component, or at least one expression product of the payload is secreted from the gastrointestinal cell.
103. The method of claim 102, wherein secretion of the at least one payload, the at least one payload component, or at least one expression product of the payload comprises apical secretion or basal secretion.
104. The method of claim 103, wherein the at least one load, the at least one load component, or at least one expression product of the load remains in a region proximal to a cell after secretion.
105. The method of claim 104, wherein the at least one payload, the at least one payload component, or at least one expression product of the payload is secreted from the gastrointestinal cell foundation and into the circulation.
106. The method of claim 105, wherein the at least one load, the at least one load component, or at least one expression product of the load is distributed systemically after entry into the circulation.
107. The method of any one of claims 95-106, wherein said at least one load comprises at least one therapeutic agent.
108. The method of claim 107, wherein the at least one therapeutic agent comprises one or more of a nucleic acid, a polypeptide, a protein, a biologic, an antibody, an enzyme, a hormone, a cytokine, an immunogen, and a gene or epigenetic editing system component.
109. The method of claim 108, wherein the at least one therapeutic agent comprises at least one nucleic acid.
110. The method of claim 109, wherein the at least one nucleic acid encodes at least one polypeptide.
111. The method of any one of claims 109 or 110, wherein the at least one nucleic acid comprises DNA.
112. The method of claim 111, wherein the at least one nucleic acid comprises plasmid DNA.
113. The method of any one of claims 109 or 110, wherein the at least one nucleic acid comprises RNA.
114. The method of claim 113, wherein the at least one nucleic acid comprises mRNA, circRNA, saRNA, and any combination thereof.
115. The method of any one of claims 108-114, comprising transfecting the at least one gastrointestinal cell with the at least one nucleic acid.
116. The method of claim 115, wherein the at least one gastrointestinal cell expresses at least one polypeptide encoded by the at least one nucleic acid.
117. The method of any one of claim 115 or claim 116, wherein the polypeptide comprises granulocyte spleen stimulating factor (G-CSF), green Fluorescent Protein (GFP), and any combination thereof.
118. The method of claim 109, wherein the at least one nucleic acid comprises at least one non-coding RNA.
119. The method of claim 118, wherein the at least one non-coding RNA comprises one or more of interfering short RNAs (siRNA), micrornas (miRNA), long non-coding RNAs, piwi-interacting RNAs (piRNA), nucleolar micrornas (snoRNA), cajal body-specific micrornas (scaRNA), transfer RNAs (tRNA), ribosomal RNAs (rRNA), and intranuclear micrornas (snRNA).
120. A method for treating at least one therapeutic indication in a subject in need thereof, comprising delivering to the subject at least one delivery vehicle described herein or at least one pharmaceutical composition described herein by at least one method for delivering a load described herein.
121. The method of claim 120, wherein the at least one therapeutic indication comprises at least one of: neurodegenerative diseases, ocular diseases, reproductive diseases, gastrointestinal diseases, brain diseases, skin diseases, skeletal diseases, musculoskeletal diseases, pulmonary diseases, thoracic diseases, cystic fibrosis, familial amaurosis dementia, fragile X syndrome, huntington's disease, neurofibromatosis, sickle cell disease, thalassemia, progressive pseudohypertrophic muscular dystrophy, familial Adenomatous Polyposis (FAP), attenuated FAP, microvilli inclusion body disease (MVID), chronic inflammatory bowel disease, ileal Crohn's disease, juvenile polyposis, hereditary diffuse gastric cancer syndrome (HDGC), peutz-Jeghers syndrome, lynch syndrome, gastric adenocarcinoma with gastric proximal polyposis (GAPPS), li-Fraomeni syndrome familial gastric cancer, gilbert syndrome, telangiectasia, mucopolysaccharidosis, osler-Weber-Rendu syndrome, pancreatitis, keratoacanthoma, biliary tract occlusion, morquio syndrome, hurler's syndrome, hunter's syndrome, crigler-Najjar syndrome, rotor syndrome, peutz-Jeghers syndrome, dubin-Johnson syndrome, osteochondrosis, osteomalacia, polyposis, gastrointestinal infection, inflammatory Bowel Disease (IBD), ulcerative colitis, crohn's disease, hemophilia, short Bowel Syndrome (SBS), diabetes, non-alcoholic steatohepatitis (NASH), hodgkin's lymphoma, non-Hodgkin's lymphoma, acute lymphoblastic leukemia or Acute Myelogenous Leukemia (AML), neutropenia, or any combination thereof.
122. The method of claim 121, wherein the at least one therapeutic indication comprises at least one immune-related indication.
123. The method of claim 122, wherein the at least one immune-related indication comprises at least one gastrointestinal indication.
124. The method of claim 123, wherein the at least one therapeutic indication comprises at least one cancer-related indication.
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US202163282421P | 2021-11-23 | 2021-11-23 | |
US63/282,421 | 2021-11-23 | ||
PCT/US2021/063182 WO2022132678A1 (en) | 2020-12-14 | 2021-12-14 | Biological delivery systems |
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