CN117659091A - 一种磷脂类阳离子脂质化合物及其制备得到的脂质纳米粒和应用 - Google Patents
一种磷脂类阳离子脂质化合物及其制备得到的脂质纳米粒和应用 Download PDFInfo
- Publication number
- CN117659091A CN117659091A CN202211057119.3A CN202211057119A CN117659091A CN 117659091 A CN117659091 A CN 117659091A CN 202211057119 A CN202211057119 A CN 202211057119A CN 117659091 A CN117659091 A CN 117659091A
- Authority
- CN
- China
- Prior art keywords
- cationic lipid
- phospholipid
- lipid
- lipid compound
- acid
- 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
Links
- -1 Phospholipid cationic lipid compound Chemical class 0.000 title claims abstract description 81
- 150000002632 lipids Chemical class 0.000 title claims abstract description 69
- 239000002105 nanoparticle Substances 0.000 title claims abstract description 43
- 150000001335 aliphatic alkanes Chemical group 0.000 claims abstract description 18
- 150000001336 alkenes Chemical group 0.000 claims abstract description 11
- 239000000203 mixture Substances 0.000 claims description 22
- 150000007523 nucleic acids Chemical class 0.000 claims description 12
- 108090000623 proteins and genes Proteins 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 11
- 102000039446 nucleic acids Human genes 0.000 claims description 11
- 108020004707 nucleic acids Proteins 0.000 claims description 11
- 229920000642 polymer Polymers 0.000 claims description 10
- 125000001424 substituent group Chemical group 0.000 claims description 8
- 102000004169 proteins and genes Human genes 0.000 claims description 7
- 150000003839 salts Chemical class 0.000 claims description 7
- 229920001184 polypeptide Polymers 0.000 claims description 6
- 238000002360 preparation method Methods 0.000 claims description 6
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 6
- 102000004196 processed proteins & peptides Human genes 0.000 claims description 6
- 229920000469 amphiphilic block copolymer Polymers 0.000 claims description 5
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 5
- 239000008177 pharmaceutical agent Substances 0.000 claims description 4
- 239000003755 preservative agent Substances 0.000 claims description 4
- 230000002335 preservative effect Effects 0.000 claims description 4
- 239000003085 diluting agent Substances 0.000 claims description 3
- 239000003381 stabilizer Substances 0.000 claims description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 238000001890 transfection Methods 0.000 abstract description 17
- 230000000694 effects Effects 0.000 abstract description 16
- 150000003904 phospholipids Chemical group 0.000 abstract description 16
- 230000015572 biosynthetic process Effects 0.000 abstract description 6
- 238000003786 synthesis reaction Methods 0.000 abstract description 6
- 239000003814 drug Substances 0.000 abstract description 5
- 239000008187 granular material Substances 0.000 abstract 1
- 108020004999 messenger RNA Proteins 0.000 description 28
- 239000000523 sample Substances 0.000 description 20
- 238000002474 experimental method Methods 0.000 description 15
- 210000004027 cell Anatomy 0.000 description 13
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- 239000000243 solution Substances 0.000 description 12
- 150000001875 compounds Chemical class 0.000 description 11
- 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 description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- 241000699670 Mus sp. Species 0.000 description 9
- 210000000170 cell membrane Anatomy 0.000 description 8
- 108020004414 DNA Proteins 0.000 description 7
- 102000053602 DNA Human genes 0.000 description 7
- 238000002835 absorbance Methods 0.000 description 7
- 239000007788 liquid Substances 0.000 description 7
- 229920001223 polyethylene glycol Polymers 0.000 description 7
- 229920002477 rna polymer Polymers 0.000 description 7
- 239000000126 substance Substances 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 125000002091 cationic group Chemical group 0.000 description 6
- 230000000052 comparative effect Effects 0.000 description 6
- 239000001257 hydrogen Substances 0.000 description 6
- 229910052739 hydrogen Inorganic materials 0.000 description 6
- 125000004433 nitrogen atom Chemical group N* 0.000 description 6
- 235000018102 proteins Nutrition 0.000 description 6
- 238000001228 spectrum Methods 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- 238000005406 washing Methods 0.000 description 6
- 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 description 5
- 239000002253 acid Substances 0.000 description 5
- 238000004113 cell culture Methods 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- 235000012000 cholesterol Nutrition 0.000 description 5
- 230000034217 membrane fusion Effects 0.000 description 5
- 108091070501 miRNA Proteins 0.000 description 5
- 125000003729 nucleotide group Chemical group 0.000 description 5
- 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 description 5
- 239000013641 positive control Substances 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 4
- 102000040650 (ribonucleotides)n+m Human genes 0.000 description 4
- KILNVBDSWZSGLL-KXQOOQHDSA-N 1,2-dihexadecanoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCCCCCCCCC KILNVBDSWZSGLL-KXQOOQHDSA-N 0.000 description 4
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- 108060001084 Luciferase Proteins 0.000 description 4
- 239000005089 Luciferase Substances 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- 241000699666 Mus <mouse, genus> Species 0.000 description 4
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 239000008280 blood Substances 0.000 description 4
- 210000004369 blood Anatomy 0.000 description 4
- RYYVLZVUVIJVGH-UHFFFAOYSA-N caffeine Chemical compound CN1C(=O)N(C)C(=O)C2=C1N=CN2C RYYVLZVUVIJVGH-UHFFFAOYSA-N 0.000 description 4
- 238000010609 cell counting kit-8 assay Methods 0.000 description 4
- UQLDLKMNUJERMK-UHFFFAOYSA-L di(octadecanoyloxy)lead Chemical compound [Pb+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O UQLDLKMNUJERMK-UHFFFAOYSA-L 0.000 description 4
- 238000005538 encapsulation Methods 0.000 description 4
- 239000007927 intramuscular injection Substances 0.000 description 4
- 238000010255 intramuscular injection Methods 0.000 description 4
- 239000002679 microRNA Substances 0.000 description 4
- 239000002773 nucleotide Substances 0.000 description 4
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 description 4
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 4
- OILXMJHPFNGGTO-UHFFFAOYSA-N (22E)-(24xi)-24-methylcholesta-5,22-dien-3beta-ol Natural products C1C=C2CC(O)CCC2(C)C2C1C1CCC(C(C)C=CC(C)C(C)C)C1(C)CC2 OILXMJHPFNGGTO-UHFFFAOYSA-N 0.000 description 3
- 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 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 3
- JZNWSCPGTDBMEW-UHFFFAOYSA-N Glycerophosphorylethanolamin Natural products NCCOP(O)(=O)OCC(O)CO JZNWSCPGTDBMEW-UHFFFAOYSA-N 0.000 description 3
- 229930195725 Mannitol Natural products 0.000 description 3
- 101001028244 Onchocerca volvulus Fatty-acid and retinol-binding protein 1 Proteins 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 229910019142 PO4 Inorganic materials 0.000 description 3
- 239000002202 Polyethylene glycol Substances 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 229930182558 Sterol Natural products 0.000 description 3
- 108020004566 Transfer RNA Proteins 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- 230000009286 beneficial effect Effects 0.000 description 3
- 230000003833 cell viability Effects 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000003480 eluent Substances 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 238000001415 gene therapy Methods 0.000 description 3
- 230000002068 genetic effect Effects 0.000 description 3
- 230000002163 immunogen Effects 0.000 description 3
- 210000003000 inclusion body Anatomy 0.000 description 3
- 239000000594 mannitol Substances 0.000 description 3
- 235000010355 mannitol Nutrition 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 239000000178 monomer Substances 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 239000002245 particle Substances 0.000 description 3
- 235000021317 phosphate Nutrition 0.000 description 3
- 150000008104 phosphatidylethanolamines Chemical class 0.000 description 3
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 150000003432 sterols Chemical class 0.000 description 3
- 235000003702 sterols Nutrition 0.000 description 3
- 239000006228 supernatant Substances 0.000 description 3
- 230000002195 synergetic effect Effects 0.000 description 3
- 229960005486 vaccine Drugs 0.000 description 3
- 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 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- LDGWQMRUWMSZIU-LQDDAWAPSA-M 2,3-bis[(z)-octadec-9-enoxy]propyl-trimethylazanium;chloride Chemical compound [Cl-].CCCCCCCC\C=C/CCCCCCCCOCC(C[N+](C)(C)C)OCCCCCCCC\C=C/CCCCCCCC LDGWQMRUWMSZIU-LQDDAWAPSA-M 0.000 description 2
- KSXTUUUQYQYKCR-LQDDAWAPSA-M 2,3-bis[[(z)-octadec-9-enoyl]oxy]propyl-trimethylazanium;chloride Chemical compound [Cl-].CCCCCCCC\C=C/CCCCCCCC(=O)OCC(C[N+](C)(C)C)OC(=O)CCCCCCC\C=C/CCCCCCCC KSXTUUUQYQYKCR-LQDDAWAPSA-M 0.000 description 2
- WXTMDXOMEHJXQO-UHFFFAOYSA-N 2,5-dihydroxybenzoic acid Chemical compound OC(=O)C1=CC(O)=CC=C1O WXTMDXOMEHJXQO-UHFFFAOYSA-N 0.000 description 2
- QCXJEYYXVJIFCE-UHFFFAOYSA-N 4-acetamidobenzoic acid Chemical compound CC(=O)NC1=CC=C(C(O)=O)C=C1 QCXJEYYXVJIFCE-UHFFFAOYSA-N 0.000 description 2
- HVBSAKJJOYLTQU-UHFFFAOYSA-N 4-aminobenzenesulfonic acid Chemical compound NC1=CC=C(S(O)(=O)=O)C=C1 HVBSAKJJOYLTQU-UHFFFAOYSA-N 0.000 description 2
- OQMZNAMGEHIHNN-UHFFFAOYSA-N 7-Dehydrostigmasterol Natural products C1C(O)CCC2(C)C(CCC3(C(C(C)C=CC(CC)C(C)C)CCC33)C)C3=CC=C21 OQMZNAMGEHIHNN-UHFFFAOYSA-N 0.000 description 2
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 108090000994 Catalytic RNA Proteins 0.000 description 2
- 102000053642 Catalytic RNA Human genes 0.000 description 2
- 108091028075 Circular RNA Proteins 0.000 description 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 2
- GZDFHIJNHHMENY-UHFFFAOYSA-N Dimethyl dicarbonate Chemical compound COC(=O)OC(=O)OC GZDFHIJNHHMENY-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- 102100022653 Histone H1.5 Human genes 0.000 description 2
- 101000899879 Homo sapiens Histone H1.5 Proteins 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- LPHGQDQBBGAPDZ-UHFFFAOYSA-N Isocaffeine Natural products CN1C(=O)N(C)C(=O)C2=C1N(C)C=N2 LPHGQDQBBGAPDZ-UHFFFAOYSA-N 0.000 description 2
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 2
- QIAFMBKCNZACKA-UHFFFAOYSA-N N-benzoylglycine Chemical compound OC(=O)CNC(=O)C1=CC=CC=C1 QIAFMBKCNZACKA-UHFFFAOYSA-N 0.000 description 2
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 2
- 108700001237 Nucleic Acid-Based Vaccines Proteins 0.000 description 2
- 108091034117 Oligonucleotide Proteins 0.000 description 2
- 108091093037 Peptide nucleic acid Proteins 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 description 2
- 108091027967 Small hairpin RNA Proteins 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 108091046869 Telomeric non-coding RNA Proteins 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- JLCPHMBAVCMARE-UHFFFAOYSA-N [3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-hydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methyl [5-(6-aminopurin-9-yl)-2-(hydroxymethyl)oxolan-3-yl] hydrogen phosphate Polymers Cc1cn(C2CC(OP(O)(=O)OCC3OC(CC3OP(O)(=O)OCC3OC(CC3O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c3nc(N)[nH]c4=O)C(COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3CO)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cc(C)c(=O)[nH]c3=O)n3cc(C)c(=O)[nH]c3=O)n3ccc(N)nc3=O)n3cc(C)c(=O)[nH]c3=O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)O2)c(=O)[nH]c1=O JLCPHMBAVCMARE-UHFFFAOYSA-N 0.000 description 2
- WNLRTRBMVRJNCN-UHFFFAOYSA-N adipic acid Chemical compound OC(=O)CCCCC(O)=O WNLRTRBMVRJNCN-UHFFFAOYSA-N 0.000 description 2
- 235000001014 amino acid Nutrition 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 229940088710 antibiotic agent Drugs 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- LGJMUZUPVCAVPU-UHFFFAOYSA-N beta-Sitostanol Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(C)CCC(CC)C(C)C)C1(C)CC2 LGJMUZUPVCAVPU-UHFFFAOYSA-N 0.000 description 2
- 230000029918 bioluminescence Effects 0.000 description 2
- 238000005415 bioluminescence Methods 0.000 description 2
- 229960001948 caffeine Drugs 0.000 description 2
- VJEONQKOZGKCAK-UHFFFAOYSA-N caffeine Natural products CN1C(=O)N(C)C(=O)C2=C1C=CN2C VJEONQKOZGKCAK-UHFFFAOYSA-N 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 150000001767 cationic compounds Chemical class 0.000 description 2
- 238000012512 characterization method Methods 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 2
- 229960001231 choline Drugs 0.000 description 2
- 239000013068 control sample Substances 0.000 description 2
- MWKFXSUHUHTGQN-UHFFFAOYSA-N decan-1-ol Chemical compound CCCCCCCCCCO MWKFXSUHUHTGQN-UHFFFAOYSA-N 0.000 description 2
- GHVNFZFCNZKVNT-UHFFFAOYSA-N decanoic acid Chemical compound CCCCCCCCCC(O)=O GHVNFZFCNZKVNT-UHFFFAOYSA-N 0.000 description 2
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 238000009826 distribution Methods 0.000 description 2
- POULHZVOKOAJMA-UHFFFAOYSA-N dodecanoic acid Chemical compound CCCCCCCCCCCC(O)=O POULHZVOKOAJMA-UHFFFAOYSA-N 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 210000001163 endosome Anatomy 0.000 description 2
- 235000013922 glutamic acid Nutrition 0.000 description 2
- 239000004220 glutamic acid Substances 0.000 description 2
- KWIUHFFTVRNATP-UHFFFAOYSA-N glycine betaine Chemical compound C[N+](C)(C)CC([O-])=O KWIUHFFTVRNATP-UHFFFAOYSA-N 0.000 description 2
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 2
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 2
- 239000005556 hormone Substances 0.000 description 2
- 229940088597 hormone Drugs 0.000 description 2
- 230000002209 hydrophobic effect Effects 0.000 description 2
- 230000001900 immune effect Effects 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 2
- KQNPFQTWMSNSAP-UHFFFAOYSA-N isobutyric acid Chemical compound CC(C)C(O)=O KQNPFQTWMSNSAP-UHFFFAOYSA-N 0.000 description 2
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 210000003141 lower extremity Anatomy 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 2
- 229940023146 nucleic acid vaccine Drugs 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- PXQPEWDEAKTCGB-UHFFFAOYSA-N orotic acid Chemical compound OC(=O)C1=CC(=O)NC(=O)N1 PXQPEWDEAKTCGB-UHFFFAOYSA-N 0.000 description 2
- 229950004354 phosphorylcholine Drugs 0.000 description 2
- 229920001610 polycaprolactone Polymers 0.000 description 2
- 239000004632 polycaprolactone Substances 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 108091092562 ribozyme Proteins 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- CXMXRPHRNRROMY-UHFFFAOYSA-N sebacic acid Chemical compound OC(=O)CCCCCCCCC(O)=O CXMXRPHRNRROMY-UHFFFAOYSA-N 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- NLQLSVXGSXCXFE-UHFFFAOYSA-N sitosterol Natural products CC=C(/CCC(C)C1CC2C3=CCC4C(C)C(O)CCC4(C)C3CCC2(C)C1)C(C)C NLQLSVXGSXCXFE-UHFFFAOYSA-N 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000012089 stop solution Substances 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 235000000346 sugar Nutrition 0.000 description 2
- 108010057210 telomerase RNA Proteins 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- YAPQBXQYLJRXSA-UHFFFAOYSA-N theobromine Chemical compound CN1C(=O)NC(=O)C2=C1N=CN2C YAPQBXQYLJRXSA-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 230000014616 translation Effects 0.000 description 2
- 239000012224 working solution Substances 0.000 description 2
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 2
- HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 description 1
- KZJWDPNRJALLNS-VPUBHVLGSA-N (-)-beta-Sitosterol Natural products O[C@@H]1CC=2[C@@](C)([C@@H]3[C@H]([C@H]4[C@@](C)([C@H]([C@H](CC[C@@H](C(C)C)CC)C)CC4)CC3)CC=2)CC1 KZJWDPNRJALLNS-VPUBHVLGSA-N 0.000 description 1
- CSVWWLUMXNHWSU-UHFFFAOYSA-N (22E)-(24xi)-24-ethyl-5alpha-cholest-22-en-3beta-ol Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(C)C=CC(CC)C(C)C)C1(C)CC2 CSVWWLUMXNHWSU-UHFFFAOYSA-N 0.000 description 1
- RQOCXCFLRBRBCS-UHFFFAOYSA-N (22E)-cholesta-5,7,22-trien-3beta-ol Natural products C1C(O)CCC2(C)C(CCC3(C(C(C)C=CCC(C)C)CCC33)C)C3=CC=C21 RQOCXCFLRBRBCS-UHFFFAOYSA-N 0.000 description 1
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- WCGUUGGRBIKTOS-GPOJBZKASA-N (3beta)-3-hydroxyurs-12-en-28-oic acid Chemical compound C1C[C@H](O)C(C)(C)[C@@H]2CC[C@@]3(C)[C@]4(C)CC[C@@]5(C(O)=O)CC[C@@H](C)[C@H](C)[C@H]5C4=CC[C@@H]3[C@]21C WCGUUGGRBIKTOS-GPOJBZKASA-N 0.000 description 1
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 1
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- WBYWAXJHAXSJNI-VOTSOKGWSA-M .beta-Phenylacrylic acid Natural products [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 1
- 239000005968 1-Decanol Substances 0.000 description 1
- WTJKGGKOPKCXLL-VYOBOKEXSA-N 1-hexadecanoyl-2-(9Z-octadecenoyl)-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/CCCCCCCC WTJKGGKOPKCXLL-VYOBOKEXSA-N 0.000 description 1
- POTBKLVBOJZRNG-UHFFFAOYSA-N 1-hydroxy-2h-naphthalene-1-carboxylic acid Chemical compound C1=CC=C2C(C(=O)O)(O)CC=CC2=C1 POTBKLVBOJZRNG-UHFFFAOYSA-N 0.000 description 1
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 1
- UVBYMVOUBXYSFV-XUTVFYLZSA-N 1-methylpseudouridine Chemical compound O=C1NC(=O)N(C)C=C1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 UVBYMVOUBXYSFV-XUTVFYLZSA-N 0.000 description 1
- UVBYMVOUBXYSFV-UHFFFAOYSA-N 1-methylpseudouridine Natural products O=C1NC(=O)N(C)C=C1C1C(O)C(O)C(CO)O1 UVBYMVOUBXYSFV-UHFFFAOYSA-N 0.000 description 1
- RTBFRGCFXZNCOE-UHFFFAOYSA-N 1-methylsulfonylpiperidin-4-one Chemical compound CS(=O)(=O)N1CCC(=O)CC1 RTBFRGCFXZNCOE-UHFFFAOYSA-N 0.000 description 1
- 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 description 1
- OWEGMIWEEQEYGQ-UHFFFAOYSA-N 100676-05-9 Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC2C(OC(O)C(O)C2O)CO)O1 OWEGMIWEEQEYGQ-UHFFFAOYSA-N 0.000 description 1
- RSMRWWHFJMENJH-LQDDAWAPSA-M 2,3-bis[[(z)-octadec-9-enoyl]oxy]propyl-trimethylazanium;methyl sulfate Chemical compound COS([O-])(=O)=O.CCCCCCCC\C=C/CCCCCCCC(=O)OCC(C[N+](C)(C)C)OC(=O)CCCCCCC\C=C/CCCCCCCC RSMRWWHFJMENJH-LQDDAWAPSA-M 0.000 description 1
- MSWZFWKMSRAUBD-IVMDWMLBSA-N 2-amino-2-deoxy-D-glucopyranose Chemical compound N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O MSWZFWKMSRAUBD-IVMDWMLBSA-N 0.000 description 1
- SHCCKWGIFIPGNJ-NSUCVBPYSA-N 2-aminoethyl [(2r)-2,3-bis[(z)-octadec-9-enoxy]propyl] hydrogen phosphate Chemical compound CCCCCCCC\C=C/CCCCCCCCOC[C@H](COP(O)(=O)OCCN)OCCCCCCCC\C=C/CCCCCCCC SHCCKWGIFIPGNJ-NSUCVBPYSA-N 0.000 description 1
- ASJSAQIRZKANQN-CRCLSJGQSA-N 2-deoxy-D-ribose Chemical group OC[C@@H](O)[C@@H](O)CC=O ASJSAQIRZKANQN-CRCLSJGQSA-N 0.000 description 1
- BFSVOASYOCHEOV-UHFFFAOYSA-N 2-diethylaminoethanol Chemical compound CCN(CC)CCO BFSVOASYOCHEOV-UHFFFAOYSA-N 0.000 description 1
- 229940013085 2-diethylaminoethanol Drugs 0.000 description 1
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 1
- KLEXDBGYSOIREE-UHFFFAOYSA-N 24xi-n-propylcholesterol Natural products C1C=C2CC(O)CCC2(C)C2C1C1CCC(C(C)CCC(CCC)C(C)C)C1(C)CC2 KLEXDBGYSOIREE-UHFFFAOYSA-N 0.000 description 1
- UAIUNKRWKOVEES-UHFFFAOYSA-N 3,3',5,5'-tetramethylbenzidine Chemical compound CC1=C(N)C(C)=CC(C=2C=C(C)C(N)=C(C)C=2)=C1 UAIUNKRWKOVEES-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- UOQHWNPVNXSDDO-UHFFFAOYSA-N 3-bromoimidazo[1,2-a]pyridine-6-carbonitrile Chemical compound C1=CC(C#N)=CN2C(Br)=CN=C21 UOQHWNPVNXSDDO-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- WUBBRNOQWQTFEX-UHFFFAOYSA-N 4-aminosalicylic acid Chemical compound NC1=CC=C(C(O)=O)C(O)=C1 WUBBRNOQWQTFEX-UHFFFAOYSA-N 0.000 description 1
- LRSASMSXMSNRBT-UHFFFAOYSA-N 5-methylcytosine Chemical compound CC1=CNC(=O)N=C1N LRSASMSXMSNRBT-UHFFFAOYSA-N 0.000 description 1
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- 108020004491 Antisense DNA Proteins 0.000 description 1
- 108020000948 Antisense Oligonucleotides Proteins 0.000 description 1
- 108020005544 Antisense RNA Proteins 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- OILXMJHPFNGGTO-NRHJOKMGSA-N Brassicasterol Natural products O[C@@H]1CC=2[C@@](C)([C@@H]3[C@H]([C@H]4[C@](C)([C@H]([C@@H](/C=C/[C@H](C(C)C)C)C)CC4)CC3)CC=2)CC1 OILXMJHPFNGGTO-NRHJOKMGSA-N 0.000 description 1
- IADDWHRSODFQAA-UHFFFAOYSA-N C(CCCCCCCCCCC)CC(CCCCCCCCCC)=O Chemical compound C(CCCCCCCCCCC)CC(CCCCCCCCCC)=O IADDWHRSODFQAA-UHFFFAOYSA-N 0.000 description 1
- YDNKGFDKKRUKPY-JHOUSYSJSA-N C16 ceramide Natural products CCCCCCCCCCCCCCCC(=O)N[C@@H](CO)[C@H](O)C=CCCCCCCCCCCCCC YDNKGFDKKRUKPY-JHOUSYSJSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- SGNBVLSWZMBQTH-FGAXOLDCSA-N Campesterol Natural products O[C@@H]1CC=2[C@@](C)([C@@H]3[C@H]([C@H]4[C@@](C)([C@H]([C@H](CC[C@H](C(C)C)C)C)CC4)CC3)CC=2)CC1 SGNBVLSWZMBQTH-FGAXOLDCSA-N 0.000 description 1
- LSPHULWDVZXLIL-UHFFFAOYSA-N Camphoric acid Natural products CC1(C)C(C(O)=O)CCC1(C)C(O)=O LSPHULWDVZXLIL-UHFFFAOYSA-N 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- 239000005632 Capric acid (CAS 334-48-5) Substances 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 108010012236 Chemokines Proteins 0.000 description 1
- 102000019034 Chemokines Human genes 0.000 description 1
- WBYWAXJHAXSJNI-SREVYHEPSA-N Cinnamic acid Chemical compound OC(=O)\C=C/C1=CC=CC=C1 WBYWAXJHAXSJNI-SREVYHEPSA-N 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- LPZCCMIISIBREI-MTFRKTCUSA-N Citrostadienol Natural products CC=C(CC[C@@H](C)[C@H]1CC[C@H]2C3=CC[C@H]4[C@H](C)[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C)C(C)C LPZCCMIISIBREI-MTFRKTCUSA-N 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- IGXWBGJHJZYPQS-SSDOTTSWSA-N D-Luciferin Chemical compound OC(=O)[C@H]1CSC(C=2SC3=CC=C(O)C=C3N=2)=N1 IGXWBGJHJZYPQS-SSDOTTSWSA-N 0.000 description 1
- RGHNJXZEOKUKBD-MGCNEYSASA-N D-galactonic acid Chemical compound OC[C@@H](O)[C@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-MGCNEYSASA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-QTVWNMPRSA-N D-mannopyranose Chemical compound OC[C@H]1OC(O)[C@@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-QTVWNMPRSA-N 0.000 description 1
- ARVGMISWLZPBCH-UHFFFAOYSA-N Dehydro-beta-sitosterol Natural products C1C(O)CCC2(C)C(CCC3(C(C(C)CCC(CC)C(C)C)CCC33)C)C3=CC=C21 ARVGMISWLZPBCH-UHFFFAOYSA-N 0.000 description 1
- CYCGRDQQIOGCKX-UHFFFAOYSA-N Dehydro-luciferin Natural products OC(=O)C1=CSC(C=2SC3=CC(O)=CC=C3N=2)=N1 CYCGRDQQIOGCKX-UHFFFAOYSA-N 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical compound C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 description 1
- 238000008157 ELISA kit Methods 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- DNVPQKQSNYMLRS-NXVQYWJNSA-N Ergosterol Natural products CC(C)[C@@H](C)C=C[C@H](C)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O)CC[C@]4(C)[C@@H]3CC[C@]12C DNVPQKQSNYMLRS-NXVQYWJNSA-N 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- BJGNCJDXODQBOB-UHFFFAOYSA-N Fivefly Luciferin Natural products OC(=O)C1CSC(C=2SC3=CC(O)=CC=C3N=2)=N1 BJGNCJDXODQBOB-UHFFFAOYSA-N 0.000 description 1
- DSLZVSRJTYRBFB-UHFFFAOYSA-N Galactaric acid Natural products OC(=O)C(O)C(O)C(O)C(O)C(O)=O DSLZVSRJTYRBFB-UHFFFAOYSA-N 0.000 description 1
- IAJILQKETJEXLJ-UHFFFAOYSA-N Galacturonsaeure Natural products O=CC(O)C(O)C(O)C(O)C(O)=O IAJILQKETJEXLJ-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 108020005004 Guide RNA Proteins 0.000 description 1
- BTEISVKTSQLKST-UHFFFAOYSA-N Haliclonasterol Natural products CC(C=CC(C)C(C)(C)C)C1CCC2C3=CC=C4CC(O)CCC4(C)C3CCC12C BTEISVKTSQLKST-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 102000014150 Interferons Human genes 0.000 description 1
- 108010050904 Interferons Proteins 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 239000005639 Lauric acid Substances 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- DDWFXDSYGUXRAY-UHFFFAOYSA-N Luciferin Natural products CCc1c(C)c(CC2NC(=O)C(=C2C=C)C)[nH]c1Cc3[nH]c4C(=C5/NC(CC(=O)O)C(C)C5CC(=O)O)CC(=O)c4c3C DDWFXDSYGUXRAY-UHFFFAOYSA-N 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-PICCSMPSSA-N Maltose Natural products O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-PICCSMPSSA-N 0.000 description 1
- CRJGESKKUOMBCT-VQTJNVASSA-N N-acetylsphinganine Chemical compound CCCCCCCCCCCCCCC[C@@H](O)[C@H](CO)NC(C)=O CRJGESKKUOMBCT-VQTJNVASSA-N 0.000 description 1
- UEEJHVSXFDXPFK-UHFFFAOYSA-N N-dimethylaminoethanol Chemical compound CN(C)CCO UEEJHVSXFDXPFK-UHFFFAOYSA-N 0.000 description 1
- HTLZVHNRZJPSMI-UHFFFAOYSA-N N-ethylpiperidine Chemical compound CCN1CCCCC1 HTLZVHNRZJPSMI-UHFFFAOYSA-N 0.000 description 1
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
- 229940123247 Neurotransmitter antagonist Drugs 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 108091028043 Nucleic acid sequence Proteins 0.000 description 1
- 239000005642 Oleic acid Substances 0.000 description 1
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 1
- 235000021314 Palmitic acid Nutrition 0.000 description 1
- 229920002732 Polyanhydride Polymers 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- 229920001710 Polyorthoester Polymers 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 108010029485 Protein Isoforms Proteins 0.000 description 1
- 102000001708 Protein Isoforms Human genes 0.000 description 1
- 229930185560 Pseudouridine Natural products 0.000 description 1
- PTJWIQPHWPFNBW-UHFFFAOYSA-N Pseudouridine C Natural products OC1C(O)C(CO)OC1C1=CNC(=O)NC1=O PTJWIQPHWPFNBW-UHFFFAOYSA-N 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 108010008281 Recombinant Fusion Proteins Proteins 0.000 description 1
- 102000007056 Recombinant Fusion Proteins Human genes 0.000 description 1
- 108700008625 Reporter Genes Proteins 0.000 description 1
- PYMYPHUHKUWMLA-LMVFSUKVSA-N Ribose Natural products OC[C@@H](O)[C@@H](O)[C@@H](O)C=O PYMYPHUHKUWMLA-LMVFSUKVSA-N 0.000 description 1
- 108020004682 Single-Stranded DNA Proteins 0.000 description 1
- 108020004688 Small Nuclear RNA Proteins 0.000 description 1
- 102000039471 Small Nuclear RNA Human genes 0.000 description 1
- 108020004459 Small interfering RNA Proteins 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- BCKXLBQYZLBQEK-KVVVOXFISA-M Sodium oleate Chemical compound [Na+].CCCCCCCC\C=C/CCCCCCCC([O-])=O BCKXLBQYZLBQEK-KVVVOXFISA-M 0.000 description 1
- 108091027544 Subgenomic mRNA Proteins 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 108091028113 Trans-activating crRNA Proteins 0.000 description 1
- HDTRYLNUVZCQOY-WSWWMNSNSA-N Trehalose Natural products O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-WSWWMNSNSA-N 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- OILXMJHPFNGGTO-ZRUUVFCLSA-N UNPD197407 Natural products C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)C=C[C@H](C)C(C)C)[C@@]1(C)CC2 OILXMJHPFNGGTO-ZRUUVFCLSA-N 0.000 description 1
- HZYXFRGVBOPPNZ-UHFFFAOYSA-N UNPD88870 Natural products C1C=C2CC(O)CCC2(C)C2C1C1CCC(C(C)=CCC(CC)C(C)C)C1(C)CC2 HZYXFRGVBOPPNZ-UHFFFAOYSA-N 0.000 description 1
- ABUBSBSOTTXVPV-UHFFFAOYSA-H [U+6].CC([O-])=O.CC([O-])=O.CC([O-])=O.CC([O-])=O.CC([O-])=O.CC([O-])=O Chemical compound [U+6].CC([O-])=O.CC([O-])=O.CC([O-])=O.CC([O-])=O.CC([O-])=O.CC([O-])=O ABUBSBSOTTXVPV-UHFFFAOYSA-H 0.000 description 1
- 210000000683 abdominal cavity Anatomy 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000001361 adipic acid Substances 0.000 description 1
- 235000011037 adipic acid Nutrition 0.000 description 1
- 229960000250 adipic acid Drugs 0.000 description 1
- IAJILQKETJEXLJ-QTBDOELSSA-N aldehydo-D-glucuronic acid Chemical compound O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)C(O)=O IAJILQKETJEXLJ-QTBDOELSSA-N 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 229940087168 alpha tocopherol Drugs 0.000 description 1
- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 description 1
- HMFHBZSHGGEWLO-UHFFFAOYSA-N alpha-D-Furanose-Ribose Natural products OCC1OC(O)C(O)C1O HMFHBZSHGGEWLO-UHFFFAOYSA-N 0.000 description 1
- 150000001371 alpha-amino acids Chemical class 0.000 description 1
- 235000008206 alpha-amino acids Nutrition 0.000 description 1
- AWUCVROLDVIAJX-UHFFFAOYSA-N alpha-glycerophosphate Natural products OCC(O)COP(O)(O)=O AWUCVROLDVIAJX-UHFFFAOYSA-N 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical class [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 229960004909 aminosalicylic acid Drugs 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 229940035674 anesthetics Drugs 0.000 description 1
- JFCQEDHGNNZCLN-UHFFFAOYSA-N anhydrous glutaric acid Natural products OC(=O)CCCC(O)=O JFCQEDHGNNZCLN-UHFFFAOYSA-N 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000002924 anti-infective effect Effects 0.000 description 1
- 230000002141 anti-parasite Effects 0.000 description 1
- 229940125681 anticonvulsant agent Drugs 0.000 description 1
- 239000001961 anticonvulsive agent Substances 0.000 description 1
- 239000000935 antidepressant agent Substances 0.000 description 1
- 229940005513 antidepressants Drugs 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 239000000427 antigen Substances 0.000 description 1
- 108091007433 antigens Proteins 0.000 description 1
- 102000036639 antigens Human genes 0.000 description 1
- 239000000030 antiglaucoma agent Substances 0.000 description 1
- 229960005475 antiinfective agent Drugs 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940125687 antiparasitic agent Drugs 0.000 description 1
- 239000003096 antiparasitic agent Substances 0.000 description 1
- 239000003816 antisense DNA Substances 0.000 description 1
- 239000000074 antisense oligonucleotide Substances 0.000 description 1
- 238000012230 antisense oligonucleotides Methods 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 229960003121 arginine Drugs 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 229960005261 aspartic acid Drugs 0.000 description 1
- JUHORIMYRDESRB-UHFFFAOYSA-N benzathine Chemical compound C=1C=CC=CC=1CNCCNCC1=CC=CC=C1 JUHORIMYRDESRB-UHFFFAOYSA-N 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 229960004365 benzoic acid Drugs 0.000 description 1
- MSWZFWKMSRAUBD-UHFFFAOYSA-N beta-D-galactosamine Natural products NC1C(O)OC(CO)C(O)C1O MSWZFWKMSRAUBD-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- WGDUUQDYDIIBKT-UHFFFAOYSA-N beta-Pseudouridine Natural products OC1OC(CN2C=CC(=O)NC2=O)C(O)C1O WGDUUQDYDIIBKT-UHFFFAOYSA-N 0.000 description 1
- MJVXAPPOFPTTCA-UHFFFAOYSA-N beta-Sistosterol Natural products CCC(CCC(C)C1CCC2C3CC=C4C(C)C(O)CCC4(C)C3CCC12C)C(C)C MJVXAPPOFPTTCA-UHFFFAOYSA-N 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QUYVBRFLSA-N beta-maltose Chemical compound OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O GUBGYTABKSRVRQ-QUYVBRFLSA-N 0.000 description 1
- NJKOMDUNNDKEAI-UHFFFAOYSA-N beta-sitosterol Natural products CCC(CCC(C)C1CCC2(C)C3CC=C4CC(O)CCC4C3CCC12C)C(C)C NJKOMDUNNDKEAI-UHFFFAOYSA-N 0.000 description 1
- 229960003237 betaine Drugs 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 229920001400 block copolymer Polymers 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- OILXMJHPFNGGTO-ZAUYPBDWSA-N brassicasterol 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)/C=C/[C@H](C)C(C)C)[C@@]1(C)CC2 OILXMJHPFNGGTO-ZAUYPBDWSA-N 0.000 description 1
- 235000004420 brassicasterol Nutrition 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- SGNBVLSWZMBQTH-PODYLUTMSA-N campesterol 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)CC[C@@H](C)C(C)C)[C@@]1(C)CC2 SGNBVLSWZMBQTH-PODYLUTMSA-N 0.000 description 1
- 235000000431 campesterol Nutrition 0.000 description 1
- LSPHULWDVZXLIL-QUBYGPBYSA-N camphoric acid Chemical compound CC1(C)[C@H](C(O)=O)CC[C@]1(C)C(O)=O LSPHULWDVZXLIL-QUBYGPBYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 239000006143 cell culture medium Substances 0.000 description 1
- 229940106189 ceramide Drugs 0.000 description 1
- ZVEQCJWYRWKARO-UHFFFAOYSA-N ceramide Natural products CCCCCCCCCCCCCCC(O)C(=O)NC(CO)C(O)C=CCCC=C(C)CCCCCCCCC ZVEQCJWYRWKARO-UHFFFAOYSA-N 0.000 description 1
- 150000001783 ceramides Chemical class 0.000 description 1
- 150000003841 chloride salts Chemical class 0.000 description 1
- 229930016911 cinnamic acid Natural products 0.000 description 1
- 235000013985 cinnamic acid Nutrition 0.000 description 1
- 239000007979 citrate buffer Substances 0.000 description 1
- 239000003184 complementary RNA Substances 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 239000003246 corticosteroid Substances 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 150000001982 diacylglycerols Chemical class 0.000 description 1
- 125000005265 dialkylamine group Chemical class 0.000 description 1
- 150000001985 dialkylglycerols Chemical class 0.000 description 1
- 238000000502 dialysis Methods 0.000 description 1
- 229960005215 dichloroacetic acid Drugs 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 239000012470 diluted sample Substances 0.000 description 1
- 229960003724 dimyristoylphosphatidylcholine Drugs 0.000 description 1
- 150000002016 disaccharides Chemical class 0.000 description 1
- MOTZDAYCYVMXPC-UHFFFAOYSA-N dodecyl hydrogen sulfate Chemical compound CCCCCCCCCCCCOS(O)(=O)=O MOTZDAYCYVMXPC-UHFFFAOYSA-N 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- DNVPQKQSNYMLRS-SOWFXMKYSA-N ergosterol Chemical compound C1[C@@H](O)CC[C@]2(C)[C@H](CC[C@]3([C@H]([C@H](C)/C=C/[C@@H](C)C(C)C)CC[C@H]33)C)C3=CC=C21 DNVPQKQSNYMLRS-SOWFXMKYSA-N 0.000 description 1
- AFAXGSQYZLGZPG-UHFFFAOYSA-N ethanedisulfonic acid Chemical compound OS(=O)(=O)CCS(O)(=O)=O AFAXGSQYZLGZPG-UHFFFAOYSA-N 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- HXQVQGWHFRNKMS-UHFFFAOYSA-M ethylmercurithiosalicylic acid Chemical compound CC[Hg]SC1=CC=CC=C1C(O)=O HXQVQGWHFRNKMS-UHFFFAOYSA-M 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- GNBHRKFJIUUOQI-UHFFFAOYSA-N fluorescein Chemical compound O1C(=O)C2=CC=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 GNBHRKFJIUUOQI-UHFFFAOYSA-N 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- DSLZVSRJTYRBFB-DUHBMQHGSA-N galactaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)C(O)=O DSLZVSRJTYRBFB-DUHBMQHGSA-N 0.000 description 1
- XGVJWXAYKUHDOO-UHFFFAOYSA-N galanthidine Natural products C1CN2CC3=CC=4OCOC=4C=C3C3C2C1=CC(O)C3O XGVJWXAYKUHDOO-UHFFFAOYSA-N 0.000 description 1
- 239000003193 general anesthetic agent Substances 0.000 description 1
- 229960005219 gentisic acid Drugs 0.000 description 1
- 239000000174 gluconic acid Substances 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- 229960002442 glucosamine Drugs 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 229940097043 glucuronic acid Drugs 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 229960002885 histidine Drugs 0.000 description 1
- 239000003667 hormone antagonist Substances 0.000 description 1
- 239000012216 imaging agent Substances 0.000 description 1
- 230000008105 immune reaction Effects 0.000 description 1
- 230000008073 immune recognition Effects 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 230000003053 immunization Effects 0.000 description 1
- 238000002649 immunization Methods 0.000 description 1
- 239000002955 immunomodulating agent Substances 0.000 description 1
- 229940121354 immunomodulator Drugs 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 230000002452 interceptive effect Effects 0.000 description 1
- 229940079322 interferon Drugs 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- FZWBNHMXJMCXLU-BLAUPYHCSA-N isomaltotriose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@@H](OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O)O1 FZWBNHMXJMCXLU-BLAUPYHCSA-N 0.000 description 1
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
- 238000005304 joining Methods 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 229940099563 lactobionic acid Drugs 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 239000003589 local anesthetic agent Substances 0.000 description 1
- 229960005015 local anesthetics Drugs 0.000 description 1
- XGVJWXAYKUHDOO-DANNLKNASA-N lycorine Chemical compound C1CN2CC3=CC=4OCOC=4C=C3[C@H]3[C@H]2C1=C[C@H](O)[C@H]3O XGVJWXAYKUHDOO-DANNLKNASA-N 0.000 description 1
- KQAOMBGKIWRWNA-UHFFFAOYSA-N lycorine Natural products OC1C=C2CCN3C2C(C1O)c4cc5OCOc5cc34 KQAOMBGKIWRWNA-UHFFFAOYSA-N 0.000 description 1
- 229960003646 lysine Drugs 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 229960001855 mannitol Drugs 0.000 description 1
- 229940041290 mannose Drugs 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- WBYWAXJHAXSJNI-UHFFFAOYSA-N methyl p-hydroxycinnamate Natural products OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 description 1
- 238000001000 micrograph Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 150000002772 monosaccharides Chemical class 0.000 description 1
- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 description 1
- 239000002086 nanomaterial Substances 0.000 description 1
- DFFZOPXDTCDZDP-UHFFFAOYSA-N naphthalene-1,5-dicarboxylic acid Chemical compound C1=CC=C2C(C(=O)O)=CC=CC2=C1C(O)=O DFFZOPXDTCDZDP-UHFFFAOYSA-N 0.000 description 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-N naphthalene-2-sulfonic acid Chemical compound C1=CC=CC2=CC(S(=O)(=O)O)=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-N 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- VVGIYYKRAMHVLU-UHFFFAOYSA-N newbouldiamide Natural products CCCCCCCCCCCCCCCCCCCC(O)C(O)C(O)C(CO)NC(=O)CCCCCCCCCCCCCCCCC VVGIYYKRAMHVLU-UHFFFAOYSA-N 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 229960003512 nicotinic acid Drugs 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 229920001542 oligosaccharide Polymers 0.000 description 1
- 150000002482 oligosaccharides Chemical class 0.000 description 1
- 229960005010 orotic acid Drugs 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 235000019371 penicillin G benzathine Nutrition 0.000 description 1
- 150000002972 pentoses Chemical class 0.000 description 1
- 150000008103 phosphatidic acids Chemical class 0.000 description 1
- 229920001606 poly(lactic acid-co-glycolic acid) Polymers 0.000 description 1
- 239000002745 poly(ortho ester) Substances 0.000 description 1
- 229920000768 polyamine Polymers 0.000 description 1
- 239000004626 polylactic acid Substances 0.000 description 1
- 229940117828 polylactic acid-polyglycolic acid copolymer Drugs 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- WSHYKIAQCMIPTB-UHFFFAOYSA-M potassium;2-oxo-3-(3-oxo-1-phenylbutyl)chromen-4-olate Chemical compound [K+].[O-]C=1C2=CC=CC=C2OC(=O)C=1C(CC(=O)C)C1=CC=CC=C1 WSHYKIAQCMIPTB-UHFFFAOYSA-M 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 239000001294 propane Substances 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000001243 protein synthesis Methods 0.000 description 1
- 230000002797 proteolythic effect Effects 0.000 description 1
- PTJWIQPHWPFNBW-GBNDHIKLSA-N pseudouridine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1C1=CNC(=O)NC1=O PTJWIQPHWPFNBW-GBNDHIKLSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 229940107700 pyruvic acid Drugs 0.000 description 1
- 125000001453 quaternary ammonium group Chemical group 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 125000000548 ribosyl group Chemical group C1([C@H](O)[C@H](O)[C@H](O1)CO)* 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- KZJWDPNRJALLNS-VJSFXXLFSA-N sitosterol 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)CC[C@@H](CC)C(C)C)[C@@]1(C)CC2 KZJWDPNRJALLNS-VJSFXXLFSA-N 0.000 description 1
- 235000015500 sitosterol Nutrition 0.000 description 1
- 229950005143 sitosterol Drugs 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- AWUCVROLDVIAJX-GSVOUGTGSA-N sn-glycerol 3-phosphate Chemical compound OC[C@@H](O)COP(O)(O)=O AWUCVROLDVIAJX-GSVOUGTGSA-N 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000007974 sodium acetate buffer Substances 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- HCXVJBMSMIARIN-PHZDYDNGSA-N stigmasterol 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)/C=C/[C@@H](CC)C(C)C)[C@@]1(C)CC2 HCXVJBMSMIARIN-PHZDYDNGSA-N 0.000 description 1
- 229940032091 stigmasterol Drugs 0.000 description 1
- 235000016831 stigmasterol Nutrition 0.000 description 1
- BFDNMXAIBMJLBB-UHFFFAOYSA-N stigmasterol Natural products CCC(C=CC(C)C1CCCC2C3CC=C4CC(O)CCC4(C)C3CCC12C)C(C)C BFDNMXAIBMJLBB-UHFFFAOYSA-N 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 229950000244 sulfanilic acid Drugs 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 150000004044 tetrasaccharides Chemical class 0.000 description 1
- 229960004559 theobromine Drugs 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 229960000984 tocofersolan Drugs 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000013519 translation Methods 0.000 description 1
- 238000004627 transmission electron microscopy Methods 0.000 description 1
- 238000011282 treatment Methods 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
- 150000004043 trisaccharides Chemical class 0.000 description 1
- 238000000108 ultra-filtration Methods 0.000 description 1
- PLSAJKYPRJGMHO-UHFFFAOYSA-N ursolic acid Natural products CC1CCC2(CCC3(C)C(C=CC4C5(C)CCC(O)C(C)(C)C5CCC34C)C2C1C)C(=O)O PLSAJKYPRJGMHO-UHFFFAOYSA-N 0.000 description 1
- 229940096998 ursolic acid Drugs 0.000 description 1
- 238000012418 validation experiment Methods 0.000 description 1
- 239000002076 α-tocopherol Substances 0.000 description 1
- 235000004835 α-tocopherol Nutrition 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Medicinal Preparation (AREA)
Abstract
本发明公开了一种磷脂类阳离子脂质化合物，结构通式如下所示：其中，R1为烷烃链，C的个数为1‑12个；R2为烷烃链或烯烃链，C的个数为1‑18个；本发明的阳离子脂质化合物引入磷脂基团，制备得到的脂质纳米粒相比市场已在使用的LNP(辉瑞样品)具有更好的转染效果，具有意想不到的技术效果；另外本发明的脂质纳米粒的安全性好，生物相容性高，合成步骤简单，适合生物医药产业化。
Description
技术领域
本发明涉及生物医药领域，特别是一种新的阳离子脂质及其制备得到的脂质纳米粒和应用。
背景技术
基因治疗(gene therapy)是通过将外源基因导入靶细胞，以纠正或补偿缺陷、异常基因引起的疾病，达到治疗目的的一种治疗方法。核酸疫苗(nucleic acid vaccine),也称基因疫苗(genetic vaccine),是指将含编码免疫原蛋白或多肽的核酸序列(如DNA、mRNA等)导入宿主体内，通过宿主细胞表达免疫原蛋白或多肽，诱导宿主细胞产生对该免疫原的免疫应答，以达到预防和治疗疾病的目的。其中，确保外源基因的顺利导入是基因治疗过程和基因疫苗免疫极为重要的一环。在众多基因导入的方法中，开发合适的脂质纳米粒(Lipid Nanoparticle，LNP)包裹核酸，使其靶向至目标细胞，并将特定基因的核酸递送至细胞内的方法逐渐为科学家所使用。
核酸药物与普通化学药物的一个明显区别是核酸带有数量庞大的磷酸根，因而呈负电，且分子量大。为了使其能够被脂质纳米粒更好地包裹，人们开发了阳离子脂质等多种脂质化合物。
“阳离子脂质化合物”指能够带正电的脂质。示例性的阳离子脂质包括一种或多种带有正电荷的胺基团。优选的阳离子脂质是可电离的，可以根据pH值以带正电的形式或中性形式存在。阳离子脂质的电离影响脂质纳米粒在不同pH条件下的表面电荷。这种电荷状态可以影响其在血液中的免疫识别、血液清除和组织分布，以及其在细胞内的内涵体逃逸的能力，对于核酸的细胞内递送是至关重要的。
本发明将磷脂引入阳离子脂质，通过这样结构的阳离子脂质制备得到的脂质纳米粒，具有比市场上脂质纳米粒更好的细胞膜融合能力和转染效果，具有意想不到的技术效果。
发明内容
为解决现有技术的不足，本发明的目的在于提供一种磷脂类阳离子脂质化合物及其制备得到的脂质纳米粒和应用，本发明的脂质纳米粒具有显著性进步的细胞膜融合能力、内涵体逃逸能力，具有更强的转染效果和药物递送效果。
为了实现上述目标，本发明采用如下的技术方案：
一种磷脂类阳离子脂质化合物，结构通式如下所示：
其中，R1为烷烃链，C的个数为1-12个；
R2为烷烃链或烯烃链，C的个数为1-18个。
前述的一种磷脂类阳离子脂质化合物，R1为烷烃链，C的个数为1-12个；R2为无取代基的烷烃链，C的个数为1-18个；作为一种实施例，结构式如下所示：
前述的一种磷脂类阳离子脂质化合物，R1为烷烃链，C的个数为1-12个；R2为有取代基的烷烃链，C的个数为1-18个；其中取代基为烷烃基，C的个数为1-12个；作为一种实施例，结构式如下所示：
前述的一种磷脂类阳离子脂质化合物，R1为烷烃链，C的个数为1-12个；R2为烯烃链，C的个数为1-18个；作为一种实施例，结构式如下所示：
前述的一种磷脂类阳离子脂质化合物，作为一种实施例，R1为：
需要说明的是，这里并非穷举，只要为烷烃链，C的个数为1-12个，无论带取代基或不带取代基，无论取代基的位置在哪，都受本发明的启示，都在本发明的保护范围内。
前述的一种磷脂类阳离子脂质化合物，R2为：
需要说明的是，这里并非穷举，只要为烷烃链或烯烃链，C的个数为1-18个；无论带取代基或不带取代基或无论取代基的位置在哪，都受本发明的启示，都在本发明的保护范围内；无论双键的位置在哪或或有几个双键，都受本发明的启示，都在本发明的保护范围内。
一种磷脂类阳离子脂质化合物制备得到的脂质纳米粒，其特征在于，包括：前述的一种或多种阳离子脂质化合物、助脂质、结构脂质、聚合物缀合脂质或两亲性嵌段共聚物中的一种或几种的组合。组分不受限制，可以是现有已知的物质也可以是未知的物质，只要是采用了本发明结构的阳离子脂质化合物均在本发明的保护范围内，且均受本发明的启示。
前述的一种磷脂类阳离子脂质化合物制备得到的脂质纳米粒，阳离子脂质化合物与助脂质的摩尔比为0.5:1-10:1，阳离子脂质化合物与结构脂质的摩尔比为0.5:1-5:1，阳离子脂质化合物与聚合物缀合脂质的摩尔比为10：1-250：1，阳离子脂质化合物与两亲性嵌段共聚物的摩尔比为0.5：1-80：1。
前述的一种磷脂类阳离子脂质化合物制备得到的脂质纳米粒，脂质纳米粒的平均尺寸为30-200nm，脂质纳米粒的制剂的多分散指数≤0.5。
一种磷脂类阳离子脂质化合物的应用，包括：应用于包含前述的阳离子脂质化合物的组合物、其立体异构体、其互变异构体或其在药学上可接受的盐。
前述的一种磷脂类阳离子脂质化合物的应用，组合物包括：前述的脂质纳米粒，所载的药物试剂，药物辅助剂；组合物的组分不受限制，可以是现有已知的物质组成的组合物也可以是未知的物质组成的组合物，只要是采用了本发明结构的阳离子脂质化合物均在本发明的保护范围内，且均受本发明的启示。
前述的一种磷脂类阳离子脂质化合物的应用，所载的药物试剂包括：核酸分子，小分子化合物，多肽或蛋白质中的一种或多种；所载的药物试剂的选择和组合配方不受限制，只要是采用了本发明结构的阳离子脂质化合物均在本发明的保护范围内，且均受本发明的启示。
前述的一种磷脂类阳离子脂质化合物的应用，药物辅助剂包括：稀释剂，稳定剂，防腐剂或冻干保护剂中的一种或多种；药物辅助剂的选择和组合配方不受限制，只要是采用了本发明结构的阳离子脂质化合物均在本发明的保护范围内，且均受本发明的启示。
本发明的有益之处在于：
本发明的阳离子脂质化合物引入磷脂基团，一方面，磷脂结构模拟了细胞膜的磷脂双分子层结构，利于细胞膜融合，另一方面，分子中的氮原子使其在酸性条件下产生质子海绵效应，增加其内含体逃逸能力，相比市场已在使用的LNP(辉瑞样品)具有更好的转染效果，具有意想不到的技术效果；
从实验可知：本发明的结构在N原子远离磷酸基的一侧是烯烃基作为尾巴时，转染效率显著性增强，说明本发明这样带磷脂基团的阳离子脂质的结构配合烯烃基在提高转染效果上具有协同作用；
本发明结构的阳离子脂质转染效率高，安全性好，生物相容性高，合成步骤简单，适合生物医药产业化。
附图说明
图1是本发明的H1的氢谱图；
图2是本发明的H2的氢谱图；
图3是本发明的H3的氢谱图；
图4是本发明的H4的氢谱图；
图5是本发明的H5的氢谱图；
图6是本发明采用样品H-1的化合物制备得到脂质纳米粒的电镜图；
图7是本发明阳离子脂质化合物制备得到的LNP和市场上的LNP的免疫效果对比实验结果示意图。
术语、英文缩写解释说明：
核酸是脱氧核糖核酸(DNA)和核糖核酸(RNA)的总称，是由多个核苷酸单体组成的生物大分子；核酸由核苷酸组成，核苷酸单体由五碳糖、磷酸基、含氮碱基、或任何修饰基团组成。如果五碳糖是核糖，则形成的聚合物是RNA；如果五碳糖是脱氧核糖，则形成的聚合物是DNA。
核酸分子包括单链DNA、双链DNA、短异构体、mRNA、tRNA、rRNA、长链非编码RNA(lncRNA)、微小非编码RNA(miRNA和siRNA)、端粒酶RNA(Telomerase RNA Component)、小分子RNA(snRNA和scRNA)、环状RNA(circRNA)、合成miRNA(miRNA mimics、miRNA agomir、miRNA antagomir)、反义DNA、反义RNA、核酶(ribozyme)、不对称干扰RNA(aiRNA)、Dicer-substrate RNA(dsRNA)、小发夹RNA(shRNA)、转移RNA(tRNA)、信使RNA(mRNA)、gRNA、sgRNA、crRNA或tracrRNA、锁核酸(LNA)、肽核酸(PNA)、吗啉反义寡核苷酸、吗啉代寡核苷酸或生物定制寡核苷酸等。这里的举例也并非穷举，只要是由核苷酸单体聚合成的都可以应用于本发明。
药学上可接受的盐是指酸加成盐或碱加成盐。
其中酸加成盐的酸包括但不限于：盐酸、氢溴酸、硫酸、硝酸、磷酸、酸式磷酸盐、乙酸、2,2-二氯乙酸、己二酸、海藻酸、抗坏血酸、天冬氨酸、苯磺酸、苯甲酸、4-乙酰氨基苯甲酸、樟脑酸、樟脑-10-磺酸、癸酸、己酸、辛酸、碳酸、肉桂酸，柠檬酸、环酰胺酸、十二烷基硫酸、乙烷-1,2-二磺酸、乙烷磺酸、2-羟基乙磺酸、甲酸、富马酸、半乳糖酸、龙胆酸、葡庚酸、葡糖酸、葡聚糖酸、葡糖醛酸、谷氨酸、戊二酸、2-氧代戊二酸、甘油磷酸、乙醇酸、马尿酸、异丁酸、乳酸、乳糖酸、月桂酸、马来酸、苹果酸、丙二酸、扁桃酸、甲磺酸、粘酸、萘-1,5二甲酸、萘-2-磺酸、1-羟基-2-萘甲酸、烟酸、油酸、乳清酸、草酸、棕榈酸、棕榈酸、丙酸、焦谷氨酸、丙酮酸、水杨酸、4-氨基水杨酸、癸二酸、硬脂酸、琥珀酸、酒石酸、硫氰酸、对甲苯磺酸、三氟乙酸、季铵酸以及十一碳烯酸。
其中碱加成盐举例包括但不限于：钠盐、钾盐、锂盐、铵盐、钙盐、镁盐、铁盐，锌盐、铜盐、锰盐、以及铝盐；有机碱包括但不限于氨、异丙胺、三甲胺、二乙胺、三乙胺、三丙胺、二乙醇胺、乙醇胺、脱醇、2-二甲基氨基乙醇、2-二乙基氨基乙醇、赖氨酸、精氨酸、组氨酸、咖啡因、普鲁卡因、肼苯胺、胆碱、甜菜碱、苯那敏(benethamine)、苄星青霉素(benzathine)、乙二胺、葡糖胺、甲基葡糖胺、可可碱、三乙醇胺、嘌呤、哌嗪、哌啶、N-乙基哌啶、以及聚胺树脂；优选地，有机碱是异丙胺、二乙胺、乙醇胺、三甲胺、二环己胺、胆碱和咖啡因。
mRNA，信使RNA，中文译名：信使核糖核酸，是由DNA的一条链作为模板转录而来的、携带遗传信息能指导蛋白质合成的一类单链核糖核酸。mRNA可以是单顺反子mRNA也可以是多顺反子mRNA。mRNA也可以包含一种或多种功能性核苷酸类似物，功能性核苷酸类似物举例包括：假尿嘧啶核苷、1-甲基-假尿嘧啶核苷或5-甲基胞嘧啶等。这里的举例也并非穷举，任何修饰的mRNA或其衍生物都可以应用于本发明。
结构脂质包括：胆固醇、非甾醇、谷固醇、麦角固醇、菜油甾醇、豆甾醇、芸苔甾醇、番茄碱、番茄碱、熊果酸、α-生育酚或皮质类固醇中的一种或几种。这里并非穷举，结构脂质的选择不受限制，只要是采用本发明结构的阳离子脂质化合物均在本发明的保护范围内，均受本发明启示。
聚合物缀合脂质为聚乙二醇化脂质；作为一种实施例，聚乙二醇化脂质包括：PEG修饰的磷脂酰乙醇胺、PEG修饰的磷脂酸、PEG修饰的神经酰胺、PEG修饰的二烷基胺、PEG修饰的二酰基甘油或PEG修饰的二烷基甘油中的一种或多种。这里并非穷举，聚合物缀合脂质的选择不受限制，只要是采用本发明结构的阳离子脂质化合物均在本发明的保护范围内，均受本发明启示。
助脂质包括：磷脂酰胆碱、磷脂酰乙醇胺、鞘磷脂(SM)、甾醇及其衍生物、神经酰胺、带电脂质中的一种或几种的组合；磷脂酰胆碱作为一种优选包括：DSPC，DPPC，DMPC，DOPC，POPC；磷脂酰乙醇胺作为一种优选为DOPE；甾醇作为一种优选为胆固醇；带电脂质作为一种实施例为DOTAP、DOTMA、18PA；这里并非穷举，只要是采用本发明结构的阳离子脂质化合物的组合物均在本发明的保护范围内，均受本发明启示。这里并非穷举，助脂质的选择不受限制，只要是采用本发明结构的阳离子脂质化合物均在本发明的保护范围内，均受本发明启示。
小分子化合物可以是用于治疗或预防的试剂中的有效成分，例如：抗肿瘤药、抗感染药、局部麻醉药、抗抑郁药、抗惊厥药、抗生素/抗菌剂、抗真菌药、抗寄生虫药、激素、激素拮抗剂、免疫调节剂、神经递质拮抗剂、抗青光眼剂、麻醉剂、或成像剂等，这里并非穷举。
多肽是α－氨基酸以肽键连接在一起而形成的化合物，是蛋白质水解的中间产物。
蛋白质是由氨基酸以“脱水缩合”的方式组成的多肽链经过盘曲折叠形成的具有一定空间结构的物质；蛋白质可以是干扰素、蛋白质激素、细胞因子、趋化因子或者酶类等。
稀释剂是本领域技术人员可知的任意可以药用的水溶性辅料，包括：氨基酸、单糖、二糖、三糖、四糖、五糖、其它寡聚糖、甘露醇、右旋糖苷、氯化钠、山梨醇、聚乙二醇、磷酸盐，或其衍生物等。
稳定剂可以是本领域技术人员可知的任意可以药用的辅料：吐温-80、十二烷基硫酸钠、油酸钠、甘露醇、甘露糖或海藻酸钠等。
防腐剂可以是本领域技术人员可知的任意可以药用的防腐剂，比如：硫柳汞等。
冻干保护剂可以是领域技术人员可知的任意可以药用的冻干保护剂，比如：葡萄糖、甘露醇、蔗糖、乳糖，海藻糖，麦芽糖等。
DSPC：英文名称：Distearoyl Phosphatidylcholine，1,2-distearoyl-sn-glycero-3-phosphocholine；中文名称：二硬脂酰基卵磷脂，CAS号:816-94-4。
DPPC：中文名称：二棕榈酸磷脂酰胆碱；英文名称：1,2-DIPALMITOYL-SN-GLYCERO-3-PHOSPHOCHOLINE，CAS号:63-89-8。
DMPC：中文名称：二肉豆蔻酰磷脂酰胆碱；英文名称：1,2-Dimyristoyl-sn-glycero-3-phosphocholine，CAS号:18194-24-6。
DOPC：中文名称：1,2-二油酰基-sn-甘油-3-磷酸胆碱；英文名称：1,2-dioleoyl-sn-glycero-3-phosphocholine，CAS号:4235-95-4。
POPC：中文名称：2-油酰-1-棕榈锡甘油-3-磷酸胆碱；英文名称：2-Oleoyl-1-palmitoyl-sn-glycero-3-phosphocholine，CAS号:26853-31-6。
DOPE：中文名称：1,2-二油酰-SN-甘油-3-磷酰乙醇胺；英文名称：1,2-DIOLEOYL-SN-GLYCERO-3-PHOSPHOETHANOLAMINE，CAS号：4004-05-1。
DOTAP：中文名称：N-[1-(2，3-二油酰氧基)丙基]-N，N，N-三甲基铵甲基-硫酸盐；英文名称：1,2-dioleoyl-3-trimethylammonium-propane(chloride salt)，CAS号：144189-73-1；化学结构式如下所示：
DOTMA：中文名称：N,N,N-三甲基-2,3-双(十八碳-9-烯-1-基氧基)丙-1-铵氯化物，CAS号:1325214-86-5，化学结构式如下所示：
18PA：CAS号：108392-02-5，化学结构式如下所示：
SM：中文名称：鞘磷脂(SM)；英文名称：sphingomyelin。
PEG：中文名称：聚乙二醇；英文名称：Polyethylene glycol。
两亲性嵌段共聚物指：PEG与下列一种或多种聚合物组分的嵌段共聚物，聚合物组分包括：聚乳酸-聚羟基乙酸共聚物(PLGA)、聚乳酸(PLA)、聚己内酯(PCL)、聚原酸酯、聚酸酐、聚(β-氨基酯)(PBAE)中的一种或多种。
具体实施方式
以下结合附图和具体实施例对本发明作具体的介绍。
通过以下实施例1的制备方法制备阳离子脂质化合物。
实施例1：
合成过程如下所示：
化合物c的合成：将1-癸醇(化合物b，5.00g，31.58mmol)，三乙胺(Et3N，4.79g，47.38mmol)溶于100mL四氢呋喃(THF)中，冰浴条件下滴加化合物a(5.85g，41.06mmol)，逐渐恢复至室温，并搅拌反应12h。TLC监测反应完全后，使用旋转蒸发仪减压蒸馏除去溶剂。加入200mL乙酸乙酯，等体积饱和碳酸氢钠溶液洗2次，等体积饱和氯化钠溶液洗1次，无水硫酸钠干燥30min，使用旋转蒸发仪减压蒸馏除去溶剂，柱分离纯化(硅胶柱，洗脱液为PE：EA＝50：1(体积比))，得7.5g无色液体，收率90％。
化合物d的合成：将化合物c(5.00g，18.92mmol)，哌嗪(3.26g，37.84mmol)溶于30mL二甲亚砜(DMSO)中，氮气保护条件下，70℃加热搅拌反应24h，TLC监测反应完全后，使用旋转蒸发仪减压蒸馏除去溶剂，柱分离纯化(硅胶柱，洗脱液为DCM：MeOH＝1：1(体积比))，得4.1g白色固体，收率62％。1H NMR(400MHz,Chloroform-d)δ4.04–3.71(m,4H),3.14(s,4H),2.73(s,4H),2.62(s,2H),1.58(p,J＝6.7Hz,2H),1.40–1.13(m,14H),0.89–0.82(m,3H).
化合物H-4的合成：将1-癸基十四醛(化合物e，0.39g，1.11mmol)，化合物d(0.3g，0.86mmol)溶于5mL二氯甲烷(DCM)中，冰浴条件下滴加三乙酰氧基硼氢化钠(0.27g，1.28mmol)，逐渐恢复至室温，并搅拌反应12h。TLC监测反应完全后，使用旋转蒸发仪减压蒸馏除去溶剂。加入100mL乙酸乙酯，等体积饱和碳酸氢钠溶液洗2次，等体积饱和氯化钠溶液洗1次，无水硫酸钠干燥30min，使用旋转蒸发仪减压蒸馏除去溶剂，柱分离纯化(硅胶柱，洗脱液为DCM：MeOH＝50：1(体积比))，得0.3g白色蜡状固体，收率51％。1H NMR(400MHz,Chloroform-d)δ4.21(s,2H),3.88(q,J＝6.7Hz,2H),3.66–2.49(m,10H),2.38–2.09(m,2H),1.59(d,J＝7.3Hz,2H),1.48–1.09(m,56H),0.86(t,J＝6.7Hz,9H).MS m/z(ESI)：687.64[M+H]+。氢谱图如图4所示。
采用实施例1的方法，同样也可以制备得到化合物H-1、H-2、H-3、H-5，对比样品h-1在此不再一一赘述。
实验一：
制备mRNA-LNP用于以下实验，制备方法为：
步骤一：将表1中H-1到H-5和对比样品h-1对应的阳离子化合物，DOPE(艾维拓(上海)医药科技有限公司)，胆固醇(艾维拓(上海)医药科技有限公司)，以及PEG-脂质以设计的处方配比(Lipid/DOPE/Cholesterol/lipid-PEG为50/40/25/2(摩尔比))，制得的脂质纳米粒。将表1中市售对比样品对应的阳离子化合物(辉瑞疫苗BNT162b2)通过其最优配比Lipid/DSPC/Cholesterol/lipid-PEG为50/10/38.5/1.5(摩尔比))制得的脂质纳米粒。将这些脂质纳米粒溶于乙醇中(Lipid的浓度20mg/mL)，并充分混匀得到阳离子脂质乙醇溶液。
步骤二：按照脂质纳米粒(LNP)与mRNA质量比为10:1到30:1准备mRNA，使用柠檬酸盐或醋酸钠缓冲液(pH＝3或5)将mRNA稀释至0.2mg/mL。
步骤三，将步骤一得到的阳离子脂质乙醇溶液与mRNA溶液以体积比为1:5到1:1的比例充分混匀。所获纳米粒通过超滤和透析的手段纯化，过滤除菌后，使用MalvernZetasizer Nano ZS表征mRNA-LNP(包载mRNA的脂质纳米粒)的粒径约和PDI，再使用Ribogreen RNA定量测定试剂盒(Thermo Fisher)测定mRNA的包封率。
表1
实验二：转染效率验证实验：
雄性ICR小鼠(6-8week，上海杰思捷实验动物有限公司)饲养在22±2℃以及相对湿度为45–75％的实验条件下，光照/黑暗周期为12h。使用编码荧光素酶的mRNA(luciferase mRNA)作为报道基因。荧光素酶催化荧光素产生生物荧光，通过检测单位时间内生物荧光强度，反映LNP的转染效率。以荧光素酶mRNA(购自ApexBio Technology)为例，准备实验一获得的mRNA-LNP样品H1-5，市售对比样品，对比样品h-1；将以上样品分别以150μg/kg mRNA的剂量，通过肌肉注射给药，每组样品一只小鼠，两条腿。取特定的时间点，于小鼠腹腔注射荧光素(20μg/mL)，5分钟后，将小鼠置于小动物活体成像仪测定荧光强度，最后的结果以平均荧光强度表示，小鼠腹腔注射给药后荧光强度实验结果如表2所示。
表2
/>
结果分析：
本发明的含有H1-H5的LNP样品与市售对比样品(辉瑞BNT162b2)的实验结果对比可知：本发明结构的阳离子脂质化合物制备得到的脂质纳米粒LNP样品的转染效率显著高于市售对比样品的转染效率，具有显著的进步；
由H1-5和h1的实验结果对比可知：本发明结构特征的阳离子脂质制备得到的LNP比h1得到的LNP的转染效率高，原因可能在于一方面磷脂结构模拟细胞膜的磷脂双分子层结构，利于细胞膜融合，另一方面，分子中的氮原子使其在酸性条件下产生质子海绵效应，增加其内含体逃逸能力；
由H1-4和H5的实验结果对比可知：在N原子远离磷酸基的一侧疏水尾部引入双键时，转染效率显著性增强，说明本发明这样带磷脂基团的阳离子脂质的结构配合烯烃基的疏水尾部在提高转染效果上具有协同作用。
实验三：脂质纳米粒结构形貌表征实验
透射电镜样品的制备及表征(以样品H-1为例)。在铜网上滴上10μ制备好的样品15L，放置10min后吸干样品并晾干。醋酸双氧铀染色5min，滤纸吸干染液后干燥过夜，利用透射电子显微镜(TEM)观察其形貌。
如图6所示，本发明的脂质纳米粒都能形成稳定的纳米结构，尺寸分布较窄，尺寸随不同的脂质纳米粒的结构有所变化，在30-150nm范围内。
实验四：生物相容性实验
使用CCK-8(cell counting kit-8)试剂盒测定细胞活力。将处于指数增长期的Hep3B细胞(100μL，细胞密度为2×104个/ml)悬浮液加入96孔板中，于细胞培养箱中孵育24h，然后从每个孔中除去细胞培养液，并添加100μL含mRNA20μg/mL的LNP的新制细胞培养液，和细胞共孵育4h。随后，除去细胞上清液，加入新鲜细胞培养液，继续孵育20h。然后，除去上清液，加入含CCK-8工作溶液(10μL/mL)的新鲜的细胞培养液100μL，孵育2h，空白孔的设置：加含CCK-8工作溶液的细胞培养液。使用多功能微孔板检测仪检测每孔于450nm处的吸光度(检测过程中孔板中不能出现气泡)，将未经LNP处理的细胞作为对照组，将其细胞活力设为100％。
细胞活力(％)＝[A1-A0]/[A2-A0]×100；
A1为加药组吸光度，A0为空白组吸光度，A2为对照组吸光度。实验结果如表3所示。
表3
实验结果表明在限定的LNP浓度内，大多数细胞活力大于95％，未见明显细胞毒性。
实验五：脂质纳米粒低温保存稳定性实验
以样品H-1为例，将按照配方制作的脂质纳米粒置于4℃条件下低温保存，取不同时间点(0天、6天、10天、15天、30天、45天)，使用Malvern Zetasizer Nano ZS表征mRNA-LNP(包载mRNA的脂质纳米粒)的粒径(Size)约和PDI，mRNA的包封率均使用Ribogreen RNA定量测定试剂盒(Thermo Fisher)测定。测定结果见表4所示。
表4
由表4可知：本发明的脂质分子形成的LNP(脂质纳米粒)可在低温储存90天粒径和包封率仍然稳定，方便产品的运输和保存，适合工业生产。
实验六：免疫效果动物试验
材料准备：六周龄雌性Balb/c小鼠，体重15～20g，30只，饲养于温度22±2℃，相对湿度45-75％的实验环境中，光照/黑暗周期为12h。小鼠购入后先于动物房内适应一周后方可进行正式的动物试验。将30只小鼠随机分成5组，第一组后腿肌肉注射等体积PBS(阴性对照组)，第二组后腿肌肉注射市售对比样品(阳性对照组1)、mRNA、PBS的混合物，第三组为后腿肌肉注射对比样品h-1(阳性对照组2)、mRNA、PBS的混合物，第四组后腿肌肉注射样品H-1(试验组)、10μg的mRNA、PBS的混合物；以上mRNA为基于自主设计的模板通过体外转录合成的可表达Spike全长的mRNA。
实验过程为：在第0和14天，按照以上五个分组将包载mRNA的LNP混合物肌肉注射到Balb/c小鼠体内。在第13和21天进行眼部取血，将血样放在37℃孵育1小时后，3500rpm离心15分钟，取上清进行分析。通过自制ELISA试剂盒检测一免和二免小鼠血清对Delta变异株S1蛋白特异性抗体滴度。
检测一免和二免小鼠血清对Delta变异株S1蛋白特异性抗体滴度的具体操作过程如下：将Spike S1重组蛋白加入96孔板，每孔加0.25μg，4℃放置过夜。第二天，弃去孔内液体，使用5％BSA的PBST溶液(200ul)在37℃条件下封闭1h。之后弃去孔内液体，用PBST洗涤液200ul洗涤3遍，每遍3min，甩板晾干。将小鼠血清用PBS稀释(稀释比列为1：20000)，或者标准品用PBS稀释为一系列浓度(母液为1ug/ul，对半稀释，共14个标曲)。将稀释后的样品和标准品100μL加入空中，37℃，孵育2h。弃去孔内液体，用PBST洗涤液200ul洗涤3遍，每遍3min，甩板晾干。加入Goat anti-mouse IgG HRP(PBS 1:5000稀释)，每孔100ul，37℃，1h。弃去孔内液体，用PBST洗涤液200ul洗涤3遍,每遍3min，甩板晾干。将TMB底物A液和B液等比例混合，每孔100μL，置37℃避光放置数分钟(3-5mins)。在650nm测吸光度，最高吸光度值在1.5附近时，即可加100ul终止液。加入终止液后15min内检测450nm处的吸光度值。根据标准曲线公式计算各组IgG含量。
实验结果如图7所示，结果显示：阳性对照组1、2和试验组三组mRNA均可产生针对S1蛋白特异性抗体，试验组的抗体滴度显著高于阳性对照组1、2，试验组可高效递送mRNA进入细胞，表达抗原，进而激起体内免疫反应，产生相应抗体，发挥保护功能。
综上所述：本发明的阳离子脂质化合物引入磷脂基团，一方面，磷脂结构模拟了细胞膜的磷脂双分子层结构，利于细胞膜融合，另一方面，分子中的氮原子使其在酸性条件下产生质子海绵效应，增加其内含体逃逸能力；从实验一到六可知：相比市场已在使用的LNP(辉瑞样品)具有更好的转染效果，安全性好，生物相容性高，稳定性好，具有意想不到的技术效果；从实验二可知：本发明的结构在N原子远离磷酸基的一侧是烯烃基作为尾巴时，转染效率显著性增强，说明本发明这样带磷脂基团的阳离子脂质的结构配合烯烃基在提高转染效果上具有协同作用。
以上显示和描述了本发明的基本原理、主要特征和优点。本行业的技术人员应该了解，上述实施例不以任何形式限制本发明，凡采用等同替换或等效变换的方式所获得的技术方案，均落在本发明的保护范围内。
Claims (10)
1.一种磷脂类阳离子脂质化合物，其特征在于，结构通式如下所示：
其中，R1为烷烃链，C的个数为1-12个；
R2为烷烃链或烯烃链，C的个数为1-18个。
2.权利要求1所述的一种磷脂类阳离子脂质化合物，其特征在于，所述R1为烷烃链，C的个数为1-12个；R2为无取代基的烷烃链，C的个数为1-18个；结构式如下所示：
3.权利要求1所述的一种磷脂类阳离子脂质化合物，其特征在于，所述R1为烷烃链，C的个数为1-12个；R2为有取代基的烷烃链，C的个数为1-18个；其中取代基为烷烃基，C的个数为1-12个；结构式如下所示：
4.权利要求1所述的一种磷脂类阳离子脂质化合物，其特征在于，所述R1为烷烃链，C的个数为1-12个；R2为烯烃链，C的个数为1-18个；结构式如下所示：
5.权利要求1所述的一种磷脂类阳离子脂质化合物，其特征在于，R1为：
6.权利要求1所述的一种磷脂类阳离子脂质化合物，其特征在于，R2为：
7.一种磷脂类阳离子脂质化合物制备得到的脂质纳米粒，其特征在于，包括：权利要求1所述的一种或多种阳离子脂质化合物、助脂质、结构脂质、聚合物缀合脂质或两亲性嵌段共聚物中的一种或几种的组合。
8.根据权利要求7所述的一种磷脂类阳离子脂质化合物制备得到的脂质纳米粒，其特征在于，所述阳离子脂质化合物与助脂质的摩尔比为0.5:1-10:1，所述阳离子脂质化合物与结构脂质的摩尔比为0.5:1-5:1，所述阳离子脂质化合物与聚合物缀合脂质的摩尔比为10：1-250：
1，所述阳离子脂质化合物与两亲性嵌段共聚物的摩尔比为0.5：1-80：1。
9.根据权利要求7所述的一种磷脂类阳离子脂质化合物制备得到的脂质纳米粒，其特征在于，所述脂质纳米粒的平均尺寸为30-200nm，所述脂质纳米粒的制剂的多分散指数≤0.5。
10.一种磷脂类阳离子脂质化合物的应用，其特征在于，包括：应用于包含权利要求1所述的阳离子脂质化合物的组合物、其立体异构体、其互变异构体或其在药学上可接受的盐；所述组合物包括：权利要求7所述的脂质纳米粒，所载的药物试剂，药物辅助剂；所述所载的药物试剂包括：核酸分子，小分子化合物，多肽或蛋白质中的一种或多种；所述药物辅助剂包括：稀释剂，稳定剂，防腐剂或冻干保护剂中的一种或多种。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211057119.3A CN117659091A (zh) | 2022-08-31 | 2022-08-31 | 一种磷脂类阳离子脂质化合物及其制备得到的脂质纳米粒和应用 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211057119.3A CN117659091A (zh) | 2022-08-31 | 2022-08-31 | 一种磷脂类阳离子脂质化合物及其制备得到的脂质纳米粒和应用 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN117659091A true CN117659091A (zh) | 2024-03-08 |
Family
ID=90072047
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202211057119.3A Pending CN117659091A (zh) | 2022-08-31 | 2022-08-31 | 一种磷脂类阳离子脂质化合物及其制备得到的脂质纳米粒和应用 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN117659091A (zh) |
-
2022
- 2022-08-31 CN CN202211057119.3A patent/CN117659091A/zh active Pending
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US11472766B2 (en) | Lipid nanoparticle composition | |
| CN115784920B (zh) | 一种转染效率高的可电离脂质化合物及其应用 | |
| CN114890907B (zh) | 一种阳离子脂质化合物及其制备方法和应用 | |
| CN116063205B (zh) | 一种含烷基化氨基甲酸酯键的脂质化合物及其应用 | |
| US20230053437A1 (en) | Lipid compounds and lipid nanoparticle compositions | |
| TW202229227A (zh) | 脂質化合物及脂質奈米顆粒組合物 | |
| CN114206463A (zh) | 脂质化合物和脂质纳米颗粒组合物 | |
| CN116615472A (zh) | 聚合物缀合的脂质化合物和脂质纳米颗粒组合物 | |
| US20230348362A1 (en) | Lipid compounds and lipid nanoparticle compositions | |
| WO2023036148A1 (zh) | 一类阳离子脂质化合物及其应用 | |
| US11964052B2 (en) | Lipid compounds and lipid nanoparticle compositions | |
| CN117659091A (zh) | 一种磷脂类阳离子脂质化合物及其制备得到的脂质纳米粒和应用 | |
| CN116947669B (zh) | 一种转染效率高的可电离脂质化合物及其应用 | |
| WO2024067639A1 (zh) | 一种转染效率高的可电离脂质化合物及其应用 | |
| CN115947671B (zh) | 一种含氨基甲酸酯键的脂质化合物及其应用 | |
| WO2024109665A1 (zh) | 一种含氨基甲酸酯键的脂质化合物及其应用 | |
| WO2024083172A1 (zh) | 脂质化合物和脂质纳米颗粒组合物 | |
| WO2024083171A1 (zh) | 脂质化合物和脂质纳米颗粒组合物 | |
| WO2024022263A1 (zh) | 脂质化合物和脂质纳米颗粒组合物 | |
| WO2024109798A1 (zh) | 脂质化合物和脂质纳米颗粒组合物 | |
| WO2023116804A1 (zh) | 脂质化合物和脂质纳米颗粒组合物 | |
| CN117069785A (zh) | 脂质化合物和脂质纳米颗粒组合物 | |
| CN114591386A (zh) | 一种含尿苷衍生物的纳米粒、核酸纳米复合物及其制备方法和用途 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination |