CN117257982A - 一种nk细胞药物递送系统及其制备方法和用途 - Google Patents
一种nk细胞药物递送系统及其制备方法和用途 Download PDFInfo
- Publication number
- CN117257982A CN117257982A CN202311050561.8A CN202311050561A CN117257982A CN 117257982 A CN117257982 A CN 117257982A CN 202311050561 A CN202311050561 A CN 202311050561A CN 117257982 A CN117257982 A CN 117257982A
- Authority
- CN
- China
- Prior art keywords
- drug
- cells
- cell
- delivery system
- loaded
- 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
- 210000000822 natural killer cell Anatomy 0.000 title claims abstract description 115
- 238000002360 preparation method Methods 0.000 title claims abstract description 25
- 238000012377 drug delivery Methods 0.000 title claims description 48
- 239000003814 drug Substances 0.000 claims abstract description 163
- 229940079593 drug Drugs 0.000 claims abstract description 127
- 239000002105 nanoparticle Substances 0.000 claims abstract description 95
- 210000004027 cell Anatomy 0.000 claims abstract description 44
- 125000003396 thiol group Chemical group [H]S* 0.000 claims abstract description 33
- 208000014644 Brain disease Diseases 0.000 claims abstract description 21
- 230000008685 targeting Effects 0.000 claims abstract description 18
- 125000005439 maleimidyl group Chemical group C1(C=CC(N1*)=O)=O 0.000 claims abstract description 9
- 210000004556 brain Anatomy 0.000 claims description 29
- 238000000034 method Methods 0.000 claims description 22
- 239000004698 Polyethylene Substances 0.000 claims description 18
- 229920000573 polyethylene Polymers 0.000 claims description 18
- 238000011282 treatment Methods 0.000 claims description 17
- 239000003638 chemical reducing agent Substances 0.000 claims description 15
- 238000002156 mixing Methods 0.000 claims description 15
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 12
- 239000002861 polymer material Substances 0.000 claims description 11
- 239000003960 organic solvent Substances 0.000 claims description 10
- 229920000642 polymer Polymers 0.000 claims description 10
- 239000000243 solution Substances 0.000 claims description 10
- 238000011534 incubation Methods 0.000 claims description 8
- 229920001184 polypeptide Polymers 0.000 claims description 8
- 102000004196 processed proteins & peptides Human genes 0.000 claims description 8
- 102000009027 Albumins Human genes 0.000 claims description 7
- 108010088751 Albumins Proteins 0.000 claims description 7
- 229920001577 copolymer Polymers 0.000 claims description 7
- 239000000725 suspension Substances 0.000 claims description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- 239000000463 material Substances 0.000 claims description 6
- 229920001610 polycaprolactone Polymers 0.000 claims description 4
- 239000004632 polycaprolactone Substances 0.000 claims description 4
- PBVAJRFEEOIAGW-UHFFFAOYSA-N 3-[bis(2-carboxyethyl)phosphanyl]propanoic acid;hydrochloride Chemical compound Cl.OC(=O)CCP(CCC(O)=O)CCC(O)=O PBVAJRFEEOIAGW-UHFFFAOYSA-N 0.000 claims description 3
- 238000000502 dialysis Methods 0.000 claims description 3
- 239000012046 mixed solvent Substances 0.000 claims description 3
- 239000004626 polylactic acid Substances 0.000 claims description 3
- 108010064942 Angiopep-2 Proteins 0.000 claims description 2
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 claims description 2
- 102000018697 Membrane Proteins Human genes 0.000 claims description 2
- 108010052285 Membrane Proteins Proteins 0.000 claims description 2
- UFULAYFCSOUIOV-UHFFFAOYSA-N cysteamine Chemical compound NCCS UFULAYFCSOUIOV-UHFFFAOYSA-N 0.000 claims description 2
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 claims description 2
- 235000018417 cysteine Nutrition 0.000 claims description 2
- WQABCVAJNWAXTE-UHFFFAOYSA-N dimercaprol Chemical compound OCC(S)CS WQABCVAJNWAXTE-UHFFFAOYSA-N 0.000 claims description 2
- VHJLVAABSRFDPM-QWWZWVQMSA-N dithiothreitol Chemical compound SC[C@@H](O)[C@H](O)CS VHJLVAABSRFDPM-QWWZWVQMSA-N 0.000 claims description 2
- DNJIEGIFACGWOD-UHFFFAOYSA-N ethyl mercaptane Natural products CCS DNJIEGIFACGWOD-UHFFFAOYSA-N 0.000 claims description 2
- 229920000747 poly(lactic acid) Polymers 0.000 claims description 2
- 238000001338 self-assembly Methods 0.000 claims description 2
- DGVVWUTYPXICAM-UHFFFAOYSA-N β‐Mercaptoethanol Chemical compound OCCS DGVVWUTYPXICAM-UHFFFAOYSA-N 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 3
- 150000003573 thiols Chemical class 0.000 claims 3
- 229940039227 diagnostic agent Drugs 0.000 claims 1
- 239000000032 diagnostic agent Substances 0.000 claims 1
- 229960001051 dimercaprol Drugs 0.000 claims 1
- 238000011321 prophylaxis Methods 0.000 claims 1
- 208000018737 Parkinson disease Diseases 0.000 description 24
- 230000008499 blood brain barrier function Effects 0.000 description 17
- 210000001218 blood-brain barrier Anatomy 0.000 description 17
- 239000002245 particle Substances 0.000 description 13
- 230000001225 therapeutic effect Effects 0.000 description 13
- 241000699670 Mus sp. Species 0.000 description 11
- PZBFGYYEXUXCOF-UHFFFAOYSA-N TCEP Chemical compound OC(=O)CCP(CCC(O)=O)CCC(O)=O PZBFGYYEXUXCOF-UHFFFAOYSA-N 0.000 description 11
- 238000010172 mouse model Methods 0.000 description 9
- 230000000694 effects Effects 0.000 description 8
- 238000002474 experimental method Methods 0.000 description 8
- 238000000338 in vitro Methods 0.000 description 8
- 238000011068 loading method Methods 0.000 description 8
- 206010061218 Inflammation Diseases 0.000 description 7
- 230000004054 inflammatory process Effects 0.000 description 7
- -1 BODIPY Chemical compound 0.000 description 6
- 238000005538 encapsulation Methods 0.000 description 6
- 238000000799 fluorescence microscopy Methods 0.000 description 6
- 208000003174 Brain Neoplasms Diseases 0.000 description 5
- 238000001356 surgical procedure Methods 0.000 description 5
- UGJMXCAKCUNAIE-UHFFFAOYSA-N Gabapentin Chemical compound OC(=O)CC1(CN)CCCCC1 UGJMXCAKCUNAIE-UHFFFAOYSA-N 0.000 description 4
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 4
- 241000699666 Mus <mouse, genus> Species 0.000 description 4
- 210000005013 brain tissue Anatomy 0.000 description 4
- VFLDPWHFBUODDF-FCXRPNKRSA-N curcumin Chemical compound C1=C(O)C(OC)=CC(\C=C\C(=O)CC(=O)\C=C\C=2C=C(OC)C(O)=CC=2)=C1 VFLDPWHFBUODDF-FCXRPNKRSA-N 0.000 description 4
- ADEBPBSSDYVVLD-UHFFFAOYSA-N donepezil Chemical compound O=C1C=2C=C(OC)C(OC)=CC=2CC1CC(CC1)CCN1CC1=CC=CC=C1 ADEBPBSSDYVVLD-UHFFFAOYSA-N 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 238000010253 intravenous injection Methods 0.000 description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 4
- 230000007246 mechanism Effects 0.000 description 4
- 235000018102 proteins Nutrition 0.000 description 4
- 102000004169 proteins and genes Human genes 0.000 description 4
- 108090000623 proteins and genes Proteins 0.000 description 4
- 210000003462 vein Anatomy 0.000 description 4
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 3
- 206010051290 Central nervous system lesion Diseases 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
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 229930195725 Mannitol Natural products 0.000 description 3
- 241000700605 Viruses Species 0.000 description 3
- 238000009825 accumulation Methods 0.000 description 3
- 229960001138 acetylsalicylic acid Drugs 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 230000004888 barrier function Effects 0.000 description 3
- 230000001413 cellular effect Effects 0.000 description 3
- 210000000805 cytoplasm Anatomy 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 239000006185 dispersion Substances 0.000 description 3
- 239000000594 mannitol Substances 0.000 description 3
- 229960001855 mannitol Drugs 0.000 description 3
- 235000010355 mannitol Nutrition 0.000 description 3
- 239000011259 mixed solution Substances 0.000 description 3
- 150000003904 phospholipids Chemical class 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 229940126586 small molecule drug Drugs 0.000 description 3
- 239000006228 supernatant Substances 0.000 description 3
- MKJIEFSOBYUXJB-HOCLYGCPSA-N (3S,11bS)-9,10-dimethoxy-3-isobutyl-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-one Chemical compound C1CN2C[C@H](CC(C)C)C(=O)C[C@H]2C2=C1C=C(OC)C(OC)=C2 MKJIEFSOBYUXJB-HOCLYGCPSA-N 0.000 description 2
- FWBHETKCLVMNFS-UHFFFAOYSA-N 4',6-Diamino-2-phenylindol Chemical compound C1=CC(C(=N)N)=CC=C1C1=CC2=CC=C(C(N)=N)C=C2N1 FWBHETKCLVMNFS-UHFFFAOYSA-N 0.000 description 2
- 208000024827 Alzheimer disease Diseases 0.000 description 2
- HJXMNVQARNZTEE-UHFFFAOYSA-N Butylphthalide Chemical compound C1=CC=C2C(CCCC)OC(=O)C2=C1 HJXMNVQARNZTEE-UHFFFAOYSA-N 0.000 description 2
- 102000004127 Cytokines Human genes 0.000 description 2
- 108090000695 Cytokines Proteins 0.000 description 2
- 206010061818 Disease progression Diseases 0.000 description 2
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- 208000023105 Huntington disease Diseases 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 208000036110 Neuroinflammatory disease Diseases 0.000 description 2
- XSVMFMHYUFZWBK-NSHDSACASA-N Rivastigmine Chemical compound CCN(C)C(=O)OC1=CC=CC([C@H](C)N(C)C)=C1 XSVMFMHYUFZWBK-NSHDSACASA-N 0.000 description 2
- RYMZZMVNJRMUDD-UHFFFAOYSA-N SJ000286063 Natural products C12C(OC(=O)C(C)(C)CC)CC(C)C=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 RYMZZMVNJRMUDD-UHFFFAOYSA-N 0.000 description 2
- 208000030886 Traumatic Brain injury Diseases 0.000 description 2
- 102000003802 alpha-Synuclein Human genes 0.000 description 2
- 108090000185 alpha-Synuclein Proteins 0.000 description 2
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 208000025698 brain inflammatory disease Diseases 0.000 description 2
- 208000026106 cerebrovascular disease Diseases 0.000 description 2
- 238000010276 construction Methods 0.000 description 2
- 235000012754 curcumin Nutrition 0.000 description 2
- 229940109262 curcumin Drugs 0.000 description 2
- 239000004148 curcumin Substances 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- VFLDPWHFBUODDF-UHFFFAOYSA-N diferuloylmethane Natural products C1=C(O)C(OC)=CC(C=CC(=O)CC(=O)C=CC=2C=C(OC)C(O)=CC=2)=C1 VFLDPWHFBUODDF-UHFFFAOYSA-N 0.000 description 2
- 230000005750 disease progression Effects 0.000 description 2
- 229960003530 donepezil Drugs 0.000 description 2
- 239000000975 dye Substances 0.000 description 2
- 206010014599 encephalitis Diseases 0.000 description 2
- 206010015037 epilepsy Diseases 0.000 description 2
- 230000017188 evasion or tolerance of host immune response Effects 0.000 description 2
- 229960002870 gabapentin Drugs 0.000 description 2
- ASUTZQLVASHGKV-JDFRZJQESA-N galanthamine Chemical compound O1C(=C23)C(OC)=CC=C2CN(C)CC[C@]23[C@@H]1C[C@@H](O)C=C2 ASUTZQLVASHGKV-JDFRZJQESA-N 0.000 description 2
- 210000002216 heart Anatomy 0.000 description 2
- 208000003906 hydrocephalus Diseases 0.000 description 2
- 230000028993 immune response Effects 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 210000003734 kidney Anatomy 0.000 description 2
- 235000014655 lactic acid Nutrition 0.000 description 2
- 239000004310 lactic acid Substances 0.000 description 2
- 230000003902 lesion Effects 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- 230000004807 localization Effects 0.000 description 2
- 210000004072 lung Anatomy 0.000 description 2
- 229960005321 mecobalamin Drugs 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 206010027191 meningioma Diseases 0.000 description 2
- 235000007672 methylcobalamin Nutrition 0.000 description 2
- JEWJRMKHSMTXPP-BYFNXCQMSA-M methylcobalamin Chemical compound C[Co+]N([C@]1([H])[C@H](CC(N)=O)[C@]\2(CCC(=O)NC[C@H](C)OP(O)(=O)OC3[C@H]([C@H](O[C@@H]3CO)N3C4=CC(C)=C(C)C=C4N=C3)O)C)C/2=C(C)\C([C@H](C/2(C)C)CCC(N)=O)=N\C\2=C\C([C@H]([C@@]/2(CC(N)=O)C)CCC(N)=O)=N\C\2=C(C)/C2=N[C@]1(C)[C@@](C)(CC(N)=O)[C@@H]2CCC(N)=O JEWJRMKHSMTXPP-BYFNXCQMSA-M 0.000 description 2
- 239000011585 methylcobalamin Substances 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 201000006417 multiple sclerosis Diseases 0.000 description 2
- 230000003959 neuroinflammation Effects 0.000 description 2
- 150000007523 nucleic acids Chemical class 0.000 description 2
- 102000039446 nucleic acids Human genes 0.000 description 2
- 108020004707 nucleic acids Proteins 0.000 description 2
- 210000004940 nucleus Anatomy 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- 230000001575 pathological effect Effects 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- BBEAQIROQSPTKN-UHFFFAOYSA-N pyrene Chemical compound C1=CC=C2C=CC3=CC=CC4=CC=C1C2=C43 BBEAQIROQSPTKN-UHFFFAOYSA-N 0.000 description 2
- 229960004136 rivastigmine Drugs 0.000 description 2
- BNRNXUUZRGQAQC-UHFFFAOYSA-N sildenafil Chemical compound CCCC1=NN(C)C(C(N2)=O)=C1N=C2C(C(=CC=1)OCC)=CC=1S(=O)(=O)N1CCN(C)CC1 BNRNXUUZRGQAQC-UHFFFAOYSA-N 0.000 description 2
- RYMZZMVNJRMUDD-HGQWONQESA-N simvastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)C(C)(C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 RYMZZMVNJRMUDD-HGQWONQESA-N 0.000 description 2
- 229960002855 simvastatin Drugs 0.000 description 2
- 210000000952 spleen Anatomy 0.000 description 2
- XOAAWQZATWQOTB-UHFFFAOYSA-N taurine Chemical compound NCCS(O)(=O)=O XOAAWQZATWQOTB-UHFFFAOYSA-N 0.000 description 2
- 229960005333 tetrabenazine Drugs 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- 230000009529 traumatic brain injury Effects 0.000 description 2
- 229910021642 ultra pure water Inorganic materials 0.000 description 2
- 239000012498 ultrapure water Substances 0.000 description 2
- 210000001835 viscera Anatomy 0.000 description 2
- AHOUBRCZNHFOSL-YOEHRIQHSA-N (+)-Casbol Chemical compound C1=CC(F)=CC=C1[C@H]1[C@H](COC=2C=C3OCOC3=CC=2)CNCC1 AHOUBRCZNHFOSL-YOEHRIQHSA-N 0.000 description 1
- XEEQGYMUWCZPDN-DOMZBBRYSA-N (-)-(11S,2'R)-erythro-mefloquine Chemical compound C([C@@H]1[C@@H](O)C=2C3=CC=CC(=C3N=C(C=2)C(F)(F)F)C(F)(F)F)CCCN1 XEEQGYMUWCZPDN-DOMZBBRYSA-N 0.000 description 1
- RTHCYVBBDHJXIQ-MRXNPFEDSA-N (R)-fluoxetine Chemical compound O([C@H](CCNC)C=1C=CC=CC=1)C1=CC=C(C(F)(F)F)C=C1 RTHCYVBBDHJXIQ-MRXNPFEDSA-N 0.000 description 1
- OQDPVLVUJFGPGQ-UHFFFAOYSA-N 2-[4-(1,3-benzodioxol-5-ylmethyl)-1-piperazinyl]pyrimidine Chemical compound C=1C=C2OCOC2=CC=1CN(CC1)CCN1C1=NC=CC=N1 OQDPVLVUJFGPGQ-UHFFFAOYSA-N 0.000 description 1
- HPOIPOPJGBKXIR-UHFFFAOYSA-N 3,6-dimethoxy-10-methyl-galantham-1-ene Natural products O1C(C(=CC=2)OC)=C3C=2CN(C)CCC23C1CC(OC)C=C2 HPOIPOPJGBKXIR-UHFFFAOYSA-N 0.000 description 1
- VHRSUDSXCMQTMA-PJHHCJLFSA-N 6alpha-methylprednisolone Chemical compound C([C@@]12C)=CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2[C@@H](O)C[C@]2(C)[C@@](O)(C(=O)CO)CC[C@H]21 VHRSUDSXCMQTMA-PJHHCJLFSA-N 0.000 description 1
- CEUORZQYGODEFX-UHFFFAOYSA-N Aripirazole Chemical compound ClC1=CC=CC(N2CCN(CCCCOC=3C=C4NC(=O)CCC4=CC=3)CC2)=C1Cl CEUORZQYGODEFX-UHFFFAOYSA-N 0.000 description 1
- 206010003571 Astrocytoma Diseases 0.000 description 1
- KPYSYYIEGFHWSV-UHFFFAOYSA-N Baclofen Chemical compound OC(=O)CC(CN)C1=CC=C(Cl)C=C1 KPYSYYIEGFHWSV-UHFFFAOYSA-N 0.000 description 1
- 208000004020 Brain Abscess Diseases 0.000 description 1
- LPCKPBWOSNVCEL-UHFFFAOYSA-N Chlidanthine Natural products O1C(C(=CC=2)O)=C3C=2CN(C)CCC23C1CC(OC)C=C2 LPCKPBWOSNVCEL-UHFFFAOYSA-N 0.000 description 1
- PNECAXHFWUCFFK-UHFFFAOYSA-N ClC=1C(=NC2=CC=CC=C2C=1)I(=O)=O Chemical compound ClC=1C(=NC2=CC=CC=C2C=1)I(=O)=O PNECAXHFWUCFFK-UHFFFAOYSA-N 0.000 description 1
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 1
- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 description 1
- ZBNZXTGUTAYRHI-UHFFFAOYSA-N Dasatinib Chemical compound C=1C(N2CCN(CCO)CC2)=NC(C)=NC=1NC(S1)=NC=C1C(=O)NC1=C(C)C=CC=C1Cl ZBNZXTGUTAYRHI-UHFFFAOYSA-N 0.000 description 1
- JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 1
- 108010011459 Exenatide Proteins 0.000 description 1
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 1
- 229930091371 Fructose Natural products 0.000 description 1
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 description 1
- 239000005715 Fructose Substances 0.000 description 1
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 1
- ZRJBHWIHUMBLCN-SEQYCRGISA-N Huperzine A Natural products N1C(=O)C=CC2=C1C[C@H]1/C(=C/C)[C@]2(N)CC(C)=C1 ZRJBHWIHUMBLCN-SEQYCRGISA-N 0.000 description 1
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 description 1
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 1
- 239000002067 L01XE06 - Dasatinib Substances 0.000 description 1
- 201000009906 Meningitis Diseases 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- PCZOHLXUXFIOCF-UHFFFAOYSA-N Monacolin X Natural products C12C(OC(=O)C(C)CC)CC(C)C=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 PCZOHLXUXFIOCF-UHFFFAOYSA-N 0.000 description 1
- 108010025020 Nerve Growth Factor Proteins 0.000 description 1
- 102000007072 Nerve Growth Factors Human genes 0.000 description 1
- 201000010133 Oligodendroglioma Diseases 0.000 description 1
- 229930012538 Paclitaxel Natural products 0.000 description 1
- 229930040373 Paraformaldehyde Natural products 0.000 description 1
- 208000027089 Parkinsonian disease Diseases 0.000 description 1
- 206010034010 Parkinsonism Diseases 0.000 description 1
- AHOUBRCZNHFOSL-UHFFFAOYSA-N Paroxetine hydrochloride Natural products C1=CC(F)=CC=C1C1C(COC=2C=C3OCOC3=CC=2)CNCC1 AHOUBRCZNHFOSL-UHFFFAOYSA-N 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- GMZVRMREEHBGGF-UHFFFAOYSA-N Piracetam Chemical compound NC(=O)CN1CCCC1=O GMZVRMREEHBGGF-UHFFFAOYSA-N 0.000 description 1
- 108010039918 Polylysine Proteins 0.000 description 1
- QNVSXXGDAPORNA-UHFFFAOYSA-N Resveratrol Natural products OC1=CC=CC(C=CC=2C=C(O)C(O)=CC=2)=C1 QNVSXXGDAPORNA-UHFFFAOYSA-N 0.000 description 1
- FTALBRSUTCGOEG-UHFFFAOYSA-N Riluzole Chemical compound C1=C(OC(F)(F)F)C=C2SC(N)=NC2=C1 FTALBRSUTCGOEG-UHFFFAOYSA-N 0.000 description 1
- ILRCGYURZSFMEG-UHFFFAOYSA-N Salidroside Natural products OC1C(O)C(O)C(CO)OC1OCCC1=CC=C(O)C=C1 ILRCGYURZSFMEG-UHFFFAOYSA-N 0.000 description 1
- ZRJBHWIHUMBLCN-UHFFFAOYSA-N Shuangyiping Natural products N1C(=O)C=CC2=C1CC1C(=CC)C2(N)CC(C)=C1 ZRJBHWIHUMBLCN-UHFFFAOYSA-N 0.000 description 1
- 208000033809 Suppuration Diseases 0.000 description 1
- BPEGJWRSRHCHSN-UHFFFAOYSA-N Temozolomide Chemical compound O=C1N(C)N=NC2=C(C(N)=O)N=CN21 BPEGJWRSRHCHSN-UHFFFAOYSA-N 0.000 description 1
- 241001122767 Theaceae Species 0.000 description 1
- KJADKKWYZYXHBB-XBWDGYHZSA-N Topiramic acid Chemical compound C1O[C@@]2(COS(N)(=O)=O)OC(C)(C)O[C@H]2[C@@H]2OC(C)(C)O[C@@H]21 KJADKKWYZYXHBB-XBWDGYHZSA-N 0.000 description 1
- LUKBXSAWLPMMSZ-OWOJBTEDSA-N Trans-resveratrol Chemical compound C1=CC(O)=CC=C1\C=C\C1=CC(O)=CC(O)=C1 LUKBXSAWLPMMSZ-OWOJBTEDSA-N 0.000 description 1
- YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 description 1
- 229930003779 Vitamin B12 Natural products 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- BZKPWHYZMXOIDC-UHFFFAOYSA-N acetazolamide Chemical compound CC(=O)NC1=NN=C(S(N)(=O)=O)S1 BZKPWHYZMXOIDC-UHFFFAOYSA-N 0.000 description 1
- 229960000571 acetazolamide Drugs 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000009056 active transport Effects 0.000 description 1
- SHGAZHPCJJPHSC-YCNIQYBTSA-N all-trans-retinoic acid Chemical compound OC(=O)\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-YCNIQYBTSA-N 0.000 description 1
- DKNWSYNQZKUICI-UHFFFAOYSA-N amantadine Chemical compound C1C(C2)CC3CC2CC1(N)C3 DKNWSYNQZKUICI-UHFFFAOYSA-N 0.000 description 1
- 229960003805 amantadine Drugs 0.000 description 1
- KRMDCWKBEZIMAB-UHFFFAOYSA-N amitriptyline Chemical compound C1CC2=CC=CC=C2C(=CCCN(C)C)C2=CC=CC=C21 KRMDCWKBEZIMAB-UHFFFAOYSA-N 0.000 description 1
- 229960000836 amitriptyline Drugs 0.000 description 1
- FROZIYRKKUFAOC-UHFFFAOYSA-N amobam Chemical compound N.N.SC(=S)NCCNC(S)=S FROZIYRKKUFAOC-UHFFFAOYSA-N 0.000 description 1
- 239000000427 antigen Substances 0.000 description 1
- 102000036639 antigens Human genes 0.000 description 1
- 108091007433 antigens Proteins 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 229960004372 aripiprazole Drugs 0.000 description 1
- 229960000794 baclofen Drugs 0.000 description 1
- YBHILYKTIRIUTE-UHFFFAOYSA-N berberine Chemical compound C1=C2CC[N+]3=CC4=C(OC)C(OC)=CC=C4C=C3C2=CC2=C1OCO2 YBHILYKTIRIUTE-UHFFFAOYSA-N 0.000 description 1
- 229940093265 berberine Drugs 0.000 description 1
- QISXPYZVZJBNDM-UHFFFAOYSA-N berberine Natural products COc1ccc2C=C3N(Cc2c1OC)C=Cc4cc5OCOc5cc34 QISXPYZVZJBNDM-UHFFFAOYSA-N 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004958 brain cell Anatomy 0.000 description 1
- 201000007983 brain glioma Diseases 0.000 description 1
- 229960000623 carbamazepine Drugs 0.000 description 1
- FFGPTBGBLSHEPO-UHFFFAOYSA-N carbamazepine Chemical compound C1=CC2=CC=CC=C2N(C(=O)N)C2=CC=CC=C21 FFGPTBGBLSHEPO-UHFFFAOYSA-N 0.000 description 1
- KQJSQWZMSAGSHN-JJWQIEBTSA-N celastrol Chemical compound C([C@H]1[C@]2(C)CC[C@@]34C)[C@](C)(C(O)=O)CC[C@]1(C)CC[C@]2(C)C4=CC=C1C3=CC(=O)C(O)=C1C KQJSQWZMSAGSHN-JJWQIEBTSA-N 0.000 description 1
- 210000003855 cell nucleus Anatomy 0.000 description 1
- 238000002659 cell therapy Methods 0.000 description 1
- 210000001175 cerebrospinal fluid Anatomy 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- JUFFVKRROAPVBI-PVOYSMBESA-N chembl1210015 Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(=O)N[C@H]1[C@@H]([C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O)[C@@H](O)[C@@H](CO[C@]3(O[C@@H](C[C@H](O)[C@H](O)CO)[C@H](NC(C)=O)[C@@H](O)C3)C(O)=O)O2)O)[C@@H](CO)O1)NC(C)=O)C(=O)NCC(=O)NCC(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CO)C(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCSC)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)CNC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 JUFFVKRROAPVBI-PVOYSMBESA-N 0.000 description 1
- GCOPXRXOORFRHV-HOFKKMOUSA-N chembl476084 Chemical compound C1([C@@H]2[C@H](C=3C=C(O)C=C4OC(=C(C=34)C3=CC(O)=CC(O)=C32)C=2C=CC(O)=CC=2)O)=CC=C(O)C=C1 GCOPXRXOORFRHV-HOFKKMOUSA-N 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- DGBIGWXXNGSACT-UHFFFAOYSA-N clonazepam Chemical compound C12=CC([N+](=O)[O-])=CC=C2NC(=O)CN=C1C1=CC=CC=C1Cl DGBIGWXXNGSACT-UHFFFAOYSA-N 0.000 description 1
- 229960003120 clonazepam Drugs 0.000 description 1
- 229960004170 clozapine Drugs 0.000 description 1
- QZUDBNBUXVUHMW-UHFFFAOYSA-N clozapine Chemical compound C1CN(C)CCN1C1=NC2=CC(Cl)=CC=C2NC2=CC=CC=C12 QZUDBNBUXVUHMW-UHFFFAOYSA-N 0.000 description 1
- FDJOLVPMNUYSCM-WZHZPDAFSA-L cobalt(3+);[(2r,3s,4r,5s)-5-(5,6-dimethylbenzimidazol-1-yl)-4-hydroxy-2-(hydroxymethyl)oxolan-3-yl] [(2r)-1-[3-[(1r,2r,3r,4z,7s,9z,12s,13s,14z,17s,18s,19r)-2,13,18-tris(2-amino-2-oxoethyl)-7,12,17-tris(3-amino-3-oxopropyl)-3,5,8,8,13,15,18,19-octamethyl-2 Chemical compound [Co+3].N#[C-].N([C@@H]([C@]1(C)[N-]\C([C@H]([C@@]1(CC(N)=O)C)CCC(N)=O)=C(\C)/C1=N/C([C@H]([C@@]1(CC(N)=O)C)CCC(N)=O)=C\C1=N\C([C@H](C1(C)C)CCC(N)=O)=C/1C)[C@@H]2CC(N)=O)=C\1[C@]2(C)CCC(=O)NC[C@@H](C)OP([O-])(=O)O[C@H]1[C@@H](O)[C@@H](N2C3=CC(C)=C(C)C=C3N=C2)O[C@@H]1CO FDJOLVPMNUYSCM-WZHZPDAFSA-L 0.000 description 1
- 235000006279 cobamamide Nutrition 0.000 description 1
- ZIHHMGTYZOSFRC-UWWAPWIJSA-M cobamamide Chemical compound C1(/[C@](C)(CCC(=O)NC[C@H](C)OP(O)(=O)OC2[C@H]([C@H](O[C@@H]2CO)N2C3=CC(C)=C(C)C=C3N=C2)O)[C@@H](CC(N)=O)[C@]2(N1[Co+]C[C@@H]1[C@H]([C@@H](O)[C@@H](O1)N1C3=NC=NC(N)=C3N=C1)O)[H])=C(C)\C([C@H](C/1(C)C)CCC(N)=O)=N\C\1=C/C([C@H]([C@@]\1(CC(N)=O)C)CCC(N)=O)=N/C/1=C(C)\C1=N[C@]2(C)[C@@](C)(CC(N)=O)[C@@H]1CCC(N)=O ZIHHMGTYZOSFRC-UWWAPWIJSA-M 0.000 description 1
- 239000011789 cobamamide Substances 0.000 description 1
- 238000001218 confocal laser scanning microscopy Methods 0.000 description 1
- 238000004624 confocal microscopy Methods 0.000 description 1
- 229960004397 cyclophosphamide Drugs 0.000 description 1
- 229960000684 cytarabine Drugs 0.000 description 1
- 239000000824 cytostatic agent Substances 0.000 description 1
- 230000001085 cytostatic effect Effects 0.000 description 1
- 229960002448 dasatinib Drugs 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 229960003957 dexamethasone Drugs 0.000 description 1
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 1
- 229960003529 diazepam Drugs 0.000 description 1
- AAOVKJBEBIDNHE-UHFFFAOYSA-N diazepam Chemical compound N=1CC(=O)N(C)C2=CC=C(Cl)C=C2C=1C1=CC=CC=C1 AAOVKJBEBIDNHE-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 210000005064 dopaminergic neuron Anatomy 0.000 description 1
- 229960004679 doxorubicin Drugs 0.000 description 1
- 238000002651 drug therapy Methods 0.000 description 1
- QELUYTUMUWHWMC-UHFFFAOYSA-N edaravone Chemical compound O=C1CC(C)=NN1C1=CC=CC=C1 QELUYTUMUWHWMC-UHFFFAOYSA-N 0.000 description 1
- 229950009041 edaravone Drugs 0.000 description 1
- 230000001490 effect on brain Effects 0.000 description 1
- HAPOVYFOVVWLRS-UHFFFAOYSA-N ethosuximide Chemical compound CCC1(C)CC(=O)NC1=O HAPOVYFOVVWLRS-UHFFFAOYSA-N 0.000 description 1
- 229960002767 ethosuximide Drugs 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 229960001519 exenatide Drugs 0.000 description 1
- 229960000556 fingolimod Drugs 0.000 description 1
- KKGQTZUTZRNORY-UHFFFAOYSA-N fingolimod Chemical compound CCCCCCCCC1=CC=C(CCC(N)(CO)CO)C=C1 KKGQTZUTZRNORY-UHFFFAOYSA-N 0.000 description 1
- GVEPBJHOBDJJJI-UHFFFAOYSA-N fluoranthrene Natural products C1=CC(C2=CC=CC=C22)=C3C2=CC=CC3=C1 GVEPBJHOBDJJJI-UHFFFAOYSA-N 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
- 238000002073 fluorescence micrograph Methods 0.000 description 1
- 239000007850 fluorescent dye Substances 0.000 description 1
- 229960002949 fluorouracil Drugs 0.000 description 1
- 229960002464 fluoxetine Drugs 0.000 description 1
- 229960004038 fluvoxamine Drugs 0.000 description 1
- CJOFXWAVKWHTFT-XSFVSMFZSA-N fluvoxamine Chemical compound COCCCC\C(=N/OCCN)C1=CC=C(C(F)(F)F)C=C1 CJOFXWAVKWHTFT-XSFVSMFZSA-N 0.000 description 1
- 229960003980 galantamine Drugs 0.000 description 1
- BGLNUNCBNALFOZ-WMLDXEAASA-N galanthamine Natural products COc1ccc2CCCC[C@@]34C=CCC[C@@H]3Oc1c24 BGLNUNCBNALFOZ-WMLDXEAASA-N 0.000 description 1
- ASUTZQLVASHGKV-UHFFFAOYSA-N galanthamine hydrochloride Natural products O1C(=C23)C(OC)=CC=C2CN(C)CCC23C1CC(O)C=C2 ASUTZQLVASHGKV-UHFFFAOYSA-N 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- ZRJBHWIHUMBLCN-YQEJDHNASA-N huperzine A Chemical compound N1C(=O)C=CC2=C1C[C@H]1\C(=C/C)[C@]2(N)CC(C)=C1 ZRJBHWIHUMBLCN-YQEJDHNASA-N 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- XXSMGPRMXLTPCZ-UHFFFAOYSA-N hydroxychloroquine Chemical compound ClC1=CC=C2C(NC(C)CCCN(CCO)CC)=CC=NC2=C1 XXSMGPRMXLTPCZ-UHFFFAOYSA-N 0.000 description 1
- 229960004171 hydroxychloroquine Drugs 0.000 description 1
- 229960001680 ibuprofen Drugs 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- 230000008004 immune attack Effects 0.000 description 1
- 210000002865 immune cell Anatomy 0.000 description 1
- 229960004657 indocyanine green Drugs 0.000 description 1
- MOFVSTNWEDAEEK-UHFFFAOYSA-M indocyanine green Chemical compound [Na+].[O-]S(=O)(=O)CCCCN1C2=CC=C3C=CC=CC3=C2C(C)(C)C1=CC=CC=CC=CC1=[N+](CCCCS([O-])(=O)=O)C2=CC=C(C=CC=C3)C3=C2C1(C)C MOFVSTNWEDAEEK-UHFFFAOYSA-M 0.000 description 1
- 210000004969 inflammatory cell Anatomy 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 230000028709 inflammatory response Effects 0.000 description 1
- 230000035990 intercellular signaling Effects 0.000 description 1
- 229960001848 lamotrigine Drugs 0.000 description 1
- PYZRQGJRPPTADH-UHFFFAOYSA-N lamotrigine Chemical compound NC1=NC(N)=NN=C1C1=CC=CC(Cl)=C1Cl PYZRQGJRPPTADH-UHFFFAOYSA-N 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 229960004002 levetiracetam Drugs 0.000 description 1
- HPHUVLMMVZITSG-ZCFIWIBFSA-N levetiracetam Chemical compound CC[C@H](C(N)=O)N1CCCC1=O HPHUVLMMVZITSG-ZCFIWIBFSA-N 0.000 description 1
- 229960004844 lovastatin Drugs 0.000 description 1
- PCZOHLXUXFIOCF-BXMDZJJMSA-N lovastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 PCZOHLXUXFIOCF-BXMDZJJMSA-N 0.000 description 1
- QLJODMDSTUBWDW-UHFFFAOYSA-N lovastatin hydroxy acid Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CC(C)C=C21 QLJODMDSTUBWDW-UHFFFAOYSA-N 0.000 description 1
- IYVSXSLYJLAZAT-NOLJZWGESA-N lycoramine Natural products CN1CC[C@@]23CC[C@H](O)C[C@@H]2Oc4cccc(C1)c34 IYVSXSLYJLAZAT-NOLJZWGESA-N 0.000 description 1
- GCOPXRXOORFRHV-UHFFFAOYSA-N malibatol A Natural products C12=C(O)C=C(O)C=C2C(C=23)=C(C=4C=CC(O)=CC=4)OC3=CC(O)=CC=2C(O)C1C1=CC=C(O)C=C1 GCOPXRXOORFRHV-UHFFFAOYSA-N 0.000 description 1
- 238000002483 medication Methods 0.000 description 1
- 229960001962 mefloquine Drugs 0.000 description 1
- LDDHMLJTFXJGPI-UHFFFAOYSA-N memantine hydrochloride Chemical compound Cl.C1C(C2)CC3(C)CC1(C)CC2(N)C3 LDDHMLJTFXJGPI-UHFFFAOYSA-N 0.000 description 1
- 229960000967 memantine hydrochloride Drugs 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 210000001259 mesencephalon Anatomy 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- XZWYZXLIPXDOLR-UHFFFAOYSA-N metformin Chemical compound CN(C)C(=N)NC(N)=N XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 description 1
- 229960003105 metformin Drugs 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- 229960004584 methylprednisolone Drugs 0.000 description 1
- 210000000274 microglia Anatomy 0.000 description 1
- 210000004925 microvascular endothelial cell Anatomy 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 230000000877 morphologic effect Effects 0.000 description 1
- 230000004660 morphological change Effects 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 230000004770 neurodegeneration Effects 0.000 description 1
- 208000015122 neurodegenerative disease Diseases 0.000 description 1
- 239000003900 neurotrophic factor Substances 0.000 description 1
- 235000020660 omega-3 fatty acid Nutrition 0.000 description 1
- 229960001816 oxcarbazepine Drugs 0.000 description 1
- CTRLABGOLIVAIY-UHFFFAOYSA-N oxcarbazepine Chemical compound C1C(=O)C2=CC=CC=C2N(C(=O)N)C2=CC=CC=C21 CTRLABGOLIVAIY-UHFFFAOYSA-N 0.000 description 1
- 230000036542 oxidative stress Effects 0.000 description 1
- 229960001592 paclitaxel Drugs 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- 229960002296 paroxetine Drugs 0.000 description 1
- 244000052769 pathogen Species 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 125000002080 perylenyl group Chemical group C1(=CC=C2C=CC=C3C4=CC=CC5=CC=CC(C1=C23)=C45)* 0.000 description 1
- CSHWQDPOILHKBI-UHFFFAOYSA-N peryrene Natural products C1=CC(C2=CC=CC=3C2=C2C=CC=3)=C3C2=CC=CC3=C1 CSHWQDPOILHKBI-UHFFFAOYSA-N 0.000 description 1
- DDBREPKUVSBGFI-UHFFFAOYSA-N phenobarbital Chemical compound C=1C=CC=CC=1C1(CC)C(=O)NC(=O)NC1=O DDBREPKUVSBGFI-UHFFFAOYSA-N 0.000 description 1
- 229960002695 phenobarbital Drugs 0.000 description 1
- 229960002790 phenytoin sodium Drugs 0.000 description 1
- 229960004526 piracetam Drugs 0.000 description 1
- 229960004310 piribedil Drugs 0.000 description 1
- 229920000656 polylysine Polymers 0.000 description 1
- 150000008442 polyphenolic compounds Chemical class 0.000 description 1
- 235000013824 polyphenols Nutrition 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 229960004618 prednisone Drugs 0.000 description 1
- XOFYZVNMUHMLCC-ZPOLXVRWSA-N prednisone Chemical compound O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 XOFYZVNMUHMLCC-ZPOLXVRWSA-N 0.000 description 1
- 229960004431 quetiapine Drugs 0.000 description 1
- URKOMYMAXPYINW-UHFFFAOYSA-N quetiapine Chemical compound C1CN(CCOCCO)CCN1C1=NC2=CC=CC=C2SC2=CC=CC=C12 URKOMYMAXPYINW-UHFFFAOYSA-N 0.000 description 1
- ZRJBHWIHUMBLCN-BMIGLBTASA-N rac-huperzine A Natural products N1C(=O)C=CC2=C1C[C@@H]1C(=CC)[C@@]2(N)CC(C)=C1 ZRJBHWIHUMBLCN-BMIGLBTASA-N 0.000 description 1
- ZAHRKKWIAAJSAO-UHFFFAOYSA-N rapamycin Natural products COCC(O)C(=C/C(C)C(=O)CC(OC(=O)C1CCCCN1C(=O)C(=O)C2(O)OC(CC(OC)C(=CC=CC=CC(C)CC(C)C(=O)C)C)CCC2C)C(C)CC3CCC(O)C(C3)OC)C ZAHRKKWIAAJSAO-UHFFFAOYSA-N 0.000 description 1
- 230000008439 repair process Effects 0.000 description 1
- 235000021283 resveratrol Nutrition 0.000 description 1
- 229940016667 resveratrol Drugs 0.000 description 1
- 229930002330 retinoic acid Natural products 0.000 description 1
- PYWVYCXTNDRMGF-UHFFFAOYSA-N rhodamine B Chemical compound [Cl-].C=12C=CC(=[N+](CC)CC)C=C2OC2=CC(N(CC)CC)=CC=C2C=1C1=CC=CC=C1C(O)=O PYWVYCXTNDRMGF-UHFFFAOYSA-N 0.000 description 1
- 229960004181 riluzole Drugs 0.000 description 1
- ILRCGYURZSFMEG-RQICVUQASA-N salidroside Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)OC1OCCC1=CC=C(O)C=C1 ILRCGYURZSFMEG-RQICVUQASA-N 0.000 description 1
- 208000011581 secondary neoplasm Diseases 0.000 description 1
- 230000003248 secreting effect Effects 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 229960002073 sertraline Drugs 0.000 description 1
- VGKDLMBJGBXTGI-SJCJKPOMSA-N sertraline Chemical compound C1([C@@H]2CC[C@@H](C3=CC=CC=C32)NC)=CC=C(Cl)C(Cl)=C1 VGKDLMBJGBXTGI-SJCJKPOMSA-N 0.000 description 1
- 238000010008 shearing Methods 0.000 description 1
- 229960003310 sildenafil Drugs 0.000 description 1
- QFJCIRLUMZQUOT-HPLJOQBZSA-N sirolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 QFJCIRLUMZQUOT-HPLJOQBZSA-N 0.000 description 1
- 229960002930 sirolimus Drugs 0.000 description 1
- 229960002232 sodium phenylbutyrate Drugs 0.000 description 1
- VPZRWNZGLKXFOE-UHFFFAOYSA-M sodium phenylbutyrate Chemical compound [Na+].[O-]C(=O)CCCC1=CC=CC=C1 VPZRWNZGLKXFOE-UHFFFAOYSA-M 0.000 description 1
- AEQFSUDEHCCHBT-UHFFFAOYSA-M sodium valproate Chemical compound [Na+].CCCC(C([O-])=O)CCC AEQFSUDEHCCHBT-UHFFFAOYSA-M 0.000 description 1
- FJPYVLNWWICYDW-UHFFFAOYSA-M sodium;5,5-diphenylimidazolidin-1-ide-2,4-dione Chemical compound [Na+].O=C1[N-]C(=O)NC1(C=1C=CC=CC=1)C1=CC=CC=C1 FJPYVLNWWICYDW-UHFFFAOYSA-M 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 229960003080 taurine Drugs 0.000 description 1
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
- 229960004964 temozolomide Drugs 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 239000010409 thin film Substances 0.000 description 1
- ANRHNWWPFJCPAZ-UHFFFAOYSA-M thionine Chemical compound [Cl-].C1=CC(N)=CC2=[S+]C3=CC(N)=CC=C3N=C21 ANRHNWWPFJCPAZ-UHFFFAOYSA-M 0.000 description 1
- 229960004394 topiramate Drugs 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 229960001727 tretinoin Drugs 0.000 description 1
- IEDVJHCEMCRBQM-UHFFFAOYSA-N trimethoprim Chemical compound COC1=C(OC)C(OC)=CC(CC=2C(=NC(N)=NC=2)N)=C1 IEDVJHCEMCRBQM-UHFFFAOYSA-N 0.000 description 1
- 229960001082 trimethoprim Drugs 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 229960005088 urethane Drugs 0.000 description 1
- 229960000604 valproic acid Drugs 0.000 description 1
- 235000019163 vitamin B12 Nutrition 0.000 description 1
- 239000011715 vitamin B12 Substances 0.000 description 1
- 229960005080 warfarin Drugs 0.000 description 1
- PJVWKTKQMONHTI-UHFFFAOYSA-N warfarin Chemical compound OC=1C2=CC=CC=C2OC(=O)C=1C(CC(=O)C)C1=CC=CC=C1 PJVWKTKQMONHTI-UHFFFAOYSA-N 0.000 description 1
- 229960000607 ziprasidone Drugs 0.000 description 1
- MVWVFYHBGMAFLY-UHFFFAOYSA-N ziprasidone Chemical compound C1=CC=C2C(N3CCN(CC3)CCC3=CC=4CC(=O)NC=4C=C3Cl)=NSC2=C1 MVWVFYHBGMAFLY-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6921—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere
- A61K47/6925—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a microcapsule, nanocapsule, microbubble or nanobubble
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
- A61K35/14—Blood; Artificial blood
- A61K35/17—Lymphocytes; B-cells; T-cells; Natural killer cells; Interferon-activated or cytokine-activated lymphocytes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
- A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6901—Conjugates being cells, cell fragments, viruses, ghosts, red blood cells or viral vectors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Epidemiology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Cell Biology (AREA)
- Inorganic Chemistry (AREA)
- Psychiatry (AREA)
- Psychology (AREA)
- Pain & Pain Management (AREA)
- Hematology (AREA)
- Immunology (AREA)
- Virology (AREA)
- Molecular Biology (AREA)
- Biotechnology (AREA)
- Hospice & Palliative Care (AREA)
- Developmental Biology & Embryology (AREA)
- Nanotechnology (AREA)
- Zoology (AREA)
- Medicinal Preparation (AREA)
Abstract
本发明属于药物领域,具体涉及一种NK细胞药物递送系统及其制备方法和用途,其中,NK细胞药物递送系统包括活化的NK细胞和结合在所述活化的NK细胞表面的载药纳米颗粒,所述活化的NK细胞为表面含巯基的NK细胞,所述载药纳米颗粒表面含有马来酰亚胺基团或者巯基基团,所述载药纳米颗粒通过马来酰亚胺基团或者巯基基团与活化的NK细胞表面的巯基相结合,本发明的NK细胞药物递送系统通过马来酰亚胺基团或者巯基基团与巯基相结合的NK细胞和载药纳米颗粒,对脑部疾病细胞或者组织具有高度的靶向性、低生物毒性,显著提高治疗脑部疾病的效果。
Description
技术领域
本发明属于药物领域,具体涉及一种NK细胞药物递送系统及其制备方法和用途。
背景技术
目前脑部疾病全球发病率高且不断上升,市场庞大。但是脑部疾病药物开发仍然具有挑战性,其开发成本高、临床使用路径长、失败率高。脑部受到生理屏障(特别是血脑屏障)的高度保护,而脑部疾病药物的研发难点主要在于血脑屏障。98%以上小分子药物难以通过血脑屏障进入中枢系统。没有主动运输,药物无法进入脑内,导致大量体外有效的药物无法通过血脑屏障而被提前宣告无效。更重要的是,药物穿越血脑屏障后还需要进一步靶向到病灶细胞。如何将药物更好地聚集在病灶细胞而不损伤正常的脑细胞,是另一个难点。如何帮助药物突破血脑屏障,提高脑部病灶部位的靶向效率,已成为脑部疾病治疗的关键。
针对目前脑部疾病的治疗主要有两种方式:手术以及小分子药物系统性或局部给药。对于一些脑部炎症疾病,如脑脓肿、脑肿瘤等,手术治疗可以通过切除病灶或引流脓液来达到治疗目的。但是手术治疗具有一定的风险,可能会导致手术相关的并发症和副作用。此外,部分脑部疾病不适合手术治疗,如脑膜炎、脑炎以及神经退行性疾病等。小分子药物治疗是最常见和常规的治疗方法之一。但是多数药物都难以有效地穿越血脑屏障,降低了药物的治疗效果;此外,药物无法直接修复受损的脑部组织,仅能减轻炎症症状;一些药物可能存在副作用和毒性反应;部分病原体可能产生耐药性,导致治疗效果下降。
近年来,细胞递药系统的快速发展为脑部疾病的治疗提供了新思路。尽管血脑屏障(BBB)和血脑脊髓液屏障(BCSFB)严格限制细胞和分子进入脑实质,但免疫细胞可以穿过这些屏障,尤其是在中风和炎症等病理条件下。另外,细胞递药系统作为一种新型的治疗策略,具有许多优势。1)靶向性:细胞递药系统可以被设计成具有针对性的治疗效应,通过识别和靶向疾病细胞或组织,提供更准确和有效的治疗。2)个体化治疗:由于细胞载体通常来源于患者自身的细胞或经过个体化处理的外源性细胞,因此可以实现个体化的治疗策略,考虑到患者的独特生物学特征和需求。3)克服免疫逃逸:细胞递药系统能够克服一些传统药物面临的免疫逃逸问题。例如,肿瘤细胞可能通过改变表面抗原表达或其他机制来逃避免疫攻击,而细胞药物可以通过多种机制来识别和攻击这些逃逸的细胞。4)长效效应:细胞药物可以在体内长时间存活和活动,提供持久的治疗效果。相比之下,一些传统药物可能需要频繁的剂量给药才能维持治疗效果。5)多种治疗机制:细胞药物可以通过多种机制发挥治疗作用,如直接杀伤疾病细胞、分泌细胞因子和细胞间信号分子、调节免疫反应等,从而在多个层面上影响疾病的发展和治疗效果。如何设计和构建新型针对脑部疾病的细胞递药系统,提高治疗脑部疾病的效果,是本发明要解决的技术问题和亟需实现的目标。
发明内容
为了克服现有药物对于脑部疾病治疗效果较差的技术问题,本发明提出了一种新型的NK细胞药物递送系统及其制备方法,该NK细胞药物递送系统对脑部疾病细胞或者组织具有高度的靶向性、低生物毒性,制备工艺简单,显著提高治疗脑部疾病的效果。
本发明提供了一种NK细胞药物递送系统,其包括活化的NK细胞和结合在所述活化的NK细胞表面的载药纳米颗粒,所述活化的NK细胞为表面含巯基的NK细胞,所述载药纳米颗粒表面含有马来酰亚胺基团或者巯基基团,所述载药纳米颗粒通过马来酰亚胺基团或者巯基基团与活化的NK细胞表面的巯基相结合。
进一步地,所述活化的NK细胞是通过巯基类还原剂将NK细胞表面蛋白的二硫键还原为巯基而制成;可选的,三(2-羧乙基)-膦盐酸盐、巯基乙醇、二硫苏糖醇、二巯基丙醇、β巯基乙胺和半胱氨酸中的一种或者多种。
进一步地,所述载药纳米颗粒包括载体外壳和包载于载体外壳内的药物,所述载体外壳包含聚合物载体或者白蛋白,其中,所述聚合物载体包括第一聚合物材料以及磷脂-酮缩硫醇-聚乙二醇-马来酰亚胺,所述第一聚合物材料选自聚乳酸-羟基乙酸共聚物(PLGA)、聚乳酸(PLA)、聚己内酯(PCL)中的至少一种;优选的,所述第一聚合物材料与磷脂-酮缩硫醇-聚乙二醇-马来酰亚胺的质量比为3-15:3-15;优选的,所述磷脂-酮缩硫醇-聚乙二醇-马来酰亚胺为二硬脂酰基磷脂酰乙醇胺-酮缩硫醇-聚乙二醇-马来酰亚胺;优选的,所述药物的质量与聚合物载体或者白蛋白的质量比为3-7:2-30。
更优选的,所述第一聚合物材料与磷脂-酮缩硫醇-聚乙二醇-马来酰亚胺的质量比为1:1。
优选的,所述药物、第一聚合物材料与磷脂-酮缩硫醇-聚乙二醇-马来酰亚胺的质量比为3-7:3-15:3-15,更优选为5:10:10。
可选的,所述第一聚合物材料的分子量为20k-100k。
具体的,第一聚合物材料可以是PLGA50k、PLGA20k、PLGA100k、PLA50k、PCL50k等。
进一步地,所述载药纳米颗粒中的药物包括模拟药物、预防或治疗脑部疾病的药物中的一种或者几种。
其中模拟药物,包括但不局限于荧光染料,例如芘、苝、BODIPY、荧光素、罗丹明、花菁染料、ICG系列染料及衍生物。
所述脑部疾病包括但不局限于阿尔茨海默症,创伤性脑损伤,癫痫,亨廷顿病,肌萎缩侧索硬化,帕金森病,多发硬化症,抑郁症,神经炎症,脑血管疾病,脑积水,脑肿瘤;其中脑肿瘤包括原发性脑胶质瘤、继发性肿瘤脑转移、少突神经胶质瘤、脑膜瘤、星形细胞瘤、脑膜瘤及其他脑肿瘤。
其中,治疗阿尔茨海默症的药物:包括芬戈莫德、3正丁基苯酞及其衍生物、姜黄素、西地那非、Exendin 4、雷公藤红素、Omega 3多元不饱和脂肪酸、Malibatol A、红景天苷、多奈哌齐、卡巴拉汀、加兰他敏、石杉碱甲、姜黄素、雷帕霉素、盐酸美金刚、二甲双胍、维甲酸、懈皮素、氯碘羟喹、辛伐他丁、白藜芦醇、茶多酚、布洛芬、小檗碱、达沙替尼、甲氟喹、马赛替尼、核酸类药物中的至少一种;治疗创伤性脑损伤的药物:包括阿司匹林、辛伐他汀、托伐他汀、华法林、甘露醇、甲钴胺、三甲氧苄嗪、神经营养因子中的至少一种;治疗癫痫的药物:包括苯妥英钠、卡马西平、苯巴比妥、丙戊酸钠、乙琥胺、氯硝西泮、奥卡西平、拉莫三嗪、左乙拉西坦、托吡酯、非氨酯、加拉喷丁、加巴喷中的至少一种;治疗亨廷顿病的药物:包括丁苯喹嗪、氚丁苯那嗪、核酸类药物中的至少一种;治疗肌萎缩侧索硬化的药物:包括利鲁唑、依拉达奉、巴氯芬、地西泮、苯海索、阿米替林、苯丁酸钠、牛磺酸二醇中的至少一种;治疗帕金森病的药物:包括安坦、金刚烷胺、美多芭、氯氮平、喹硫平、齐拉西酮、卡巴拉汀、多奈哌齐、哌马色林、阿立哌唑、吡贝地尔中的至少一种;治疗多发硬化症的药物:包括地塞米松、甲泼尼龙、环磷酰胺、强的松中的至少一种;治疗抑郁症的药物:包括帕罗西汀、舍曲林、氟西汀、氟伏沙明中的至少一种;治疗神经炎症的药物:包括甲钴胺、腺苷钴胺、维生素B12、阿司匹林中的至少一种;治疗脑血管疾病的药物:包括洛伐他汀、阿司匹林、罗吡唑、甘露醇、吡拉西坦中的至少一种;治疗脑积水的药物:包括乙酰唑胺、甘露醇、甘油果糖中的至少一种;治疗脑肿瘤的药物:包括紫杉醇、阿霉素、替莫唑胺、甲氨蝶呤、氟尿嘧啶、阿糖胞苷、伊布替尼、羟氯喹中的至少一种。
进一步地,所述载药纳米颗粒的表面还结合有脑靶向多肽;可选的,所述脑靶向多肽选自Angiopep-2肽和/或RVG29肽。
本发明还提供了上述任一所述的NK细胞药物递送系统的制备方法,包括,将所述活化的NK细胞和所述载药纳米颗粒混合,孵育,制得NK细胞药物递送系统。
进一步地,所述制备方法满足如下(1)-(2)中的一项或者多项:
(1)每1×105-2×106个NK细胞中混入大于0mg小于等于0.2mg的载药纳米颗粒,优选的,每2×106个NK细胞中混入0.03mg-0.2mg的载药纳米颗粒;
(2)孵育的温度为30-40℃,时间为10-45min。
进一步地,每2×106个NK细胞中混入0.125mg的载药纳米颗粒。
进一步地,所述载药纳米颗粒通过聚合物载体或者白蛋白自组装制成,优选的,所述载药纳米颗粒的制备方法包括,将药物、第一聚合物材料以及磷脂-酮缩硫醇-聚乙二醇-马来酰亚胺溶解在有机溶剂中,超声条件下滴加水,透析去除有机溶剂和游离药物,获得含有载药纳米颗粒的悬液;更优选的,所述载药纳米颗粒的制备方法还满足如下A-F中的至少一项:
A、超声功率为10-30W,优选为30W;
B、透析时间为24-72h,优选为48h;
C、有机溶剂选自乙醇、二甲基亚砜中的一种或者多种,优选为体积比为1:8-10的乙醇与二甲基亚砜的混合溶剂;
D、所述药物、第一聚合物材料与磷脂-酮缩硫醇-聚乙二醇-马来酰亚胺的质量比为3-7:3-15:3-15,优选为5:10:10;
E、所述药物的质量与有机溶剂、水的体积之比为3-7mg:0.5-2.5mL:2-10mL;
F、透析之后还包括将脑靶向多肽与含有载药纳米颗粒的悬液混合,超滤去除载药纳米颗粒中游离的脑靶向多肽,获得靶向载药纳米颗粒的步骤;优选的,混合时间为0.5-4h。
进一步地,超声的时间为30s以上,例如30s-2min。
所述活化的NK细胞的制备方法包括,将NK细胞与含巯基类还原剂的溶液混合,孵育,即得;优选的,孵育的温度为30-37℃,时间为10-45min;优选的,每1×106-10×106个细胞中混入0.3-4mg的巯基类还原剂;优选的,含巯基类还原剂的溶液为含巯基类还原剂的PBS溶液;优选的,含巯基类还原剂的溶液中巯基类还原剂的浓度为0.1-0.5mg/mL。
本发明还提供了上述任一所述的NK细胞药物递送系统或者上述任一所述的制备方法制得的NK细胞药物递送系统在制备脑部疾病的诊断试剂或者制备预防或治疗脑部疾病的药物中的用途。
与现有技术相比,本发明的上述技术方案具有以下优点:
1、本发明提供的NK细胞药物递送系统,包括活化的NK细胞和结合在所述活化的NK细胞表面的载药纳米颗粒,所述活化的NK细胞为表面含巯基的NK细胞,所述载药纳米颗粒表面含有马来酰亚胺基团或者巯基基团,所述载药纳米颗粒通过马来酰亚胺基团或者巯基基团与活化的NK细胞表面的巯基相结合,通过NK细胞显著提高了载药纳米颗粒穿越血脑屏障能力进入脑部炎症病灶;此外,NK细胞能够通过识别炎症病灶中的靶标细胞,如感染细胞或炎症细胞,实现特异性细胞治疗;更重要的是NK细胞能够分泌多种细胞因子和介质,调节免疫反应和减轻炎症反应,从而在多个层面上影响疾病的发展和治疗效果,从而产生更强的治疗效果。载药纳米颗粒通过化学偶联在NK细胞表面,通过“搭便车”方式穿越血脑屏障,到达脑内的炎症部位,提高了药物利用率,减少了游离药物对机体的毒副作用。总之,本发明的NK细胞药物递送系统通过马来酰亚胺基团或者巯基基团与巯基相结合的NK细胞和载药纳米颗粒,对脑部疾病细胞或者组织具有高度的靶向性、低生物毒性,显著提高治疗脑部疾病的效果。
2、本发明提供的NK细胞药物递送系统,通过优化聚合物载体的原料,即包括第一聚合物材料以及磷脂-酮缩硫醇-聚乙二醇-马来酰亚胺,所述第一聚合物材料选自聚乳酸-羟基乙酸共聚物、聚乳酸、聚己内酯中的至少一种;尤其是以二硬脂酰基磷脂酰乙醇胺-酮缩硫醇-聚乙二醇-马来酰亚胺和聚乳酸-羟基乙酸共聚物(PLGA50k,乳酸:羟基乙酸=50:50)为原料,并且控制所述第一聚合物材料与磷脂-酮缩硫醇-聚乙二醇-马来酰亚胺的质量比为3-15:3-15时(尤其是1:1)使得药物可以高效地负载在聚合物颗粒内,形成稳定的、高包封率、高负载量的载药纳米颗粒,载药纳米颗粒具有较好的生物相容性、生物可降解性;此外,载药纳米颗粒可以在炎症部位的氧化应激(ROS)的作用下,从NK细胞表面脱落释放,更好的发挥作用。
附图说明
为了使本发明的内容更容易被清楚的理解,下面根据本发明的具体实施例并结合附图,对本发明作进一步详细的说明,其中:
图1为实施例1制备的载药纳米颗粒RVG-NPs的粒径分布图。横坐标Size为粒径,纵坐标intensity为含量百分数。
图2为实验例3中有无TCEP处理的情况下,载药纳米颗粒RVG-NPs连接NK细胞的共聚焦荧光成像图。
图3实验例2中为不同浓度RVG-NPs连接NK细胞的效率的统计图以及荧光成像图。横坐标:RVG-NPs concentration为RVG-NPs的浓度,纵坐标FL intensity为荧光强度。
图4为实验例4中通过Transwell实验检测RVG-NPs和RVG-NPs@NKcell处理组穿越体外模拟BBB细胞层,到达Transwell下层培养基和下层细胞的RVG-NPs和RVG-NPs@NK cell的光学显微镜(A)以及荧光显微镜图(B)。
图5为实验例4中通过Transwell实验检测RVG-NPs和RVG-NPs@NKcell处理组穿越体外模拟BBB细胞层,到达Transwell下层培养基的NK细胞的计数统计图。
图6为实验例4中通过Transwell实验检测RVG-NPs和RVG-NPs@NKcell处理组穿越体外模拟BBB细胞层,到达Transwell下层细胞的RVG-NPs和RVG-NPs@NK cell的荧光统计图。α-syn(+)为加入α-syn蛋白处理组,而α-syn(-)为不加入α-syn蛋白处理组。
图7为实验例5中在野生型小鼠和帕金森疾病(PD)模型小鼠通过尾静脉注射RVG-NPs@NK cell后9h的脑部荧光成像图(A)和荧光强度统计图(B)。Control为野生型小鼠;PDmice为PD模型小鼠。纵坐标FL intensity为荧光强度。
图8为实验例6中PD模型小鼠尾静脉注射RVG-NPs和RVG-NPs@NK cell之后不同时间点的脑部荧光成像图。
图9为实验例6中PD模型小鼠尾静脉注射RVG-NPs和RVG-NPs@NK cell之后不同时间点的脑部荧光强度统计图。纵坐标Relative Fluorescence intensity为相对荧光强度。
图10为实验例6中PD模型小鼠尾静脉注射RVG-NPs和RVG-NPs@NK cell后24小时主要脏器的荧光成像图。
图11为实验例6中PD模型小鼠尾静脉注射RVG-NPs和RVG-NPs@NK cell后24小时主要脏器中的荧光强度统计图。纵坐标Relative Fluorescence intensity为相对荧光强度。
上述附图中,Heart、Liver、Spleen、Lung、Kidney、Brain依次为心脏、肝脏、脾脏、肺脏、肾脏、脑。
*表示两组之间的显著性差异p<0.05,**表示p<0.01,***表示p<0.001。
具体实施方式
下面将结合附图对本发明的技术方案进行清楚、完整地描述,显然,所描述的实施例是本发明一部分实施例,而不是全部的实施例。基于本发明中的实施例,本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例,都属于本发明保护的范围。本发明中,术语ICG为吲哚菁绿。
实施例1载药纳米颗粒的制备
本实施例提供了一种载药纳米颗粒的制备方法,包括如下步骤:
(1)称取模拟药物ICG(5mg)、聚乳酸-羟基乙酸共聚物(PLGA50k,乳酸:羟基乙酸=50:50,10mg)和ROS响应性磷脂(二硬脂酰基磷脂酰乙醇胺-酮缩硫醇-聚乙二醇-马来酰亚胺,DSPE-TK-PEG2k-Mal,10mg)溶解在1mL的乙醇与二甲基亚砜的混合溶剂(1/9,v/v)中。
(2)在超声条件下(功率:30W,时间:1min),向上述混合溶液中滴加超纯水(5mL)。
(3)上述混合液用超纯水透析(48h)(透析袋MWCO=3500Da),除去有机溶剂和游离药物,获得载药纳米颗粒(NPs)悬液。
(4)将RVG29肽(2μg)加入载药纳米颗粒(NPs)悬液中,混合2h,超滤去除载药纳米颗粒中游离的RVG29肽,获得靶向载药纳米颗粒(RVG-NPs)。
用粒度仪表征载药纳米颗粒的粒径及粒径分布(如图1所示),4℃保存备用。从图1可以看出,RVG-NPs的粒径分布在80-130nm之间,其中平均粒径为105nm。PDI多分散系数是0.2±0.1。
实施例2载药纳米颗粒的制备
本实施例提供了一种载药纳米颗粒的制备方法,包括如下步骤:
将白蛋白(HSA)溶于水中配成5mL浓度为0.375mg/mL的水溶液,得到水相;然后将5mg的ICG溶解在1mL二氯甲烷/乙醇(体积比9:1)的混合溶液中,得到油相;将油相滴加到水相中,边滴加边剪切2min,并通过薄膜蒸发法去除有机溶剂,获得载药纳米颗粒。
实施例3载药纳米颗粒的制备
本实施例提供了一种载药纳米颗粒的制备方法,基本与实施例1相同,区别仅在于:步骤(1)中模拟药物ICG的质量由5mg调整为2mg。
实施例4载药纳米颗粒的制备
本实施例提供了一种载药纳米颗粒的制备方法,基本与实施例1相同,区别仅在于:步骤(1)中ROS响应性磷脂的质量由10mg调整为3mg。
实施例5载药纳米颗粒的制备
本实施例提供了一种载药纳米颗粒的制备方法,基本与实施例1相同,区别仅在于:步骤(1)中聚乳酸-羟基乙酸共聚物的质量由10mg调整为3mg。
实施例6载药纳米颗粒的制备
本实施例提供了一种载药纳米颗粒的制备方法,基本与实施例1相同,区别仅在于:步骤(2)的超声功率由30W调整为10W。经检测制得的RVG-NPs的粒径分布为165-205nm之间。
实施例7载药纳米颗粒的制备
本实施例提供了一种载药纳米颗粒的制备方法,基本与实施例1相同,区别仅在于:步骤(2)的超声功率由30W调整为20W。经检测制得的RVG-NPs的粒径分布为140-180nm之间。
实施例8NK细胞药物递送系统的制备
本实施例提供了一种NK细胞药物递送系统的制备方法,包括如下步骤:
(1)将NK细胞(2mL,细胞总数2×106个)加入到含有三(2-羧乙基)-膦盐酸盐(TCEP,浓度:0.3mg/mL)的PBS(5mL)中,在37℃下孵育30min,再用PBS洗涤3次,最后将TCEP处理后的NK细胞分散到0.1mL的PBS中。
(2)在上述TCEP处理过的体积为0.1mL的NK细胞中,加入体积为0.1mL、浓度为1.25mg/mL的载药纳米颗粒RVG-NPs(实施例1方法制得)的PBS分散液并混合,在37℃下孵育30min,用PBS洗涤NK细胞药物递送系统3次,除去未连接的载药纳米颗粒,得到NK细胞药物递送系统(RVG-NPs@NK cell)。
实验例1
测试载药纳米颗粒的粒径、载药量和包封率。载药量和包封率的具体测试方法如下:载药纳米颗粒经冷冻干燥后,称重,再将其溶于二甲基亚砜(DMSO)。通过紫外分光光度计测量药物在最大吸收峰处的吸光度值,按照下述公式计算载药纳米颗粒的载药量和包封率。载药量和包封率结果如下表1所示。
表1各实施例载药纳米颗粒的表征结果
项目 | 粒径分布 | 包封率 | 载药量 |
实施例1 | 140-180nm | 90% | 28% |
实施例2 | 79-100nm | 87% | 7% |
实施例3 | 125-175nm | 88% | 8% |
实施例4 | 310-450nm | 78% | 23% |
实施例5 | 137-189nm | 67% | 10% |
将实施例2与实施例1、实施例3-5相比,在投药量相同的情况下,相比于HSA为原料制得的载药纳米颗粒来说,采用PLGA50k/DSPE-TK-PEG2k-Mal制成的聚合物载药纳米颗粒的包封率和载药量明显提高。由实施例1和实施例3-5相比较可知,采用实施例1通过控制药物ICG、聚乳酸-羟基乙酸共聚物和ROS响应性磷脂的质量比得到的聚合物载药纳米颗粒的尺寸恰当,载药量最高。由实施例1,实施例6-7比较可知,超声功率对于聚合物载药纳米颗粒的尺寸影响不大,10W-30W下均可得到粒径分布均匀的载药纳米颗粒。
实验例2荧光强度
考察不同的载药纳米颗粒浓度(或者药物量)对制备NK细胞药物递送系统的影响。在NK细胞药物递送系统的制备过程中,分别加入1mL的PBS溶液或者1mL浓度分别为31.25、62.5、125或者162.5μg/mL的载药纳米颗粒RVG-NPs的PBS分散液,其余工艺和条件均按照实施例8的方法制备NK细胞药物递送系统。将实施例8构建的NK细胞药物递送系统(RVG-NPs@NK cell)加入24孔板中,使用小动物成像检测其荧光强度来计算负载效率(如图3所示)。
图3为实施例8制备的NK细胞药物负载效率的统计结果。从图3我们可以看出其最大负载效率在62.5μg/106细胞,荧光强度约为1.0×107。
实验例3形态分析
1、实验方法
将NK细胞随机分为两组,TCEP+组和TCEP-组。TCEP+组为取NK细胞按照实施例8方法经过TCEP处理后,与载药纳米颗粒RVG-NPs共混得到NK细胞药物递送系统。而TCEP-组为取NK细胞未经过TCEP处理,直接与载药纳米颗粒RVG-NPs共混得到的实验结果,即与实施例8区别仅在于省略步骤(1)。然后向上述NK细胞中加入4%的多聚甲醛固定,并加入DAPI对NK细胞核进行染色。用共聚焦显微镜观察两组NK细胞形态变化及NK细胞表面接枝载药纳米颗粒的效率(如图2所示)。
2、实验结果
图2为实施例8的共聚焦显微镜的观察结果。蓝色荧光来源于NK细胞核,红色点状荧光来源于RVG-NPs。从图2可以看出,经过TCEP处理的NK细胞的实验组中,RVG-NPs点状荧光基本都分布在NK细胞膜表面(白色箭头所示),证明利用TCEP处理的方法能能够将RVG-NPs有效地接枝在NK细胞的表面;而未经TCEP处理的NK细胞的对照组中,多数RVG-NPs点状荧光分布在细胞浆中,表明RVG-NPs都被NK细胞摄取并进入细胞浆中。以上实验结果证明了NK细胞药物递送系统的成功构建。
实验例4NK体外迁移实验
1、实验方法
构建体外BBB和模拟PD病灶的实验模型:首先在Transwell小室里面铺上10万个bEnd.3细胞(小鼠脑微血管内皮细胞),培养至细胞紧密贴合。在放置Transwell小室的下层深孔24孔板中铺上10万个BV2细胞(小鼠小胶质细胞)和10万个MN9D细胞(小鼠中脑多巴胺能神经元细胞),待细胞贴壁后向Transwell小室下层培养基中加入α-syn蛋白(即α-突触核蛋白,帕金森病(PD)的病理标志之一是在脑中积累α-突触核蛋白)。继续将Transwell小室放入下层深孔24孔板中,培养24h。在Transwell小室中,分别加入30μL实施例8制得的NK细胞药物递送系统(RVG-NPs@NK cell)或者30μL浓度为1.25mg/mL的载药纳米颗粒RVG-NPs(实施例1方法制得)的PBS分散液。以不加入α-syn蛋白只加RVG-NPs@NK cell作为对照,相同条件下处理。6h后分离下层的上清液和下层细胞。在上清液和下层细胞中加入多聚赖氨酸固定细胞,1h后用光学显微镜观察和统计上清液中穿过体外BBB的NK细胞的数量;用DAPI对下层细胞核进行染色,然后用荧光显微镜观察下层细胞和统计下层细胞中RVG-NPs的荧光强度。
2、实验结果
从图4A和图5结果可以看出,在α-syn存在的条件下,NK细胞的穿越效率显著提升,证明了NK细胞药物递送系统具有靶向PD病灶或炎症部位归巢的能力。从图4B和图6结果可以看出,NK细胞药物递送系统处理组的下层细胞(BV2细胞和MN9D细胞)胞浆内的红色荧光信号(来源于RVG-NPs)明显增加,表明NK细胞药物递送系统可以有效地携带载药纳米颗粒穿越体外BBB;同时,载药纳米颗粒进入PD病灶部位后,能从NK细胞表面脱落,最后被靶细胞(BV2细胞和MN9D细胞)摄取。
实验例5NK体内靶向脑部病灶实验
1、实验方法
将6只C57小鼠按性别及体重随机分为实验对照组(Control)和帕金森疾病模型组(PD mice组或者PD模型组),每组3只。对于PD模型组的小鼠,通过脑定位注射AAV-A53Tα-Syn病毒(3个TCID50,0.5μL);对于实验对照组的小鼠,通过脑定位注射对照病毒(AAV,0.5μL),并在肌肉中注射青霉素。病毒注射完1个月后,小鼠帕金森疾病模型构建成功。分别在实验对照组和帕金森疾病模型组小鼠的尾静脉中注射CM-DiI标记的NK细胞(注射剂量为2×106个,200μL),在9小时后取出小鼠的脑部进行荧光成像及荧光强度分析。
2、实验结果
结果见图7所示。从图7的荧光成像图和荧光强度统计结果可以看出,相对于实验对照组小鼠来说,PD模型组的脑组织荧光强度更高,表明更多的NK细胞富集在PD模型鼠的脑组织或蓄积在具有炎症的脑部病灶部位。
实验例6NK细胞药物递送系统体内靶向脑部病灶实验
1、实验方法
按照实验例5的方法构建帕金森疾病(PD)模型小鼠。将PD模型小鼠随机分为载药纳米颗粒(RVG-NPs)组和NK细胞药物递送系统(RVG-NPs@NK cell)组。对于RVG-NPs组,通过尾静脉注射给予RVG-NPs的悬液(载药纳米颗粒浓度为1.25mg/mL);对于RVG-NPs@NK cell组,通过尾静脉注射给予实施例8制得的RVG-NPs@NK cell,给药体积均为150μL。分别在1,3,6,9,12,24小时通过小动物成像仪观察和检测脑组织部位的荧光强度。在24小时取出主要脏器对其进行荧光成像及荧光强度分析。
2、实验结果
从图8-9的结果可以看出,NK细胞药物递送系统脑内蓄积效率明显高于载药纳米颗粒组,证明了NK细胞药物递送系统能够在脑内炎症部位高效蓄积。
从图10-11的结果可以看出,NK细胞药物递送系统和载药纳米颗粒组在主要脏器中的分布没有显著性差异,但是NK细胞药物递送系统在脑内的荧光强度为3.3×108,载药纳米颗粒在脑内的荧光强度为1.1×108,NK细胞药物递送系统脑内的蓄积效率约为载药纳米颗粒的3倍,证明利用NK细胞药物递送策略能显著提升药物在脑内的蓄集效率,有望提升脑部疾病的治疗效果。
显然,上述实施例仅仅是为清楚地说明所作的举例,而并非对实施方式的限定。对于所属领域的普通技术人员来说,在上述说明的基础上还可以做出其它不同形式的变化或变动。这里无需也无法对所有的实施方式予以穷举。而由此所引申出的显而易见的变化或变动仍处于本发明创造的保护范围之中。
Claims (10)
1.一种NK细胞药物递送系统,其特征在于,其包括活化的NK细胞和结合在所述活化的NK细胞表面的载药纳米颗粒,所述活化的NK细胞为表面含巯基的NK细胞,所述载药纳米颗粒表面含有马来酰亚胺基团或者巯基基团,所述载药纳米颗粒通过马来酰亚胺基团或者巯基基团与活化的NK细胞表面的巯基相结合。
2.根据权利要求1所述的NK细胞药物递送系统,其特征在于,所述活化的NK细胞是通过巯基类还原剂将NK细胞表面蛋白的二硫键还原为巯基而制成;可选的,所述巯基类还原剂选自三(2-羧乙基)-膦盐酸盐、巯基乙醇、二硫苏糖醇、二巯基丙醇、β巯基乙胺和半胱氨酸中的一种或者多种。
3.根据权利要求1所述的NK细胞药物递送系统,其特征在于,所述载药纳米颗粒包括载体外壳和包载于载体外壳内的药物,所述载体外壳包含聚合物载体或者白蛋白,其中所述聚合物载体包括第一聚合物材料以及磷脂-酮缩硫醇-聚乙二醇-马来酰亚胺,所述第一聚合物材料选自聚乳酸-羟基乙酸共聚物、聚乳酸、聚己内酯中的至少一种;
优选的,所述第一聚合物材料与磷脂-酮缩硫醇-聚乙二醇-马来酰亚胺的质量比为3-15:3-15;
优选的,所述磷脂-酮缩硫醇-聚乙二醇-马来酰亚胺为二硬脂酰基磷脂酰乙醇胺-酮缩硫醇-聚乙二醇-马来酰亚胺;
优选的,所述药物的质量与聚合物载体或者白蛋白的质量比为3-7:2-30。
4.根据权利要求1所述的NK细胞药物递送系统,其特征在于,所述载药纳米颗粒中的药物包括模拟药物、预防或治疗脑部疾病的药物中的一种或者几种。
5.根据权利要求1-4中任一所述的NK细胞药物递送系统,其特征在于,所述载药纳米颗粒的表面还结合有脑靶向多肽;可选的,所述脑靶向多肽选自Angiopep-2肽和/或RVG29肽。
6.权利要求1-5中任一所述的NK细胞药物递送系统的制备方法,其特征在于,包括,将所述活化的NK细胞和所述载药纳米颗粒混合,孵育,制得NK细胞药物递送系统。
7.根据权利要求6所述的NK细胞药物递送系统的制备方法,其特征在于,所述制备方法满足如下(1)-(2)中的一项或者多项:
(1)每1×105-2×106个NK细胞中混入大于0mg小于等于0.2mg的载药纳米颗粒,优选的,每2×106个NK细胞中混入0.03mg-0.2mg的载药纳米颗粒;
(2)孵育的温度为30-40℃,时间为10-45min。
8.根据权利要求6所述的NK细胞药物递送系统的制备方法,其特征在于,所述载药纳米颗粒通过聚合物载体或者白蛋白自组装制成,优选的,所述载药纳米颗粒的制备方法包括,将药物、第一聚合物材料以及磷脂-酮缩硫醇-聚乙二醇-马来酰亚胺溶解在有机溶剂中,超声条件下滴加水,透析去除有机溶剂和游离药物,获得含有载药纳米颗粒的悬液;更优选的,所述载药纳米颗粒的制备方法还满足如下A-F中的至少一项:
A、超声功率为10-30W,优选为30W;
B、透析时间为24-72h,优选为48h;
C、有机溶剂选自乙醇、二甲基亚砜中的一种或者多种,优选为体积比为1:8-10的乙醇与二甲基亚砜的混合溶剂;
D、所述药物、第一聚合物材料与磷脂-酮缩硫醇-聚乙二醇-马来酰亚胺的质量比为3-7:3-15:3-15,优选为5:10:10;
E、所述药物的质量与有机溶剂、水的体积之比为3-7mg:0.5-2.5mL:2-10mL;
F、透析之后还包括将脑靶向多肽与含有载药纳米颗粒的悬液混合,超滤去除载药纳米颗粒中游离的脑靶向多肽,获得靶向载药纳米颗粒的步骤;优选的,混合时间为0.5-4h。
9.根据权利要求7所述的NK细胞药物递送系统的制备方法,其特征在于,所述活化的NK细胞的制备方法包括,将NK细胞与含巯基类还原剂的溶液混合,孵育,即得;优选的,孵育的温度为30-37℃,时间为10-45min;优选的,每1×106-10×106个细胞中混入0.3-4mg的巯基类还原剂;优选的,含巯基类还原剂的溶液为含巯基类还原剂的PBS溶液;优选的,所述含巯基类还原剂的溶液中巯基类还原剂的浓度为0.1-0.5mg/mL。
10.权利要求1-5中任一所述的NK细胞药物递送系统或者权利要求6-9中任一所述的制备方法制得的NK细胞药物递送系统在制备脑部疾病的诊断试剂或者制备预防或治疗脑部疾病的药物中的用途。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202311050561.8A CN117257982A (zh) | 2023-08-18 | 2023-08-18 | 一种nk细胞药物递送系统及其制备方法和用途 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202311050561.8A CN117257982A (zh) | 2023-08-18 | 2023-08-18 | 一种nk细胞药物递送系统及其制备方法和用途 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN117257982A true CN117257982A (zh) | 2023-12-22 |
Family
ID=89201636
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202311050561.8A Pending CN117257982A (zh) | 2023-08-18 | 2023-08-18 | 一种nk细胞药物递送系统及其制备方法和用途 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN117257982A (zh) |
-
2023
- 2023-08-18 CN CN202311050561.8A patent/CN117257982A/zh active Pending
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Crommelin et al. | Towards more effective advanced drug delivery systems | |
Zhang et al. | Development of curcumin-loaded zein nanoparticles for transport across the blood–brain barrier and inhibition of glioblastoma cell growth | |
Chang et al. | Transferrin adsorption onto PLGA nanoparticles governs their interaction with biological systems from blood circulation to brain cancer cells | |
US20070148074A1 (en) | Nanoparticle based stabilization of ir fluorescent dyes | |
CN108136023A (zh) | 血小板膜包覆的药物递送系统 | |
Huang et al. | The effect of lipid nanoparticle PEGylation on neuroinflammatory response in mouse brain | |
WO2007141050A2 (de) | Funktionalisierte, feste polymernanopartikel für diagnostische und therapeutische anwendungen | |
Guo et al. | Direct site-specific treatment of skin cancer using doxorubicin-loaded nanofibrous membranes | |
Victorelli et al. | Chick embryo chorioallantoic membrane as a suitable in vivo model to evaluate drug delivery systems for cancer treatment: A review | |
Liu et al. | Design of polyaspartic acid peptide-poly (ethylene glycol)-poly (ε-caprolactone) nanoparticles as a carrier of hydrophobic drugs targeting cancer metastasized to bone | |
JP2017530941A (ja) | 脳内に蓄積する治療用ナノ粒子 | |
US20050084456A1 (en) | Functionalized particles | |
Li et al. | Metal ion-responsive nanocarrier derived from phosphonated calix [4] arenes for delivering dauricine specifically to sites of brain injury in a mouse model of intracerebral hemorrhage | |
WO2011101859A1 (en) | A novel water soluble curcumin loaded nanoparticulate system for cancer therapy | |
Hani et al. | A systematic study of novel drug delivery mechanisms and treatment strategies for pancreatic cancer | |
Naidu et al. | Protein corona formation moderates the release kinetics of ion channel antagonists from transferrin-functionalized polymeric nanoparticles | |
Baghirov et al. | The effect of poly (ethylene glycol) coating and monomer type on poly (alkyl cyanoacrylate) nanoparticle interactions with lipid monolayers and cells | |
Karimian et al. | Synthesis of biocompatible nanocrystalline cellulose against folate receptors as a novel carrier for targeted delivery of doxorubicin | |
Shi et al. | The delivery of thrombi-specific nanoparticles incorporating oligonucleotides into injured cerebrovascular endothelium | |
CN117257982A (zh) | 一种nk细胞药物递送系统及其制备方法和用途 | |
Hu et al. | A multifunctional AIE nanoprobe as a drug delivery bioimaging and cancer treatment system | |
Soleimani et al. | Poliglusam Nanoparticles activate T cell response in breast cancer cell: An in vivo and in vitro study | |
JP6824535B2 (ja) | 脳間質内のナノ粒子分布を改善するための組成物および方法 | |
Zivari-Ghader et al. | Recent progresses in natural based therapeutic materials for Alzheimer's disease | |
Yang | Nano-Hydrogel for the Treatment of Depression and Epilepsy |
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 |