CN114163481A - 一种含铂类药物纳米囊泡及其制备方法与应用 - Google Patents
一种含铂类药物纳米囊泡及其制备方法与应用 Download PDFInfo
- Publication number
- CN114163481A CN114163481A CN202111477036.5A CN202111477036A CN114163481A CN 114163481 A CN114163481 A CN 114163481A CN 202111477036 A CN202111477036 A CN 202111477036A CN 114163481 A CN114163481 A CN 114163481A
- Authority
- CN
- China
- Prior art keywords
- platinum
- copper
- prodrug
- drug
- metal organic
- 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.)
- Granted
Links
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 title claims abstract description 139
- 229910052697 platinum Inorganic materials 0.000 title claims abstract description 68
- 239000003814 drug Substances 0.000 title claims abstract description 58
- 229940079593 drug Drugs 0.000 title claims abstract description 56
- 238000002360 preparation method Methods 0.000 title claims abstract description 39
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 31
- 239000013084 copper-based metal-organic framework Substances 0.000 claims abstract description 29
- 208000003721 Triple Negative Breast Neoplasms Diseases 0.000 claims abstract description 23
- 208000022679 triple-negative breast carcinoma Diseases 0.000 claims abstract description 23
- 239000002502 liposome Substances 0.000 claims abstract description 11
- 239000002243 precursor Substances 0.000 claims abstract description 9
- 229940002612 prodrug Drugs 0.000 claims description 49
- 239000000651 prodrug Substances 0.000 claims description 49
- 239000002105 nanoparticle Substances 0.000 claims description 26
- 238000003756 stirring Methods 0.000 claims description 23
- 238000000034 method Methods 0.000 claims description 17
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 claims description 14
- 239000002202 Polyethylene glycol Substances 0.000 claims description 11
- 229920001223 polyethylene glycol Polymers 0.000 claims description 11
- 239000004475 Arginine Substances 0.000 claims description 10
- 206010006187 Breast cancer Diseases 0.000 claims description 9
- 208000026310 Breast neoplasm Diseases 0.000 claims description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 9
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 8
- 229960004316 cisplatin Drugs 0.000 claims description 7
- 238000002156 mixing Methods 0.000 claims description 6
- 239000010949 copper Substances 0.000 claims description 5
- 239000000203 mixture Substances 0.000 claims description 5
- 238000001914 filtration Methods 0.000 claims description 4
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 3
- 239000002246 antineoplastic agent Substances 0.000 claims description 3
- 238000010992 reflux Methods 0.000 claims description 3
- 229940041181 antineoplastic drug Drugs 0.000 claims description 2
- 238000005805 hydroxylation reaction Methods 0.000 claims description 2
- 206010027476 Metastases Diseases 0.000 abstract description 16
- 230000009401 metastasis Effects 0.000 abstract description 16
- 230000000694 effects Effects 0.000 abstract description 14
- 230000005764 inhibitory process Effects 0.000 abstract description 14
- 229940011871 estrogen Drugs 0.000 abstract description 13
- 239000000262 estrogen Substances 0.000 abstract description 13
- 238000001727 in vivo Methods 0.000 abstract description 9
- 210000004072 lung Anatomy 0.000 abstract description 9
- 230000004087 circulation Effects 0.000 abstract description 6
- 230000000903 blocking effect Effects 0.000 abstract description 5
- 230000035755 proliferation Effects 0.000 abstract description 4
- 230000033228 biological regulation Effects 0.000 abstract description 3
- 231100000331 toxic Toxicity 0.000 abstract description 3
- 230000002588 toxic effect Effects 0.000 abstract description 3
- 230000000214 effect on organisms Effects 0.000 abstract description 2
- 230000002195 synergetic effect Effects 0.000 abstract description 2
- 239000000243 solution Substances 0.000 description 39
- LFERELMXERXKKQ-KMXXXSRASA-N Fenugreekine Chemical compound NC(=O)C1=CC=CC([C@H]2[C@@H]([C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OC[C@@H]3[C@H]([C@@H](O)[C@@H](O3)N3C4=NC=NC(N)=C4N=C3)O)O2)O)=N1 LFERELMXERXKKQ-KMXXXSRASA-N 0.000 description 34
- 102100038742 Cytochrome P450 2A13 Human genes 0.000 description 33
- 101000957389 Homo sapiens Cytochrome P450 2A13 Proteins 0.000 description 33
- 210000004027 cell Anatomy 0.000 description 28
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 24
- JPVYNHNXODAKFH-UHFFFAOYSA-N Cu2+ Chemical compound [Cu+2] JPVYNHNXODAKFH-UHFFFAOYSA-N 0.000 description 21
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 description 20
- 230000000052 comparative effect Effects 0.000 description 18
- 229910001431 copper ion Inorganic materials 0.000 description 17
- 238000011282 treatment Methods 0.000 description 15
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 14
- 238000005406 washing Methods 0.000 description 14
- 210000001772 blood platelet Anatomy 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 11
- 210000001519 tissue Anatomy 0.000 description 11
- 210000004881 tumor cell Anatomy 0.000 description 11
- 229960003180 glutathione Drugs 0.000 description 10
- 239000002244 precipitate Substances 0.000 description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical group CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 9
- 238000012258 culturing Methods 0.000 description 9
- ODKSFYDXXFIFQN-BYPYZUCNSA-N L-arginine Chemical compound OC(=O)[C@@H](N)CCCN=C(N)N ODKSFYDXXFIFQN-BYPYZUCNSA-N 0.000 description 8
- 229930064664 L-arginine Natural products 0.000 description 8
- 235000014852 L-arginine Nutrition 0.000 description 8
- LNTHITQWFMADLM-UHFFFAOYSA-N gallic acid Chemical compound OC(=O)C1=CC(O)=C(O)C(O)=C1 LNTHITQWFMADLM-UHFFFAOYSA-N 0.000 description 8
- 241000699670 Mus sp. Species 0.000 description 7
- 230000006907 apoptotic process Effects 0.000 description 7
- 229960003121 arginine Drugs 0.000 description 7
- HDMXIELEUKTYFR-UHFFFAOYSA-N bis(2-ethylhexyl) butanedioate;sodium Chemical group [Na].CCCCC(CC)COC(=O)CCC(=O)OCC(CC)CCCC HDMXIELEUKTYFR-UHFFFAOYSA-N 0.000 description 7
- 239000000693 micelle Substances 0.000 description 7
- 239000002245 particle Substances 0.000 description 7
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- 101710151806 72 kDa type IV collagenase Proteins 0.000 description 6
- 102100026802 72 kDa type IV collagenase Human genes 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- 230000009471 action Effects 0.000 description 6
- 230000002401 inhibitory effect Effects 0.000 description 6
- 239000002504 physiological saline solution Substances 0.000 description 6
- 238000001556 precipitation Methods 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 229910021642 ultra pure water Inorganic materials 0.000 description 6
- 239000012498 ultrapure water Substances 0.000 description 6
- 230000007705 epithelial mesenchymal transition Effects 0.000 description 5
- BOPGDPNILDQYTO-NNYOXOHSSA-N nicotinamide-adenine dinucleotide Chemical compound C1=CCC(C(=O)N)=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OC[C@@H]2[C@H]([C@@H](O)[C@@H](O2)N2C3=NC=NC(N)=C3N=C2)O)O1 BOPGDPNILDQYTO-NNYOXOHSSA-N 0.000 description 5
- 229930027945 nicotinamide-adenine dinucleotide Natural products 0.000 description 5
- 230000010118 platelet activation Effects 0.000 description 5
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 4
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 description 4
- 238000012377 drug delivery Methods 0.000 description 4
- 229940074391 gallic acid Drugs 0.000 description 4
- 235000004515 gallic acid Nutrition 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 238000011534 incubation Methods 0.000 description 4
- 239000011259 mixed solution Substances 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- 239000006228 supernatant Substances 0.000 description 4
- 238000012546 transfer Methods 0.000 description 4
- SJSSFUMSAFMFNM-NSHDSACASA-N (2s)-5-(diaminomethylideneamino)-2-(phenylmethoxycarbonylamino)pentanoic acid Chemical compound NC(N)=NCCC[C@@H](C(O)=O)NC(=O)OCC1=CC=CC=C1 SJSSFUMSAFMFNM-NSHDSACASA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 241000699666 Mus <mouse, genus> Species 0.000 description 3
- 108010087230 Sincalide Proteins 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 102000007637 Soluble Guanylyl Cyclase Human genes 0.000 description 3
- 108010007205 Soluble Guanylyl Cyclase Proteins 0.000 description 3
- 238000002835 absorbance Methods 0.000 description 3
- 230000004913 activation Effects 0.000 description 3
- 238000010609 cell counting kit-8 assay Methods 0.000 description 3
- 230000003511 endothelial effect Effects 0.000 description 3
- 102000015694 estrogen receptors Human genes 0.000 description 3
- 108010038795 estrogen receptors Proteins 0.000 description 3
- 235000019441 ethanol Nutrition 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 239000001963 growth medium Substances 0.000 description 3
- 238000011065 in-situ storage Methods 0.000 description 3
- 238000003760 magnetic stirring Methods 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 239000013110 organic ligand Substances 0.000 description 3
- 102000003998 progesterone receptors Human genes 0.000 description 3
- 108090000468 progesterone receptors Proteins 0.000 description 3
- 230000002685 pulmonary effect Effects 0.000 description 3
- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 3
- 238000005303 weighing Methods 0.000 description 3
- HNICLNKVURBTKV-NDEPHWFRSA-N (2s)-5-[[amino-[(2,2,4,6,7-pentamethyl-3h-1-benzofuran-5-yl)sulfonylamino]methylidene]amino]-2-(9h-fluoren-9-ylmethoxycarbonylamino)pentanoic acid Chemical compound C12=CC=CC=C2C2=CC=CC=C2C1COC(=O)N[C@H](C(O)=O)CCCN=C(N)NS(=O)(=O)C1=C(C)C(C)=C2OC(C)(C)CC2=C1C HNICLNKVURBTKV-NDEPHWFRSA-N 0.000 description 2
- ZOOGRGPOEVQQDX-UUOKFMHZSA-N 3',5'-cyclic GMP Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=C(NC2=O)N)=C2N=C1 ZOOGRGPOEVQQDX-UUOKFMHZSA-N 0.000 description 2
- 102100025172 Calpain-1 catalytic subunit Human genes 0.000 description 2
- 101710124171 Calpain-1 catalytic subunit Proteins 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 2
- 101000851181 Homo sapiens Epidermal growth factor receptor Proteins 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 239000012752 auxiliary agent Substances 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 230000017531 blood circulation Effects 0.000 description 2
- 239000006285 cell suspension Substances 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 238000002512 chemotherapy Methods 0.000 description 2
- 238000013270 controlled release Methods 0.000 description 2
- 150000001879 copper Chemical class 0.000 description 2
- 210000000805 cytoplasm Anatomy 0.000 description 2
- 238000000684 flow cytometry Methods 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 238000001095 inductively coupled plasma mass spectrometry Methods 0.000 description 2
- 230000003834 intracellular effect Effects 0.000 description 2
- 229940124280 l-arginine Drugs 0.000 description 2
- 238000011068 loading method Methods 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 230000001394 metastastic effect Effects 0.000 description 2
- 206010061289 metastatic neoplasm Diseases 0.000 description 2
- 239000002073 nanorod Substances 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 230000001590 oxidative effect Effects 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 2
- 238000010186 staining Methods 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- 230000004083 survival effect Effects 0.000 description 2
- 230000008685 targeting Effects 0.000 description 2
- WMSUFWLPZLCIHP-UHFFFAOYSA-N (2,5-dioxopyrrolidin-1-yl) 9h-fluoren-9-ylmethyl carbonate Chemical compound C12=CC=CC=C2C2=CC=CC=C2C1COC(=O)ON1C(=O)CCC1=O WMSUFWLPZLCIHP-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- VOXZDWNPVJITMN-ZBRFXRBCSA-N 17β-estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 VOXZDWNPVJITMN-ZBRFXRBCSA-N 0.000 description 1
- PRDFBSVERLRRMY-UHFFFAOYSA-N 2'-(4-ethoxyphenyl)-5-(4-methylpiperazin-1-yl)-2,5'-bibenzimidazole Chemical compound C1=CC(OCC)=CC=C1C1=NC2=CC=C(C=3NC4=CC(=CC=C4N=3)N3CCN(C)CC3)C=C2N1 PRDFBSVERLRRMY-UHFFFAOYSA-N 0.000 description 1
- HLJKUZUILACRPQ-UHFFFAOYSA-N 2,2,4,6,7-pentamethyl-3h-1-benzofuran-5-sulfonyl chloride Chemical compound CC1=C(S(Cl)(=O)=O)C(C)=C2CC(C)(C)OC2=C1C HLJKUZUILACRPQ-UHFFFAOYSA-N 0.000 description 1
- NHBKXEKEPDILRR-UHFFFAOYSA-N 2,3-bis(butanoylsulfanyl)propyl butanoate Chemical compound CCCC(=O)OCC(SC(=O)CCC)CSC(=O)CCC NHBKXEKEPDILRR-UHFFFAOYSA-N 0.000 description 1
- QOZFCKXEVSGWGS-ZHIYBZGJSA-N 4-hydroxy-17beta-estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1O QOZFCKXEVSGWGS-ZHIYBZGJSA-N 0.000 description 1
- 239000011547 Bouin solution Substances 0.000 description 1
- 101150075734 CAPNS1 gene Proteins 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 206010053567 Coagulopathies Diseases 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 238000008157 ELISA kit Methods 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 108010024636 Glutathione Proteins 0.000 description 1
- 101001012157 Homo sapiens Receptor tyrosine-protein kinase erbB-2 Proteins 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 102000002274 Matrix Metalloproteinases Human genes 0.000 description 1
- 108010000684 Matrix Metalloproteinases Proteins 0.000 description 1
- 206010027458 Metastases to lung Diseases 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 208000034530 PLAA-associated neurodevelopmental disease Diseases 0.000 description 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 1
- 108010019160 Pancreatin Proteins 0.000 description 1
- 206010050661 Platelet aggregation inhibition Diseases 0.000 description 1
- 102100030086 Receptor tyrosine-protein kinase erbB-2 Human genes 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical group [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 238000003917 TEM image Methods 0.000 description 1
- 102000004887 Transforming Growth Factor beta Human genes 0.000 description 1
- 108090001012 Transforming Growth Factor beta Proteins 0.000 description 1
- 210000000577 adipose tissue Anatomy 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 230000003698 anagen phase Effects 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000002001 anti-metastasis Effects 0.000 description 1
- 230000001640 apoptogenic effect Effects 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 description 1
- 229940073608 benzyl chloride Drugs 0.000 description 1
- HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000001185 bone marrow Anatomy 0.000 description 1
- 229910002091 carbon monoxide Inorganic materials 0.000 description 1
- 238000010523 cascade reaction Methods 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229940044683 chemotherapy drug Drugs 0.000 description 1
- 230000035602 clotting Effects 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000011254 conventional chemotherapy Methods 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 229910000365 copper sulfate Inorganic materials 0.000 description 1
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 description 1
- XTVVROIMIGLXTD-UHFFFAOYSA-N copper(II) nitrate Chemical compound [Cu+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O XTVVROIMIGLXTD-UHFFFAOYSA-N 0.000 description 1
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 230000001086 cytosolic effect Effects 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 125000003963 dichloro group Chemical group Cl* 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 230000003828 downregulation Effects 0.000 description 1
- 238000004043 dyeing Methods 0.000 description 1
- 238000009261 endocrine therapy Methods 0.000 description 1
- 229940034984 endocrine therapy antineoplastic and immunomodulating agent Drugs 0.000 description 1
- 229940088598 enzyme Drugs 0.000 description 1
- 239000007850 fluorescent dye Substances 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 230000002439 hemostatic effect Effects 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 238000007327 hydrogenolysis reaction Methods 0.000 description 1
- 210000002865 immune cell Anatomy 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 210000003712 lysosome Anatomy 0.000 description 1
- 230000001868 lysosomic effect Effects 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 238000013507 mapping Methods 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 210000003593 megakaryocyte Anatomy 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 230000003340 mental effect Effects 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 239000012621 metal-organic framework Substances 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 125000005740 oxycarbonyl group Chemical group [*:1]OC([*:2])=O 0.000 description 1
- 229940055695 pancreatin Drugs 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 238000004393 prognosis Methods 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 235000019624 protein content Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 230000000384 rearing effect Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 229920002994 synthetic fiber Polymers 0.000 description 1
- 238000002626 targeted therapy Methods 0.000 description 1
- ZRKFYGHZFMAOKI-QMGMOQQFSA-N tgfbeta Chemical compound C([C@H](NC(=O)[C@H](C(C)C)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CCSC)C(C)C)[C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O)C1=CC=C(O)C=C1 ZRKFYGHZFMAOKI-QMGMOQQFSA-N 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 230000006444 vascular growth Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 238000001262 western blot Methods 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
- C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table compounds of the platinum group
- C07F15/0086—Platinum compounds
- C07F15/0093—Platinum compounds without a metal-carbon linkage
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
- A61K33/243—Platinum; Compounds thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
- A61K33/34—Copper; Compounds thereof
-
- 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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
-
- 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
- A61K47/54—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 an organic compound
- A61K47/542—Carboxylic acids, e.g. a fatty acid or an amino acid
-
- 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
- A61K47/6949—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 inclusion complexes, e.g. clathrates, cavitates or fullerenes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Liposomes
- A61K9/1271—Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers
- A61K9/1273—Polymersomes; Liposomes with polymerisable or polymerised bilayer-forming substances
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y40/00—Manufacture or treatment of nanostructures
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
-
- 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
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Nanotechnology (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Crystallography & Structural Chemistry (AREA)
- Inorganic Chemistry (AREA)
- Molecular Biology (AREA)
- Biophysics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Oncology (AREA)
- Manufacturing & Machinery (AREA)
- General Physics & Mathematics (AREA)
- Condensed Matter Physics & Semiconductors (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Physics & Mathematics (AREA)
- Dispersion Chemistry (AREA)
- Biotechnology (AREA)
- General Engineering & Computer Science (AREA)
- Medical Informatics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明涉及一种含铂类药物纳米囊泡及其制备方法与应用。包括铜基金属有机框架和包裹在铜基金属有机框架内的铂类药物前体,所述铜基金属有机框架表面修饰有长循环脂质体。该含铂类药物纳米囊泡对局部雌激素调控和血小板阻断抑制三阴性乳腺癌增殖和转移有协同作用,抑瘤率为80.9%,肺转移抑制率高达88.4%,其稳定性和分散性较好,药物泄露率低,增强了体内长循环效果,对生物体的毒副作用小。
Description
技术领域
本发明涉及医药配制品领域,具体地涉及一种含铂类药物纳米囊泡及其制备方法与应用。
背景技术
三阴性乳腺癌(Triple-negative breast cancer,TNBC)是雌激素受体(ER)、孕激素受体(PR)和人表皮生长因子受体(HER-2)均阴性的乳腺癌。众所周知ER、PR、HER2的表达是目前临床乳腺癌治疗的靶点,但TNBC患者因为缺少这些靶点,不能从传统的内分泌治疗及靶向治疗中获益,治疗方法几乎只有化疗。尽管三阴性乳腺癌对化疗具有一定敏感性,然而经过常规化疗治疗后预后仍较差。研究表明,Ⅲ-Ⅳ期三阴性乳腺癌患者5年生存率仅为13%。TNBC与生俱来的高侵袭性特点,使其转移率几乎无法避免,研究表明转移是造成TNBC患者死亡的主要原因,然而,现阶段缺乏有效的TNBC转移治疗方法,如何有效抑制TNBC转移已成为目前乳腺癌治疗领域的难题之一。
雌激素在乳腺癌的转移过程中起着重要的作用,尤其是17β-雌二醇(E2)。E2可促进MCF-7的迁移和上皮间质转化;此外,E2还可介导快速的非基因效应,通过加速肿瘤组织的血管生长,促进基质金属蛋白酶表达等多种机制,促进TNBC的增殖和转移,然而目前肿瘤雌激素水平的调节仍面临巨大挑战,限制了TNBC的治疗。
血小板来源于骨髓成熟的巨核细胞,它是一种胞浆脱落下来的小块胞质,没有细胞核,其在体内主要发挥凝血和止血功能。研究发现,血小板可在瘤内的非血管部位聚集,进而加重肿瘤细胞诱导的血小板活化,活化的血小板可分泌TGF-β,促进肿瘤细胞发生上皮-间质转化(EMT),驱动肿瘤细胞的转移。此外,一旦肿瘤细胞内渗侵入血液,激活的血小板会与肿瘤细胞结合形成复合物,保护其免受循环系统中免疫细胞的攻击。而研究发现一氧化氮(NO)可显著抑制血小板的激活。它通过与血小板中的可溶性鸟甘酸环化酶(sGC)结合后,使其激活,激活的sGC在Mg2+存在下产生大量的cGMP,然后依赖cGMP途径抑制血小板的活化。这使NO成为一种很有前景的方法来抑制血小板活化诱导的肿瘤转移。
纳米药物递送系统(nano-DDS)是新型药物递送系统,其是将药物包埋在纳米粒中,具有缓控释、靶向等诸多优点,可以实现肿瘤的精确靶向,但现有的纳米递送系统对于三阴性乳腺癌存在治疗效果差、尤其在抑制三阴性乳腺癌转移方面效果不佳等问题。
发明内容
为解决上述技术问题,本发明目的是提供一种含铂类药物纳米囊泡,以解决上述纳米递送系统对三阴性乳腺癌治疗效果差、在抑制三阴性乳腺癌转移方面效果不佳的问题。
本发明另一目的是提供一种含铂类药物纳米囊泡的制备方法。
本发明又一目的是提供上述含铂类药物纳米囊泡的应用。
本发明一方面,提供一种铂类药物前体,其分子结构式如式Ⅰ所示:
本发明另一方面,提供一种铂类药物前体的制备方法,包括以下步骤:
S1:将顺铂与H2O2进行羟基化反应,得到羟基化顺铂;
S2:将步骤S1得到的羟基化顺铂和Fmoc-Pbf-精氨酸反应,得到铂类药物前体。
优选的,步骤S1中,具体方法为:将顺铂溶于H2O2中搅拌、静置得到;
步骤S2中,具体方法为:将Fmoc-Pbf-精氨酸溶于二氯甲烷溶液,加入羟基化顺铂和4-二甲胺基吡啶,置于冰浴内至澄清,加入N,N-二环己基碳二亚胺,室温回流过滤得到。
本发明又一方面,提供一种含铂类药物纳米囊泡,包括铜基金属有机框架和包裹在铜基金属有机框架内的铂类药物前体,所述铂类药物前体的分子结构式如上述式1所示,所述铜基金属有机框架表面修饰有长循环脂质体。
其中,按质量比,铜基金属有机框架:铂类药物前体:长循环脂质体为1-0.5:1:2-1。
其中,所述铜基金属有机框架为MIL-53-Cu;
优选地,所述长循环脂质体为二硬脂酰基磷脂酰乙醇胺-聚乙二醇、磷脂酰乙醇胺-聚乙二醇、磷脂酰胆碱-聚乙二醇、二硬脂酰磷脂酰胆碱-聚乙二醇中的一种或几种。
本发明的另一方面,提供所述的一种含铂类药物纳米囊泡的制备方法,包括以下步骤:
S1:将铜基金属有机框架与铂类药物前体混合,搅拌,得到铂类药物前体纳米粒;
S2:将长循环脂质体与步骤S1制备的铂类药物前体纳米粒混合,搅拌,得到含铂类药物纳米囊泡。
优选地,步骤S1中,搅拌时间为8-12h,搅拌速度为500-600rpm;步骤S2中,搅拌时间为4-8h,搅拌速度为500-600rpm。
本发明再一方面,提供所述一种铂类药物前体、一种含铂类药物纳米囊泡在制备抗肿瘤药物中的应用。
其中,所述肿瘤为乳腺癌,优选地,所述乳腺癌为三阴性乳腺癌。
本发明的实施例中还提供了一种铜基金属有机框架的制备方法,包括以下步骤:
(1)将表面活性剂、助剂溶解,搅拌,制备胶束溶液;
(2)将铜离子、有机配体加入到步骤(1)中的胶束溶液中,加热,得到铜基金属有机框架。
其中,步骤(1)中,所述表面活性剂为双(2-乙基己基)琥珀酸酯磺酸钠,溶解浓度为8-10g/L;所述助剂为正丁醇,溶解浓度为1.5-2.0%(V/V);
其中,步骤(2)中,所述铜离子以铜盐的形式加入,所述铜盐包括醋酸铜、氯化铜、硝酸铜、硫酸铜中的一种或几种;所述有机配体为没食子酸;所述铜离子:有机配体摩尔比为1:1-1:3;加热温度为70-80℃,加热时间为11-13h。
本发明的有益效果是:
(1)本发明中铜基金属有机框架作为药物储库,将铂类药物前体包埋在框架内,可有效避免游离前药在血液循环过程中产生的毒副作用,对生物体的毒副作用小。长循环脂质体具有亲水作用,修饰在有机金属框架表面,通过调节含铂类药物纳米囊泡的电位,可有效延长制剂在体内的血液循环时间,减少其被内皮系统清除,体内长循环时间长。
(2)本发明的含铂类药物纳米囊泡具有高渗透长滞留效应(EPR效应),可以使药物在肿瘤组织中的聚集。
(3)本发明通过pH/GSH级联反应设计保证了药物在肿瘤部位的特异性控释。含铂类药物纳米囊泡中所采用的MOF骨架可在肿瘤酸性溶酶体环境下降解,导致Cu2+和铂类药物前体在特异性位点的释放;铜离子催化雌激素氧化,降低肿瘤原位雌激素水平,抑制MMP-2的表达,从而通过ERK/CANP途径抑制TNBC转移;前药可响应胞浆中的谷胱甘肽(GSH)而发生解离,释放出活性化疗药物顺铂(Pt)和L-精氨酸(L-Arg),顺铂在NOX酶诱导下生成H2O2,进而氧化L-Arg,产生NO,阻断血小板激活介导的肿瘤的上皮细胞-间充质转化(EMT),起到协同局部雌激素调控和血小板阻断的作用。
(4)该纳米囊泡粒径约为190±20nm,粒径均一,具有良好的分散性。CPAD纳米粒的电位约为-33.1mV,该负电位可有效延长制剂在体内的循环时间,减少其被内皮系统清除,体内长循环时间长。其粒径和电位在7天内没有发生明显的变化,具有良好的稳定性。
(5)本发明合成方法简单,材料易得,成本低。
综上,本发明的纳米囊泡通过EPR效应在肿瘤组织聚集,然后协同局部雌激素调控和血小板阻断抑制三阴性乳腺癌增殖和转移,抑瘤率达80.9%,肺转移抑制率达88.4%,实现纳米递送系统在治疗三阴性乳腺癌中的应用。
附图说明
图1为前药Pt-Arg的核磁共振氢谱;
图2为本发明制备的含铂类药物纳米囊泡的TEM图(a),EDS-Mapping图(b),粒径图(c)及电位图(d);
图3为本发明制备的含铂类药物纳米囊泡的稳定性数据;
图4为本发明制备的含铂类药物纳米囊泡的铜离子释放(a)和前药Pt-Arg的释放(b);
图5为本发明制备的含铂类药物纳米囊泡的铜离子消耗雌激素实验分组(a)和过氧化氢的生成(b);
图6为不同Pt-Arg浓度下NO的产生(a)和不同H2O2浓度下NO的产生(b);
图7为本发明制备的含铂类药物纳米囊泡作用后4T1细胞内的E2含量(a),4-OHE2含量(b);Capn4和MMP-2的蛋白含量(c)及相应的灰度分析(d);
图8为本发明制备的含铂类药物纳米囊泡作用后血小板的聚集抑制;
图9为本发明制备的不同浓度含铂类药物纳米囊泡作用后4T1细胞的存活率;
图10为本发明制备的不同浓度含铂类药物纳米囊泡作用后4T1细胞的凋亡情况;
图11为本发明制备的含铂类药物纳米囊泡治疗后,小鼠肺部Bouin's染色图片及相应的H&E切片;
图12为本发明制备的含铂类药物纳米囊泡治疗后,小鼠肺部的肺转移结节统计。
图13为本发明制备的含铂类药物纳米囊泡给药期间,小鼠肿瘤体积的变化;
图14为本发明制备的含铂类药物纳米囊泡治疗后,小鼠的肿瘤组织质量;
图15为本发明制备的含铂类药物纳米囊泡治疗后,小鼠的肿瘤组织H&E切片和TUNEL荧光染色切片。
具体实施方式
以下实施例用于说明本发明,但不用来限制本发明的范围。在不背离本发明精神和实质的情况下,对本发明方法、步骤或条件所作的修改或替换,均属于本发明的范围。
若未特别指明,实施例中所用的技术手段为本领域技术人员所熟知的常规手段。所用试剂或仪器未注明生产厂商者,均可通过正规渠道商业购买得到的常规产品。
4T1细胞株购自武汉尚码生物科技有限公司,细胞凋亡试剂盒购自江苏凯基生物技术股份有限公司;仪器BH-2型荧光显微镜,德国徕卡公司产品;Accuri C6型流式细胞仪,美国BD公司产品。
实施例1含铂类药物的纳米囊泡的制备
(1)铜基MOF(Cu-MOF)的制备:称取0.22g的双(2-乙基己基)琥珀酸酯磺酸钠(AOT),置于50mL圆底烧瓶中,加入25mL超纯水,室温下搅拌超声使其充分溶解,浓度为8.8g/L,然后在磁力搅拌的条件下加入400μL的正丁醇,浓度为1.6%(V/V),形成透明的胶束溶液,将其放置于油浴锅中加热至75℃。然后向混合溶液中依次加入0.1M醋酸铜溶液200μL(溶剂:N,N-二甲基甲酰胺)的和0.1M没食子酸溶液200μL(溶剂:N,N-二甲基甲酰胺),继续反应12h。待反应液降至室温后,加入无水乙醇使其沉淀,将所得沉淀液于12000rpm条件下离心10min,并用乙醇和超纯水洗两遍得到铜基MOF(缩写为:Cu-GA);
(2)GSH响应前药顺铂-精氨酸(Pt-Arg)的制备:称取20mg顺铂(Pt)溶于1mL的30%H2O2溶液中,于50℃条件下搅拌1h后,室温静置24h,经离心、真空干燥后,得到羟基化顺铂(CDDPOH,化学名为二氯二羟基二氨合铂)。
称取5g L-Arg中加入含有7.5gNaHCO3的水中(29.6mL),随后将5mL氯苄氧羰基(Z-Cl)滴加到上述水溶液中,室温反应8h,过滤,乙醚洗涤,得到物质CBZ-L-精氨酸(Z-L-Arg-OH,化学名为N-苄氧羰基-L-精氨酸)。
称取3.5g Z-L-Arg-OH溶于NaOH与丙酮混合液中,冰浴下滴加5g的Pbf-Cl,冰浴反应1h,室温反应2h,减压蒸馏,得到物质Z-L-Arg(Pbf)-OH·CHA。量取2g的Z-L-Arg(Pbf)-OH·CHA溶于50mL甲醇,加入0.2g 10%的Pd/C,于55℃氢解12h,过滤,得到物质L-Arg(Pbf)–OH。
接着称取1.8g物质L-Arg(Pbf)–OH溶于含有7.5g NaHCO3的水溶液中(29.6mL),加入5mL二氧六环和1g Fmoc-OSu,冰浴反应30min,随后室温反应2h,析出固体分别用乙酸乙酯、水、饱和食盐水洗涤,干燥过滤,得产物Fmoc-Pbf-精氨酸(Fmoc-L-Arg(Pbf)–OH)。
将制备的Fmoc-L-Arg(Pbf)–OH加入无水二氯甲烷溶液中配置成1mmoL的溶液,随后加入1.5mmoL的CDDPOH和0.1mmoL的4-二甲胺基吡啶(DMAP),并置于在冰浴内,当上述混合物完全澄清时,加入1.1mmoLN,N-二环己基碳二亚胺(DCC),室温回流12h,过滤,加入三氟乙酸(90%),并用乙醚沉析,柱层析分离产物,制得Pt-Arg前药;
(3)装载前药Pt-Arg纳米粒的制备:取步骤(1)中所得的Cu-GA8mg分散在20mL生理盐水中,加入4mg步骤(2)的Pt-Arg,室温搅拌12h后,离心收集沉淀(12000rpm×10min),并用PBS洗3次,所得沉淀为装载前药Pt-Arg的纳米粒Cu-GA@Pt-Arg(缩写为:CPA);
(4)CPAD纳米粒的制备:取步骤(3)中所得的CPA,将其分散在16mL含有8mg二硬脂酰基磷脂酰乙醇胺-聚乙二醇(DSPE-PEG)的生理盐水中,室温搅拌4h,离心收集沉淀(12000rpm×10min),并用PBS洗涤3次,得到Cu-GA@Pt-Arg@DSPE-PEG纳米粒(缩写为:CPAD)。
实施例2含铂类药物的纳米囊泡的制备
(1)铜基MOF(Cu-MOF)的制备:称取0.2g的双(2-乙基己基)琥珀酸酯磺酸钠(AOT),置于50mL圆底烧瓶中,加入25mL超纯水,室温下搅拌超声使其充分溶解,浓度为8.0g/L,然后在磁力搅拌的条件下加入375μL的正丁醇,浓度为1.5%(V/V),形成透明的胶束溶液,将其放置于油浴锅中加热至80℃,然后向混合溶液中依次加入0.1M的醋酸铜溶液200μL(溶剂:DMF)和0.2M的没食子酸溶液200μL(溶剂:DMF),继续反应11h。待反应液降至室温后,加入无水乙醇使其沉淀,将所得沉淀液于12000rpm条件下离心10min,并用乙醇和超纯水洗两遍得到铜基MOF(缩写为:Cu-GA);
(2)GSH响应前药顺铂-精氨酸(Pt-Arg)的制备:同实施例一;
(3)装载前药Pt-Arg纳米粒的制备:取步骤(1)中所得的Cu-MOF4mg分散在20mL生理盐水中,加入4mg步骤(2)的Pt-Arg,室温搅拌8h后,离心收集沉淀(12000rpm×10min),并用PBS洗3次,所得沉淀为装载前药Pt-Arg的纳米粒Cu-GA@Pt-Arg(缩写为:CPA);
(4)CPAD纳米粒的制备:取步骤(3)中所得的CPA,将其分散在16mL含有4mg磷脂酰乙醇胺-聚乙二醇(DSPE-PEG)的生理盐水中,室温搅拌6h,离心收集沉淀(12000rpm×10min),并用PBS洗涤3次,得到Cu-GA@Pt-Arg@DSPE-PEG纳米粒(缩写为:CPAD)。
实施例3含铂类药物的纳米囊泡的制备
(1)铜基MOF(Cu-MOF)的制备:称取0.25g的双(2-乙基己基)琥珀酸酯磺酸钠(AOT),置于50mL圆底烧瓶中,加入25mL超纯水,室温下搅拌超声使其充分溶解,浓度为10g/L,然后在磁力搅拌的条件下加入500μL的正丁醇,浓度为2%(V/V),形成透明的胶束溶液,将其放置于油浴锅中加热至70℃,然后向混合溶液中依次加入0.1M的醋酸铜溶液200μL(溶剂:DMF)和0.3M没食子酸溶液200μL(溶剂:DMF),继续反应13h。待反应液降至室温后,加入无水乙醇使其沉淀,将所得沉淀液于12000rpm条件下离心10min,并用乙醇和超纯水洗两遍得到铜基MOF(Cu-GA)纳米粒;
(2)GSH响应前药顺铂-精氨酸(Pt-Arg)的制备:同实施例一;
(3)装载前药Pt-Arg纳米粒的制备:取步骤(1)中所得的Cu-GA2mg分散在20mL生理盐水中,加入4mg步骤(2)的Pt-Arg,室温搅拌10h后,离心收集沉淀(12000rpm×10min),并用PBS洗3次,所得沉淀为装载前药Pt-Arg的纳米粒Cu-GA@Pt-Arg(缩写为:CPA);
(4)CPAD纳米粒的制备:取步骤(3)中所得的CPA,将其分散在16mL含有2mg二硬脂酰磷脂酰胆碱-聚乙二醇(DSPC-PEG)的生理盐水中,室温搅拌4h,离心收集沉淀(12000rpm×10min),并用PBS洗涤3次,得到Cu-GA@Pt-Arg@DSPC-PEG纳米粒(缩写为:CPAD)。
对比例1
制备方法与实施例1的区别在于省去步骤(1)。
对比例2铜基纳米囊泡的制备
制备方法与实施例1的区别在于省去步骤(2)。
试验例1合成物质的性能检测
将实施例1合成的前药Pt-Arg通过核磁共振氢谱仪(Bruker 600MHz,DMSO-d6,δppm)进行表征。通过化学位移、偶合常数和积分曲线等重要参考数据,推测质子在碳链上的位置,分析前药的结构。结果如图1所示,结果显示:1HNMR谱图与Pt-Arg分子的结构相符,表示成功合成了前药Pt-Arg。
将实施例1合成的Cu-GA、CPD和CPAD通过DLS、TEM、Zeta进行表征,结果如图2、图3所示。
图2实验结果表明:所制得的CPAD粒径约为190±20nm,形貌似梭型的纳米棒。Cu-GA纳米粒电位约为-36.0mV,而装载前药Pt-Arg后,CPA纳米粒的电位增加至-21.4mV,进一步说明药物的成功装载。修饰DSPE-PEG后,CPAD纳米粒的电位约为-33.1mV,该负电位可有效延长制剂在体内的循环时间,减少其被内皮系统清除。由此可知所制得的CPAD粒径均一,分散性好,体内长循环时间长。
图3实验结果表明:CPAD纳米粒的粒径和电位在7天内没有发生明显的变化,表明CPAD纳米粒具有良好的稳定性,以保证其在体内发挥良好的递药效应。
试验例2铜离子和前药Pt-Arg的释放
将实施例1制备的CPAD纳米颗粒分散在不同pH的磷酸盐缓冲液中(pH7.4,6.5,4.5),使终浓度为100μg/mL,并于37℃恒温震荡保存。孵育不同时间后,离心(12000rpm×20min)收集上清,采用电感耦合等离子体质谱(Inductively Coupled Plasma-MassSpectrometry,ICP-MS)检测上清中铜离子和Pt-Arg的含量。结果如图4所示。
实验结果表明:CPAD释放铜离子和前药的速率受pH的影响,在pH 4.5条件下铜离子和前药Pt-Arg的释放量高,而在pH 7.4的条件下则释放较少。
试验例3铜离子的雌激素调控
将实验分为5组(A-E),分别为Cu2+,NADH,Cu2++4-OHE2,NADH+4-OHE2和Cu2++NADH+4-OHE2,其中各溶液的反应浓度分别为50μM(Cu2+),0.1mM(NADH)和40μM(4-OHE2),各组混合孵育24h后,使用过氧化氢试剂盒检测H2O2的生成。结果如图5所示。
实验结果表明:铜离子与4-羟雌二醇(4-OHE2)在NADH的作用下可发生反应,消耗4-OHE2,生成H2O2,从而为下调E2奠定基础。
试验例4前药产生NO的性质考察
将实施例1制备的CPAD置于pH4.5的条件下使前药Pt-Arg充分释放,然后在不同浓度的前药Pt-Arg溶液(0、2、4、6、8、10mM)中依次加入10mM GSH和10mM H2O2,37℃恒温孵育24h后,按一氧化氮试剂盒说明书进行检测,并记录450nm处的吸光度。使用相同方法检测前药H2O2浓度依赖性的NO释放,在10mM的Pt-Arg溶液中依次加入10mM GSH和不同浓度的H2O2(0、0.25、0.5、1、5、10mM),于37℃恒温孵育24h后,使用试剂盒检测并记录450nm处的吸光度。结果如图6所示。
实验结果表明:前药可响应GSH和H2O2,生成NO,且NO的生成受Pt-Arg和H2O2浓度的影响,并随浓度的增加而增大。
试验例5 CPAD对细胞E2及MMP-2水平的调控
取对数生长期的4T1细胞,使用无酚红1640+10%CS-FBS培养24h后,弃去上清,并用无菌PBS清洗三次,再用不含血清的无酚红1640继续培养24h,以耗尽细胞的内源性激素,待细胞密度为80%左右,将其消化离心后收集沉淀,铺板并置于培养箱中过夜培养,按实验分组分别加入PBS、10-9mol/L E2、和CPAD+10-9mol/L E2(Pt-Arg:1μg/mL),继续培养24h后,弃去上清并用PBS洗涤三次,离心收集细胞沉淀,使用ELISA试剂盒和Western Blot检测胞内E2、4-OHE2的含量,及MMP-2的蛋白表达。结果如图7所示。
实验结果表明:CPAD能有效下调胞内的E2和4-OHE2含量,降低MMP-2的表达,说明铜离子可发挥雌激素的调控作用。
试验例6 CPAD对肿瘤细胞诱导血小板聚集的抑制作用
收集血小板,并使用DIL膜性荧光染料染色20min,离心并用PBS洗涤3次,除去游离的荧光染料,待用。将3×1054T1细胞接种于共聚焦培养皿上,随后置于37℃,5%CO2条件下培养24h后,按实验分组依次加入:Pla和CPAD+Pla(Platelets:4×106;Pt-Arg:1μg/mL),继续培养8h后,弃去含药培养基并用PBS洗涤3次,Hoechst33342孵育10min,PBS洗涤三次后,使用激光共聚焦显微镜观察血小板的聚集并拍照记录。结果如图8所示。
实验结果表明:CPAD由于能产生NO,可显著抑制肿瘤细胞引起的血小板激活和聚集。
试验例7 CPAD对肿瘤细胞的抑制作用
4T1细胞用10%血清的培养基置于细胞培养箱(5%CO2、37℃)中培养,待细胞生长至90%左右进行胰酶消化,离心后重悬细胞,按照8000/孔的细胞密度接种于96孔细胞板中,24h后,将其分为对照组和实验组,对照组细胞不做任何处理,实验组细胞分别加入不同浓度梯度的实施例1制备的CPAD、对比例1制备的药物、对比例2制备的药物,实验重复3次。
用CCK-8法检测CPAD对于细胞的增殖抑制能力。加入不同的制剂和药物后,继续培养24h,弃去培养基并加入CCK-8溶液,37℃孵育1-4h,酶标仪检测450nm处的吸光度,评估CPAD的细胞增殖抑制能力,实验结果如图9。用流式细胞术检测不同制剂处理对于细胞凋亡的影响,制剂作用24h,使用不含乙二胺四乙酸(EDTA)的胰酶消化,离心收集培养基及细胞,采用凋亡试剂盒及流式细胞仪检测细胞的凋亡率,实验结果如图10。实验结果见表1和表2。
表1 CCK-8法检测50μg/mL CPAD对细胞的抑制作用
分组 | 实施例1 | 对比例1 | 对比例2 | 对照组 |
抑制率 | 80.9% | 55.4% | 32.6% | 0.0% |
表2流式细胞术检测CPAD对细胞的凋亡作用
分组 | 实施例1 | 对比例1 | 对比例2 | 对照组 |
凋亡率 | 60.09% | 24.02% | 11.98% | 0.145% |
实验结果表明:实施例1制备的纳米药物对乳腺癌细胞的抑制率,明显高于对比例1(未加铜基金属有机框架)和对比例2(未加铂类药物前体)。说明铜基金属有机框架和铂类药物前体在抑制肿瘤细胞上具有协同作用。
试验例8 CPAD对肺转移的抑制作用
(1)建立动物模型:将4T1细胞培养,待其生长状态良好时,消化离心后计数并调整细胞悬液的细胞浓度为2×107个/mL。对BALB/c雌性小鼠进行腹腔注射麻醉后,使用1mL无菌注射器将50μL细胞悬液注射到小鼠第三对乳腺脂肪垫处,随后正常饲养,并每日观察小鼠精神状况和肿瘤生长情况,同时用游标卡尺测量肿瘤的长径和短径,根据公式计算肿瘤体积,当肿瘤体积至300mm3左右时,将老鼠随机分为4组(A/B/C/D组),每组5只,开始进行给药治疗。A组:实施例1的CPAD;B组:对比例1;C组:对比例2;D组:生理盐水组。
(2)前药的工作浓度为1mg/kg/只,隔天给药,共给药7次,并在第0、2、4、6、8、10、12、14天量取肿瘤体积,如图13所示。治疗结束后,脱臼法处死实验小鼠,分别收集各组肺组织、肿瘤组织。对肺组织进行Bouin's固定液染色,同时进行H&E染色切片分析,结果如图11所示。并统计肺转移灶,结果如图12所示。称取肿瘤的质量,如图14所示,然后对肿瘤组织进行H&E切片和TUNEL荧光染色切片,如图15所示。CPAD对肺转移的抑制作用结果见表3。
实验结果表明:CPAD组治疗后能显著阻止肺转移,使肿瘤体积增速减慢,治疗后肿瘤的质量明显小于对比例1和对比例2,对肿瘤细胞的损伤和凋亡作用优于对比例1和对比例2。
表3 CPAD对肺转移的抑制作用
组别 | 实施例1 | 对比例1 | 对比例2 | 对照组 |
肺转移抑制率 | 88.4% | 22.1% | 26.9% | 0%(5/5) |
进一步的实验表明,实施例2、3制备的药物制剂与实施例1制备的药物制剂具有相似的效果。
本发明的含铂类药物纳米囊泡的作用机制为:其可在酸性条件下特异性释放铜离子和前药Pt-Arg,铜离子催化雌激素氧化,降低肿瘤原位雌激素水平,从而通过ERK/CANP途径抑制TNBC转移。Cu2+可与E2的胞内代谢产物4-OHE2反应,从而消耗肿瘤组织的雌激素水平,抑制MMP-2的表达。同时,释放的Pt-Arg前药在肿瘤组织GSH的激活下产生游离的Pt和L-Arg,Pt在NOX酶诱导下生成H2O2,进而氧化L-Arg产生NO,产生的NO可以原位阻断肿瘤细胞诱导的血小板激活,从而阻断活化血小板引发的肿瘤组织EMT转化。铜离子和前药P协同作用于TNBC的抗转移治疗。
虽然,上文中已经用一般性说明及具体实施方案对本发明作了详尽的描述,但在本发明基础上,可以对之作一些修改或改进,这对本领域技术人员而言是显而易见的。因此,在不偏离本发明精神的基础上所做的这些修改或改进,均属于本发明要求保护的范围。
Claims (10)
2.一种铂类药物前体的制备方法,包括以下步骤:
S1:将顺铂与H2O2进行羟基化反应,得到羟基化顺铂;
S2:将步骤S1得到的羟基化顺铂和Fmoc-Pbf-精氨酸反应,得到铂类药物前体。
3.根据权利要求2所述的一种铂类药物前体的制备方法,其特征在于:步骤S1中,具体方法为:将顺铂溶于H2O2中搅拌、静置得到;
步骤S2中,具体方法为:将Fmoc-Pbf-精氨酸溶于二氯甲烷溶液,加入羟基化顺铂和4-二甲胺基吡啶,置于冰浴内至澄清,加入N,N-二环己基碳二亚胺,室温回流过滤得到。
4.一种含铂类药物纳米囊泡,其特征在于:包括铜基金属有机框架和包裹在铜基金属有机框架内的铂类药物前体,所述铂类药物前体的分子结构式如权利要求1中式1所示,所述铜基金属有机框架表面修饰有长循环脂质体。
5.根据权利要求4所述的一种含铂类药物纳米囊泡,其特征在于:按质量比,铜基金属有机框架:铂类药物前体:长循环脂质体为1-0.5:1:2-1。
6.根据权利要求4所述的一种含铂类药物纳米囊泡,其特征在于:所述铜基金属有机框架为MIL-53-Cu;
优选地,所述长循环脂质体为二硬脂酰基磷脂酰乙醇胺-聚乙二醇、磷脂酰乙醇胺-聚乙二醇、磷脂酰胆碱-聚乙二醇、二硬脂酰磷脂酰胆碱-聚乙二醇中的一种或几种。
7.权利要求4-6任一项所述的一种含铂类药物纳米囊泡的制备方法,包括以下步骤:
S1:将铜基金属有机框架与铂类药物前体混合,搅拌,得到铂类药物前体纳米粒;
S2:将长循环脂质体与步骤S1制备的铂类药物前体纳米粒混合,搅拌,得到含铂类药物纳米囊泡。
8.根据权利要求7所述的一种含铂类药物纳米囊泡的制备方法,其特征在于:步骤S1中,搅拌时间为8-12h,搅拌速度为500-600rpm;步骤S2中,搅拌时间为4-8h,搅拌速度为500-600rpm。
9.权利要求1所述的一种铂类药物前体、权利要求4-6任一项所述一种含铂类药物纳米囊泡在制备抗肿瘤药物中的应用。
10.根据权利要求9所述的应用,其特征在于,所述肿瘤为乳腺癌,优选地,所述乳腺癌为三阴性乳腺癌。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202111477036.5A CN114163481B (zh) | 2021-12-06 | 2021-12-06 | 一种含铂类药物纳米囊泡及其制备方法与应用 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202111477036.5A CN114163481B (zh) | 2021-12-06 | 2021-12-06 | 一种含铂类药物纳米囊泡及其制备方法与应用 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN114163481A true CN114163481A (zh) | 2022-03-11 |
CN114163481B CN114163481B (zh) | 2023-06-23 |
Family
ID=80483364
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202111477036.5A Active CN114163481B (zh) | 2021-12-06 | 2021-12-06 | 一种含铂类药物纳米囊泡及其制备方法与应用 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN114163481B (zh) |
Citations (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5945122A (en) * | 1996-08-23 | 1999-08-31 | Sequus Pharmaceuticals, Inc. | Liposomes containing a cisplatin compound |
US20120189571A1 (en) * | 2009-02-04 | 2012-07-26 | The Brigham And Women's Hospital., Inc. | Nanoscale platinum compounds and methods of use thereof |
CN104606127A (zh) * | 2015-01-21 | 2015-05-13 | 浙江峰盛生物工程有限公司 | 靶向egfr的载铂类药物白蛋白纳米粒及其制备与应用 |
CN106798730A (zh) * | 2017-03-09 | 2017-06-06 | 苏州大学 | 一种乏氧改善的顺铂前药脂质体制剂及其制备方法与应用 |
CN110731961A (zh) * | 2014-10-14 | 2020-01-31 | 芝加哥大学 | 金属有机框架、药物制剂及其在制备药物中的用途 |
CN110787146A (zh) * | 2019-09-25 | 2020-02-14 | 中国人民解放军第四军医大学 | 氧化还原响应性肿瘤靶向顺铂纳米递药系统的制备方法及其应用 |
CN110882396A (zh) * | 2019-11-22 | 2020-03-17 | 中国人民解放军第四军医大学 | 肿瘤微环境与氧化还原逐级响应性纳米递药系统的制备方法及应用 |
CN112274648A (zh) * | 2020-11-23 | 2021-01-29 | 郑州大学 | 一种胆固醇氧化酶修饰的杂化金属有机框架肿瘤靶向纳米制剂的制备方法 |
CN112961188A (zh) * | 2021-02-07 | 2021-06-15 | 山东省第二人民医院(山东省耳鼻喉医院、山东省耳鼻喉研究所) | 一种四价铂前药苄达酸铂、其制剂及制备方法和应用 |
-
2021
- 2021-12-06 CN CN202111477036.5A patent/CN114163481B/zh active Active
Patent Citations (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5945122A (en) * | 1996-08-23 | 1999-08-31 | Sequus Pharmaceuticals, Inc. | Liposomes containing a cisplatin compound |
US20120189571A1 (en) * | 2009-02-04 | 2012-07-26 | The Brigham And Women's Hospital., Inc. | Nanoscale platinum compounds and methods of use thereof |
CN109293927A (zh) * | 2009-02-04 | 2019-02-01 | 布里格姆及妇女医院股份有限公司 | 纳米级铂化合物及其使用方法 |
CN110731961A (zh) * | 2014-10-14 | 2020-01-31 | 芝加哥大学 | 金属有机框架、药物制剂及其在制备药物中的用途 |
CN104606127A (zh) * | 2015-01-21 | 2015-05-13 | 浙江峰盛生物工程有限公司 | 靶向egfr的载铂类药物白蛋白纳米粒及其制备与应用 |
CN106798730A (zh) * | 2017-03-09 | 2017-06-06 | 苏州大学 | 一种乏氧改善的顺铂前药脂质体制剂及其制备方法与应用 |
CN110787146A (zh) * | 2019-09-25 | 2020-02-14 | 中国人民解放军第四军医大学 | 氧化还原响应性肿瘤靶向顺铂纳米递药系统的制备方法及其应用 |
CN110882396A (zh) * | 2019-11-22 | 2020-03-17 | 中国人民解放军第四军医大学 | 肿瘤微环境与氧化还原逐级响应性纳米递药系统的制备方法及应用 |
CN112274648A (zh) * | 2020-11-23 | 2021-01-29 | 郑州大学 | 一种胆固醇氧化酶修饰的杂化金属有机框架肿瘤靶向纳米制剂的制备方法 |
CN112961188A (zh) * | 2021-02-07 | 2021-06-15 | 山东省第二人民医院(山东省耳鼻喉医院、山东省耳鼻喉研究所) | 一种四价铂前药苄达酸铂、其制剂及制备方法和应用 |
Non-Patent Citations (6)
Title |
---|
SAMUEL G. AWUAH 等: "A Pt(IV) Pro-drug Preferentially Targets Indoleamine-2,3- dioxygenase, Providing Enhanced Ovarian Cancer Immuno- Chemotherapy", 《J. AM. CHEM. SOC.》 * |
SIJIE WANG 等, 《JOURNAL OF NANOBIOTECHNOLOGY》 * |
SUMITRA MUKHOPADHYAY 等: "Conjugated Platinum(IV)-Peptide Complexes for Targeting Angiogenic Tumor Vasculature", 《BIOCONJUGATE CHEM》 * |
张佩路: "四种新型铜基配合物体外抗人三阴性乳腺癌性能探索", 《中国优秀硕士学位论文全文数据库 医药卫生科技辑》 * |
王思洁: "铜基纳米嚢泡通过局部雌激素调控和血小板阻断协同抑制三阴性乳腺癌增殖和转移研究", 《中国优秀硕士学位论文全文数据库 医药卫生科技》 * |
陈志强 等: "多肽p166结合顺铂对结肠癌裸鼠移植瘤抑制作用的观察", 中华肿瘤防治杂志 * |
Also Published As
Publication number | Publication date |
---|---|
CN114163481B (zh) | 2023-06-23 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Hu et al. | Nanozyme-catalyzed oxygen release from calcium peroxide nanoparticles for accelerated hypoxia relief and image-guided super-efficient photodynamic therapy | |
US9005757B2 (en) | Metal-salen complex compound and method for producing the same | |
CN105669964A (zh) | 卵巢癌特异靶向的生物可降解双亲性聚合物、由其制备的聚合物囊泡及应用 | |
EP2738158B1 (en) | Metal salen complex compound, local anesthetic, and anti-malignant tumor agent | |
CN106692059B (zh) | 一种低氧响应脂质体药物载体及其制备方法与应用 | |
Inose et al. | Development of X-ray contrast agents using single nanometer-sized gold nanoparticles and lactoferrin complex and their application in vascular imaging | |
CN110585238B (zh) | 一种具有协同作用的抗肿瘤药物组合物及其应用 | |
CN110403916A (zh) | 一种纳米治疗剂及其制备方法与应用 | |
CN113230418A (zh) | 一种超小核壳结构铁纳米颗粒的制备方法及应用 | |
CN114163481B (zh) | 一种含铂类药物纳米囊泡及其制备方法与应用 | |
CN112121182A (zh) | 一种检测缺氧细胞用纳米探针及其制备方法与应用 | |
CN111821469A (zh) | 归巢靶向rsgrvsn肽修饰的聚乙二醇-聚多巴胺-普鲁士蓝复合纳米粒子及制备方法 | |
CN108853056B (zh) | 一种叶酸靶向修饰共载盐酸阿霉素和藤黄酸纳米结构脂质载体制剂及其制备方法 | |
CN113549611B (zh) | 一种级联纳米酶及其制备方法与应用 | |
CN110448700B (zh) | 一种用于靶向诊疗胃癌的纳米载药复合物及制备方法 | |
CN102895669A (zh) | 一种顺铂配合物及其制备方法 | |
CN109276720B (zh) | 一种金属-有机物配合物纳米材料及其制备方法和应用 | |
CN113171469B (zh) | 靶向肿瘤细胞表面Trop2蛋白的肿瘤治疗纳米药物及其制备方法 | |
CN101716352B (zh) | 抗中期因子反义寡核苷酸纳米制剂及其制备与应用 | |
CN112656764B (zh) | 一种紫杉醇铂类共载靶向长循环脂质体及应用 | |
CN110037989A (zh) | 一类自裂解多功能脂质体及其应用 | |
CN113318234B (zh) | 一种精氨酸和熊果酸修饰的壳聚糖纳米递药载体及其制备方法和应用 | |
CN113402630B (zh) | 一种壳聚糖衍生物递药载体及其制备方法和应用 | |
CN115068443B (zh) | 一种双响应的核-壳结构树状大分子包裹铜离子/药物复合物及其制备和应用 | |
CN112545979B (zh) | 预防膀胱癌术后复发的灌注凝胶及其制备方法和应用 |
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 | ||
GR01 | Patent grant | ||
GR01 | Patent grant |