CN110101848A - 一种逆转肿瘤细胞顺铂耐药纳米药物及其制备方法和应用 - Google Patents
一种逆转肿瘤细胞顺铂耐药纳米药物及其制备方法和应用 Download PDFInfo
- Publication number
- CN110101848A CN110101848A CN201910289349.4A CN201910289349A CN110101848A CN 110101848 A CN110101848 A CN 110101848A CN 201910289349 A CN201910289349 A CN 201910289349A CN 110101848 A CN110101848 A CN 110101848A
- Authority
- CN
- China
- Prior art keywords
- nano medication
- platinum
- cis
- added
- cell
- 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
- 239000003814 drug Substances 0.000 title claims abstract description 94
- 229940079593 drug Drugs 0.000 title claims abstract description 87
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 title claims abstract description 30
- 229960004316 cisplatin Drugs 0.000 title claims abstract description 30
- 210000004881 tumor cell Anatomy 0.000 title claims abstract description 25
- 238000002360 preparation method Methods 0.000 title claims abstract description 18
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Substances [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims abstract description 79
- 229910052697 platinum Inorganic materials 0.000 claims abstract description 48
- 235000019420 glucose oxidase Nutrition 0.000 claims abstract description 40
- 210000004027 cell Anatomy 0.000 claims abstract description 36
- 108010015776 Glucose oxidase Proteins 0.000 claims abstract description 22
- 239000004366 Glucose oxidase Substances 0.000 claims abstract description 22
- 229940116332 glucose oxidase Drugs 0.000 claims abstract description 22
- 229940002612 prodrug Drugs 0.000 claims abstract description 22
- 239000000651 prodrug Substances 0.000 claims abstract description 22
- QVMPZNRFXAKISM-UHFFFAOYSA-N tirapazamine Chemical compound C1=CC=C2[N+]([O-])=NC(=N)N(O)C2=C1 QVMPZNRFXAKISM-UHFFFAOYSA-N 0.000 claims abstract description 20
- 229950002376 tirapazamine Drugs 0.000 claims abstract description 20
- 239000002502 liposome Substances 0.000 claims abstract description 13
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims abstract description 9
- 239000008103 glucose Substances 0.000 claims abstract description 9
- 238000001338 self-assembly Methods 0.000 claims abstract description 6
- 230000002209 hydrophobic effect Effects 0.000 claims abstract description 4
- 150000003904 phospholipids Chemical class 0.000 claims abstract description 4
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 claims description 16
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 15
- 238000000034 method Methods 0.000 claims description 9
- KILNVBDSWZSGLL-KXQOOQHDSA-N 1,2-dihexadecanoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCCCCCCCCC KILNVBDSWZSGLL-KXQOOQHDSA-N 0.000 claims description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 8
- 235000012000 cholesterol Nutrition 0.000 claims description 8
- 239000012528 membrane Substances 0.000 claims description 8
- 229920001223 polyethylene glycol Polymers 0.000 claims description 8
- 239000003960 organic solvent Substances 0.000 claims description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- 239000002202 Polyethylene glycol Substances 0.000 claims description 6
- 238000006243 chemical reaction Methods 0.000 claims description 5
- 201000007270 liver cancer Diseases 0.000 claims description 5
- 208000014018 liver neoplasm Diseases 0.000 claims description 5
- 238000002156 mixing Methods 0.000 claims description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 5
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 4
- 238000005119 centrifugation Methods 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- 230000001376 precipitating effect Effects 0.000 claims description 4
- 239000006228 supernatant Substances 0.000 claims description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethyl sulfoxide Natural products CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 3
- 238000004090 dissolution Methods 0.000 claims description 3
- 235000019441 ethanol Nutrition 0.000 claims description 3
- 238000010438 heat treatment Methods 0.000 claims description 3
- 239000008363 phosphate buffer Substances 0.000 claims description 3
- 238000002604 ultrasonography Methods 0.000 claims description 3
- YIDSTEJLDQMWBR-UHFFFAOYSA-N 1-isocyanatododecane Chemical compound CCCCCCCCCCCCN=C=O YIDSTEJLDQMWBR-UHFFFAOYSA-N 0.000 claims description 2
- FFRBMBIXVSCUFS-UHFFFAOYSA-N 2,4-dinitro-1-naphthol Chemical compound C1=CC=C2C(O)=C([N+]([O-])=O)C=C([N+]([O-])=O)C2=C1 FFRBMBIXVSCUFS-UHFFFAOYSA-N 0.000 claims description 2
- OKTJSMMVPCPJKN-IGMARMGPSA-N Carbon-12 Chemical compound [12C] OKTJSMMVPCPJKN-IGMARMGPSA-N 0.000 claims description 2
- 238000001816 cooling Methods 0.000 claims description 2
- 239000013078 crystal Substances 0.000 claims description 2
- 238000002425 crystallisation Methods 0.000 claims description 2
- 230000008025 crystallization Effects 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 238000005374 membrane filtration Methods 0.000 claims description 2
- 239000007787 solid Substances 0.000 claims description 2
- 238000003756 stirring Methods 0.000 claims description 2
- 238000001291 vacuum drying Methods 0.000 claims description 2
- 238000005406 washing Methods 0.000 claims description 2
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 claims 2
- 108090000854 Oxidoreductases Proteins 0.000 claims 1
- 102000004316 Oxidoreductases Human genes 0.000 claims 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 abstract description 17
- 229910052760 oxygen Inorganic materials 0.000 abstract description 17
- 239000001301 oxygen Substances 0.000 abstract description 17
- 206010028980 Neoplasm Diseases 0.000 abstract description 16
- 230000000694 effects Effects 0.000 abstract description 14
- 206010021143 Hypoxia Diseases 0.000 abstract description 7
- 108010088751 Albumins Proteins 0.000 abstract description 4
- 102000009027 Albumins Human genes 0.000 abstract description 4
- 230000001146 hypoxic effect Effects 0.000 abstract description 4
- 238000011069 regeneration method Methods 0.000 abstract description 4
- 230000004044 response Effects 0.000 abstract description 4
- 238000013467 fragmentation Methods 0.000 abstract description 3
- 238000006062 fragmentation reaction Methods 0.000 abstract description 3
- 239000002245 particle Substances 0.000 abstract description 3
- 229940044683 chemotherapy drug Drugs 0.000 abstract description 2
- 238000002483 medication Methods 0.000 abstract 1
- 238000005457 optimization Methods 0.000 abstract 1
- 239000013598 vector Substances 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 13
- 108020004414 DNA Proteins 0.000 description 10
- 239000007788 liquid Substances 0.000 description 8
- 206010059866 Drug resistance Diseases 0.000 description 6
- 238000011282 treatment Methods 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 231100000135 cytotoxicity Toxicity 0.000 description 4
- 230000003013 cytotoxicity Effects 0.000 description 4
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- 230000005540 biological transmission Effects 0.000 description 3
- 235000013339 cereals Nutrition 0.000 description 3
- 238000009826 distribution Methods 0.000 description 3
- 229940088598 enzyme Drugs 0.000 description 3
- 239000001963 growth medium Substances 0.000 description 3
- 230000002147 killing effect Effects 0.000 description 3
- 238000012545 processing Methods 0.000 description 3
- 238000010186 staining Methods 0.000 description 3
- 230000002195 synergetic effect Effects 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 2
- 108020005124 DNA Adducts Proteins 0.000 description 2
- 238000007400 DNA extraction Methods 0.000 description 2
- 108010067770 Endopeptidase K Proteins 0.000 description 2
- 240000007594 Oryza sativa Species 0.000 description 2
- 235000007164 Oryza sativa Nutrition 0.000 description 2
- 239000006180 TBST buffer Substances 0.000 description 2
- 230000001093 anti-cancer Effects 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 231100001157 chemotherapeutic toxicity Toxicity 0.000 description 2
- 238000002512 chemotherapy Methods 0.000 description 2
- 229910052802 copper Inorganic materials 0.000 description 2
- 239000010949 copper Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000002296 dynamic light scattering Methods 0.000 description 2
- 230000007954 hypoxia Effects 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 230000036284 oxygen consumption Effects 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 235000009566 rice Nutrition 0.000 description 2
- 230000004083 survival effect Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 238000001262 western blot Methods 0.000 description 2
- 102000007469 Actins Human genes 0.000 description 1
- 108010085238 Actins Proteins 0.000 description 1
- 240000003291 Armoracia rusticana Species 0.000 description 1
- 235000011330 Armoracia rusticana Nutrition 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- 108010078791 Carrier Proteins Proteins 0.000 description 1
- 108010033040 Histones Proteins 0.000 description 1
- 108010087230 Sincalide Proteins 0.000 description 1
- 235000018259 Solanum vestissimum Nutrition 0.000 description 1
- 240000002825 Solanum vestissimum Species 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000003698 anagen phase Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000010609 cell counting kit-8 assay Methods 0.000 description 1
- 230000022534 cell killing Effects 0.000 description 1
- 230000003833 cell viability Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 238000005336 cracking Methods 0.000 description 1
- 230000009089 cytolysis Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 229940042399 direct acting antivirals protease inhibitors Drugs 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- 238000001962 electrophoresis Methods 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 230000005484 gravity Effects 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 239000011229 interlayer Substances 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 239000012160 loading buffer Substances 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 239000006166 lysate Substances 0.000 description 1
- 230000002101 lytic effect Effects 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 235000013336 milk Nutrition 0.000 description 1
- 239000008267 milk Substances 0.000 description 1
- 210000004080 milk Anatomy 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000002086 nanomaterial Substances 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- IYDGMDWEHDFVQI-UHFFFAOYSA-N phosphoric acid;trioxotungsten Chemical compound O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.OP(O)(O)=O IYDGMDWEHDFVQI-UHFFFAOYSA-N 0.000 description 1
- 238000010298 pulverizing process Methods 0.000 description 1
- 238000000197 pyrolysis Methods 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 230000008439 repair process Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000008261 resistance mechanism Effects 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 238000005464 sample preparation method Methods 0.000 description 1
- 238000007790 scraping Methods 0.000 description 1
- 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 1
- 239000002904 solvent Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 238000012876 topography Methods 0.000 description 1
- 230000005748 tumor development Effects 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/28—Compounds containing heavy metals
- A61K31/282—Platinum compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/43—Enzymes; Proenzymes; Derivatives thereof
- A61K38/44—Oxidoreductases (1)
- A61K38/443—Oxidoreductases (1) acting on CH-OH groups as donors, e.g. glucose oxidase, lactate dehydrogenase (1.1)
-
- 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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/28—Steroids, e.g. cholesterol, bile acids or glycyrrhetinic acid
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Y—ENZYMES
- C12Y101/00—Oxidoreductases acting on the CH-OH group of donors (1.1)
- C12Y101/03—Oxidoreductases acting on the CH-OH group of donors (1.1) with a oxygen as acceptor (1.1.3)
- C12Y101/03004—Glucose oxidase (1.1.3.4)
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Dispersion Chemistry (AREA)
- Molecular Biology (AREA)
- General Engineering & Computer Science (AREA)
- Wood Science & Technology (AREA)
- Biochemistry (AREA)
- Zoology (AREA)
- Biophysics (AREA)
- Genetics & Genomics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Gastroenterology & Hepatology (AREA)
- Immunology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明提供了一种逆转肿瘤细胞顺铂耐药纳米药物及其制备方法和应用,所述纳米药物由脂质体自组装形成,其中,包括脂质体磷脂双分子层之间疏水腔负载的疏水性顺铂前药和自组装形成亲水腔包载亲水性药物替拉扎明和葡萄糖氧化酶。脂质体载体与负载的药物以亲疏水作用力形成非缀合的位置关系。本发明通过优化制备工艺,最终成功制备得到纳米药物,产物粒径适中可控。纳米药物中葡萄糖氧化酶与肿瘤细胞中丰富的葡萄糖反应可消耗耐药肿瘤细胞中的氧气从而激活化疗药物TPZ的生物毒性。此外,在乏氧条件下纳米药物中TPZ能够抑制顺铂耐药细胞高表达的DNA自我修复蛋白XPF,从而有助于增强顺铂对细胞的杀伤效果。
Description
技术领域
本发明属于纳米材料技术领域,涉及一种逆转肿瘤细胞顺铂耐药纳米药物载体及其制备方法和应用。
背景技术
顺铂因具有抗癌效果显著、抗癌种类广谱等特点,被广泛用于恶性肿瘤的临床治疗中。但顺铂在治疗过程中具有非特异性会产生许多副作用,同时有些患者肿瘤对顺铂存在天然耐药性,更为严重的是在用药过程中,很多早期对顺铂敏感的患者逐渐产生耐药性,从而严重降低对肿瘤的治疗效果,极大限制了顺铂在临床中的进一步应用。肿瘤细胞产生耐药性的机制非常复杂,顺铂的作用靶点为DNA,因此顺铂的转运和代谢改变、DNA修复或耐受增强以及细胞的凋亡受阻等耐药机理都会造成细胞顺铂耐药。此外,还有研究发现肿瘤细胞对顺铂的敏感性与肿瘤微环境中的缺氧有关。Vaupel等在统计分析肿瘤中氧合含量与肿瘤发生发展关系时发现,局部复发的缺氧程度高于各自的原发肿瘤。
缺氧是许多恶性实体瘤的共同特征。过去大量的研究表明,携带缺氧肿瘤的患者经常降低总体存活率。尽管在开发可有效克服肿瘤乏氧和控制肿瘤生长的疗法方面取得了一些进展,但肿瘤细胞几乎总是会用耐药予以反击,使得治疗效果降低,甚至发生复发和转移。从根源上彻底杀死肿瘤耐药细胞,才能实现肿瘤的根除。
因此,如何设计一种利用肿瘤乏氧微环境逆转肿瘤细胞顺铂耐药的纳米药物来达到更好的肿瘤治疗效果是本领域的研究重点
发明内容
针对现有技术的不足,本发明的目的在于提供一种逆转肿瘤细胞顺铂耐药的纳米药物及其制备方法和应用。本发明能够特异性有效杀伤乏氧的顺铂耐药肿瘤细胞。
为达到此发明目的,本发明采用以下技术方案:
一方面,本发明提供一种纳米药物,所述纳米药物由脂质体自组装形成,其中,包括脂质体磷脂双分子层之间疏水腔负载的疏水性顺铂前药和自组装形成亲水腔包载亲水性药物替拉扎明和葡萄糖氧化酶。
在本发明中,所述顺铂前药合成过程可以表示为如下路线:
本发明中,所述纳米药物以磷脂双分子层为载体,疏水性顺铂前药扦插入双分子层间的疏水腔,亲水药物替拉扎明和葡萄糖氧化酶在脂质体自组装过程中被包载在亲水腔中。纳米药物中的葡萄糖氧化酶与肿瘤中丰富的葡萄糖反应进一步消耗肿瘤中的氧气,营造的乏氧环境能够激活药物替拉扎明的化疗毒性,特异性的实现对肿瘤的化学治疗。此外,在乏氧条件下纳米药物中TPZ能够抑制顺铂耐药细胞高表达的DNA自我修复蛋白XPF,从而有助于增强顺铂对细胞的杀伤效果。因此,该纳米药物有望逆转肿瘤细胞的顺铂耐药。
优选地,所述纳米药物的平均粒径为80~90nm,例如:80nm、81nm、83nm、84nm、85nm、86nm、87nm、89nm、90nm等。
本发明所述纳米载体药物呈类球形,粒径分布均一。
优选地,所述纳米药物中顺铂前药的载药率为7.5~8.0%,例如:7.55%、7.65%、7.7%、7.85%、7.95%等。
优选地,所述纳米药物中替拉扎明的载药率为1.8~2.0%,例如:1.85%、1.89%、1.92%、1.95%、2.0%等。
优选地,所述纳米药物中葡萄糖氧化酶活性为2.0~2.5U/mg,例如:2.0U/mg、2.1U/mg、2.3U/mg、2.4U/mg、2.5U/mg等。
另一方面,本发明提供一种如上所述的纳米药物的制备方法,其特征在于,所述制备方法为:脂质体与顺铂前药旋蒸得到均匀分散的薄膜,而后脂质体薄膜在溶有亲水药物替拉扎明和葡萄糖氧化酶的磷酸盐缓冲液中水化,即为所述纳米药物。
在本发明中,所述顺铂前药制备方法包括以下步骤:
(1)将1g顺铂加入到100ml圆底烧瓶中,加入36ml 30%的双氧水,55℃加热2小时,温度升高至100℃加热30min,此时溶液变成澄清淡黄色。将反应移出冷却30min后放到4℃冰箱中过夜结晶,将生产的淡黄色结晶物,过滤,分别用水,乙醇,乙醚洗涤。至于真空干燥箱中干燥过夜,最后得到金黄色颗粒状固体,即为四价羟基顺铂。
(2)称取200mg四价羟基顺铂放入圆底烧瓶中,加入40ml N,N-二甲基甲酰胺搅拌均匀,加热到65℃,加入266mg异氰酸十二烷基酯,继续反应直到变成澄清黄色溶液。在65℃下将N,N-二甲基甲酰胺旋干,加入少量甲醇溶解,加入大量乙醚沉淀,离心去除上层清液,沉淀放到真空干燥箱中干燥,即得轴向接碳十二的四价铂前药。
在本发明中,所述纳米药物组装方法包括以下步骤:
分别用有机溶剂溶解二棕榈酰磷脂酰胆碱、胆固醇、磷脂聚乙二醇和四价铂前药,加入圆底烧瓶中混合均匀,用旋转蒸发仪旋蒸,使其逐渐旋干,确保有机溶剂完全挥发。加入溶有替拉扎明和葡萄糖氧化酶的PBS溶液,超声。再用脂质体挤出器挤推,用超滤管洗三次,再用滤膜过滤,即得所述纳米药物。
优选地,所述有机溶剂为二甲基亚砜、三氯甲烷其中的任意一种或至少两种的组合;
优选地,所述二棕榈酰磷脂酰胆碱、胆固醇、磷脂聚乙二醇和四价铂前药的浓度为5~20mg/mL,例如:5mg/mL、10mg/mL、20mg/mL;
优选地,所述二棕榈酰磷脂酰胆碱、胆固醇、磷脂聚乙二醇和四价铂前药混合的体积比例为12:4:1:4或8:8:1:4;
优选地,所述旋蒸温度为40℃~60℃,例如:40℃、50℃、60℃;
优选地,所述旋蒸转速为50rpm,旋蒸时间为3~5h,例如:3h、4h、5h;
优选地,所述替拉扎明和葡萄糖氧化酶混合的质量比为1:0.5~1:2,例如:1:0.5、1:1、1:2;
优选地,所述替拉扎明和葡萄糖氧化酶混合的水化体积为2~6mL,例如:2mL、4mL、6mL;
优选地,所述超声温度为40℃~60℃,例如:40℃、50℃、60℃;
优选地,所述超声时间为15~45min,例如:15min、30min、45min;
优选地,所述滤膜为220nm水系滤膜。
另一方面,本发明提供了如上所述的纳米药物在逆转肿瘤细胞顺铂耐药中的应用。
优选地,所述肿瘤细胞为人源肝癌顺铂耐药细胞株BEL 7404-CP20。
在肝癌顺铂耐药细胞治疗中,纳米药物中的葡萄糖氧化酶与肿瘤中丰富的葡萄糖反应进一步消耗肿瘤中的氧气,营造的乏氧环境能够激活药物替拉扎明的化疗毒性,实现对肿瘤特异性的化学治疗。顺铂前药呈反应惰性,需要进入细胞被还原为二价铂配合物后才产生细胞毒性,因此可同时避免产生系统毒性和药物失活。肿瘤细胞产生顺铂耐药的原因之一为DNA自我修复蛋白XPF高表达,能够有效修复顺铂损伤的DNA,降低作用效果。在乏氧条件下激活的TPZ能够抑制顺铂耐药细胞高表达的XPF蛋白,从而提高顺铂对细胞的杀伤效果。因此,该纳米药物有望逆转肿瘤细胞的顺铂耐药。本发明纳米药物通过协同治疗实现对肝癌顺铂耐药细胞的有效杀伤。
相对于现有技术,本发明具有以下有益效果:
本发明通过脂质体作为载体,以葡萄糖氧化酶作为耗氧剂,替拉扎明作为乏氧可激活的治疗剂,在葡萄糖存在条件先可增强乏氧程度激活化疗药物替拉扎明。此外,乏氧激活的替拉扎明能够抑制顺铂耐药细胞高表达的XPF蛋白,有助于提高顺铂杀伤细胞的效果,具有逆转肿瘤细胞顺铂耐药的应用前景。
附图说明
图1为本发明提供的逆转肿瘤细胞顺铂耐药纳米药物的透射电子显微镜图片;
图2为本发明提供的逆转肿瘤细胞顺铂耐药纳米药物的粒径分布图;
图3为本发明提供的验证纳米药物中葡萄糖氧化酶与葡萄糖反应消耗氧气的结果图;
图4为本发明提供的纳米药物对BEL 7404-CP20细胞活性影响的CCK-8结果图;
图5为本发明提供的纳米药物对XPF蛋白抑制的结果图;
图6为本发明提供的纳米药物对形成Pt/DNA加合物影响的结果图。
具体实施方式
为更进一步阐述本发明所采取的技术手段及其效果,以下结合附图并通过具体实施方式来进一步说明本发明的技术方案,但本发明并非局限在实施例范围内。
实施例1
在本实施例中,所述纳米药物为脂质体与顺铂前药旋蒸得到均匀分散的薄膜,而后脂质体薄膜在溶有亲水药物替拉扎明和葡萄糖氧化酶的磷酸盐缓冲液中水化自组装得到。
通过以下方法制备得到纳米药物,具体包括以下步骤:
分别用三氯甲烷配置10mg/mL(5mg/mL、20mg/mL)的二棕榈酰磷脂酰胆碱、胆固醇和DSPE-PEG,四价铂前药用N,N-二甲基甲酰胺配置为10mg/mL(5mg/mL、20mg/mL)溶液,在圆底烧瓶中按照12:4:1:4或8:8:1:4的摩尔比分别加入1.76mL二棕榈酰磷脂酰胆碱、0.31mL胆固醇、0.55mL DSPE-PEG和0.6mL四价铂混合均匀,用旋转蒸发仪在50℃(40℃、60℃)条件下以50rpm的转速旋蒸3h(4h、5h),使其逐渐旋干,确保有机溶剂完全挥发。加入4mL(2mL、6mL)含有1mg/mL TPZ和1mg/mL GOx的PBS溶液,50℃(40℃、60℃)水浴超声30min。再用脂质体挤出器在50℃下用200nm膜挤推21次,用超滤管洗三次,再过220nm滤膜,4℃保存,即得纳米药物Pt/TPZ/GOx@Lipo。
对照组纳米药物Pt@Lipo,Pt/TPZ@Lipo,TPZ/GOx@Lipo,Pt/GOx@Lipo、TPZ@Lipo的制备方法类似,即在Pt/TPZ/GOx@Lipo的制备方法中减去相应的四价铂前药,TPZ以及GOx,在无四价铂前药组,旋蒸时间可缩短至0.5h(1h、1.5h)。
实施例2
本实施例中采用生物透射电子显微镜和动态光散射仪对纳米药物进行尺寸形貌分析。
透射电子显微镜样品制备方法如下:将制得的纳米药物稀释200倍,并超声2min进行分散处理,取7μL稀释后的纳米药物水溶液滴于TEM测试铜网上,室温静置,待溶剂完全挥发晾干后,将2%磷钨酸负染液12000rpm离心5min,取7μL上清液轻轻滴于载有纳米药物的铜网上负染1min,用滤纸侧面吸走负染液,晾干后用生物透射电镜观察,结果如图1所示,纳米药物呈现球状且分散性良好,尺寸在40-50nm之间。
动态光散射结果如图2所示,显示该纳米药物平均水合粒径约为87nm,粒径分布区间较窄。
实施例3
本实施例中采用溶氧仪检测纳米药物中葡萄糖氧化酶消耗氧气的能力。
将所述纳米药物稀释不同倍数得到不同酶活的溶液,如500mU/mL,250mU/mL,125mU/mL,50mU/mL,0mU/mL,取5mL待测溶液放于50mL离心管中,将溶氧仪探头深入液面以下,待读数稳定后加入50μL 100mg/mL的葡萄糖,葡萄糖终浓度为1mg/mL,每30s读一次数,得耗氧曲线。
如图3所示,该纳米药物中包载的葡萄糖氧化酶活性保持良好,其消耗氧气能力随着酶活增加而增强。
实施例4
本实施例中,对实施例1制备的纳米药物在顺铂耐药肝癌细胞BEL7404-CP20上检测细胞毒性,方法如下:
将对数生长期的BEL 7404-CP20细胞以7000个细胞/孔的密度接种在96孔板中培养24h。向各孔中加入100μL用新鲜培养基稀释不同倍数的Pt@Lipo,Pt/TPZ@Lipo,TPZ/GOx@Lipo,Pt/TPZ/GOx@Lipo溶液。以无药物处理细胞作为对照,只含培养基的孔作为空白,共孵育24h后,将培养基更换回新鲜培养基以除去溶液中的游离药物,每孔加入10μL CCK-8,2h后用酶标仪摇20s,测定450nm处的吸光度,计算细胞活力。结果见图4。
如图4所示,与Pt@Lipo比,纳米药物中替拉扎明的加入对细胞存活率影响不大,替拉扎明与葡萄糖氧化酶同时存在时,细胞杀伤能力较强,与TPZ/GOx@Lipo单独作用细胞效果相比,Pt/TPZ/GOx@Lipo的细胞毒性明显增强,说明该纳米药物具有良好的协同效应,能够增强细胞毒性。
实施例5
本实施例中采用Western Blots验证纳米药物对XPF蛋白表达的抑制效果。
将BEL 7404-CP20顺铂耐药细胞株以10万/mL的细胞密度分散于培养基中,以每孔3×105个细胞的密度接种在6孔板中。培养24h后将四组纳米药物Pt@Lipo,Pt/TPZ@Lipo,TPZ/GOx@Lipo,Pt/TPZ/GOx@Lipo以Pt当量浓度1μM的浓度分别加入各个孔处理细胞7h后,PBS洗三遍,用含有蛋白酶抑制剂的细胞裂解液Ripa在冰上裂解细胞30min,裂解结束用刮刀刮下收集每组收集液超声粉碎30s,在4℃以13000rpm转速离心15min,取上清用Nanodrop进行蛋白定量后,稀释至相同浓度,加入上样缓冲液混匀,100℃煮沸10min,-20℃保存待用。再通过Western Blots实验,从左到右分别以对照组,Pt@Lipo,Pt/TPZ@Lipo,TPZ/GOx@Lipo,Pt/TPZ/GOx@Lipo处理组蛋白的顺序上样,电泳、转膜后取出放于封闭盒中,加入5%牛奶置于摇床封闭1h,加入1:2000稀释好的XPF一抗4℃过夜。用TBST溶液洗膜,5min/次,洗五次,加入1:5000TBST稀释的辣根酶标记山羊抗兔IgG(H+L),摇床摇1h,再用TBST洗五遍,按1:1混合化学发光液中的AB液进行曝光。
图5为总蛋白量β-actin一定的条件下,不同处理组XPF蛋白表达水平的差异性,同时含有TPZ和GOx的纳米药物TPZ/GOx@Lipo,Pt/TPZ/GOx@Lipo处理组XPF蛋白表达量明显降低,与对照组Pt@Lipo具有显著性差异。
实施例6
本实施例中,验证了纳米药物对Pt/DNA加合物形成的影响做了验证。
药物与细胞作用后DNA-Pt加合定量实验首先采用DNA提取试剂盒对药物处理后细胞的DNA进行提取。将10万/mL的BEL 7404-CP20顺铂耐药细胞以每孔2mL的密度加入12孔板中,培养24小时细胞密度达80%后,以Pt有效浓度1μM将Pt@Lipo,Pt/TPZ@Lipo和Pt/TPZ/GOx@Lipo分别加入培养基处理细胞7h后,用PBS将细胞洗三遍,胰酶消化收集,PBS再洗两遍,按照试剂盒说明进行DNA提取,用200μL重悬液重选,加入20mL 20mg/mL的蛋白酶K(Proteinase K)和200mL裂解液(Lysis Solution C),涡旋15s后在70℃加热10min,加入200μL95%乙醇,涡旋10s。将得到的溶解物加入经柱子准备液12000g离心1min清洗过的柱子中,6500g离心1min。换上新的2mL离心管,向柱子中加入500μL清洗液12000g离心3min。待晾干后向柱子中加入200μL洗脱液,6500g离心1min收集提取的DNA。
结果如图6所示,在XPF蛋白被显著抑制组Pt/TPZ/GOx@Lipo中Pt与DNA加合量明显增加,进一步说明乏氧条件下TPZ能够抑制XPF蛋白表达,增强顺铂与DNA结合。
综上所述,本发明提供的纳米药物粒径适中可控,与葡萄糖反应消耗氧气,有效激活化疗药物替拉扎明,对细胞产生毒性,同时抑制顺铂耐药肿瘤细胞高表达的DNA自我修复蛋白XPF,有利于提高顺铂对细胞的杀伤效果,具有协同治疗效果,有望逆转肿瘤细胞顺铂耐药性,具有广阔的应用前景和巨大的市场价值。
申请人声明,本发明通过上述实施例来说明本发明的逆转肿瘤细胞顺铂耐药纳米药物及其制备方法和应用,但本发明并不局限于上述实施例中的详细方法,即不意味着本发明必须依赖上述实施例才能实施。所属技术领域的技术人员应该明了,对本发明的任何改进,对本发明产品各原料的等效替换及辅助成分的添加、具体方式的选择等,均落在本发明的保护范围和公开范围之内。
Claims (10)
1.一种逆转肿瘤细胞顺铂耐药纳米药物,其特征在于,所述纳米药物包括脂质体磷脂双分子层之间疏水腔负载疏水性顺铂前药和自组装形成亲水腔包载亲水性药物替拉扎明和葡萄糖氧化酶。
2.根据权利要求1所述的纳米药物,其特征在于,所述纳米药物的平均粒径为80~90nm。
3.根据权利要求1或2所述的纳米药物,其特征在于,所述纳米药物中顺铂前药的载药率为7.5~8.0%。
4.根据权利要求1~2中任一项所述的纳米药物,其特征在于,所述纳米药物中替拉扎明的载药率为1.8~2.0%。
5.根据权利要求1~2中任一项所述的纳米药物,其特征在于,所述纳米药物中葡萄糖氧化酶活性为2.0~2.5U/mg。
6.根据权利要求1~2中任一项所述的纳米药物的制备方法,其特征在于,所述制备方法为:脂质体与顺铂前药旋蒸得到均匀分散的薄膜,而后脂质体薄膜在溶有亲水药物替拉扎明和葡萄糖氧化酶的磷酸盐缓冲液中水化,即为所述纳米药物。
7.根据权利要求6所述的制备方法,其特征在于,所述顺铂前药制备方法包括以下步骤:
(1)将1g顺铂加入到100ml圆底烧瓶中,加入36ml30%的双氧水,55℃加热2小时,温度升高至100℃加热30min,此时溶液变成澄清淡黄色;
将反应移出冷却30min后放到4℃冰箱中过夜结晶,将生产的淡黄色结晶物,过滤,分别用水,乙醇,乙醚洗涤;
置于真空干燥箱中干燥过夜,最后得到金黄色颗粒状固体,即为四价羟基顺铂;
(2)称取200mg四价羟基顺铂放入圆底烧瓶中,加入40ml N,N-二甲基甲酰胺搅拌均匀,加热到65℃,加入266mg异氰酸十二烷基酯,继续反应直到变成澄清黄色溶液;
在65℃下将N,N-二甲基甲酰胺旋干,加入少量甲醇溶解,加入大量乙醚沉淀,离心去除上层清液,沉淀放到真空干燥箱中干燥,即得轴向接碳十二的四价铂前药。
8.根据权利要求6所述纳米药物的制备方法,其特征在于,所述纳米药物组装方法包括以下步骤:
分别用有机溶剂溶解二棕榈酰磷脂酰胆碱、胆固醇、磷脂聚乙二醇和四价铂前药,加入圆底烧瓶中混合均匀,用旋转蒸发仪旋蒸,使其逐渐旋干,确保有机溶剂完全挥发;
加入溶有替拉扎明和葡萄糖氧化酶的PBS溶液,超声;
再用脂质体挤出器挤推,用超滤管洗三次,再用滤膜过滤,即得所述纳米药物。
9.根据权利要求6或8所述的制备方法,其特征在于,所述有机溶剂为二甲基亚砜、三氯甲烷其中的任意一种或至少两种的组合;
优选地,所述二棕榈酰磷脂酰胆碱、胆固醇、磷脂聚乙二醇和四价铂前药的浓度为5~20mg/mL;
优选地,所述二棕榈酰磷脂酰胆碱、胆固醇、磷脂聚乙二醇和四价铂前药混合的体积比例为12:4:1:4或8:8:1:4;
优选地,所述旋蒸温度为40℃~60℃;
优选地,所述旋蒸转速为50rpm,旋蒸时间为3~5h;
优选地,所述替拉扎明和葡萄糖氧化酶混合的质量比为1:0.5~1:2;
优选地,所述替拉扎明和葡萄糖氧化酶混合的水化体积为2~6mL;
优选地,所述超声温度为40℃~60℃;
优选地,所述超声时间为15~45min;
优选地,所述滤膜为220nm水系滤膜。
10.根据权利要求1~5中任一项所述的纳米药物在逆转肿瘤细胞顺铂耐药中的应用;
优选地,所述肿瘤细胞为人源肝癌顺铂耐药细胞株BEL 7404-CP20。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201910289349.4A CN110101848A (zh) | 2019-04-11 | 2019-04-11 | 一种逆转肿瘤细胞顺铂耐药纳米药物及其制备方法和应用 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201910289349.4A CN110101848A (zh) | 2019-04-11 | 2019-04-11 | 一种逆转肿瘤细胞顺铂耐药纳米药物及其制备方法和应用 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN110101848A true CN110101848A (zh) | 2019-08-09 |
Family
ID=67485356
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201910289349.4A Pending CN110101848A (zh) | 2019-04-11 | 2019-04-11 | 一种逆转肿瘤细胞顺铂耐药纳米药物及其制备方法和应用 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN110101848A (zh) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN112957342A (zh) * | 2021-02-05 | 2021-06-15 | 中国科学院化学研究所 | 一种人血清白蛋白负载的四价铂纳米粒子及其制备方法 |
CN114652820A (zh) * | 2022-03-22 | 2022-06-24 | 中国药科大学 | 一种阳离子脂质体纳米粒及其制备方法和应用 |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20140271820A1 (en) * | 2013-03-13 | 2014-09-18 | Mallinckrodt Llc | Liposome oxaliplatin compositions for cancer therapy |
CN106267229A (zh) * | 2016-08-12 | 2017-01-04 | 南开大学 | 一种肝靶向载铂纳米前药的结构及其制备方法 |
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 |
CN108976342A (zh) * | 2018-05-02 | 2018-12-11 | 上海交通大学 | 四价顺铂类前药与生物还原性药物联用的用途 |
-
2019
- 2019-04-11 CN CN201910289349.4A patent/CN110101848A/zh active Pending
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20140271820A1 (en) * | 2013-03-13 | 2014-09-18 | Mallinckrodt Llc | Liposome oxaliplatin compositions for cancer therapy |
CN106267229A (zh) * | 2016-08-12 | 2017-01-04 | 南开大学 | 一种肝靶向载铂纳米前药的结构及其制备方法 |
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 |
CN108976342A (zh) * | 2018-05-02 | 2018-12-11 | 上海交通大学 | 四价顺铂类前药与生物还原性药物联用的用途 |
Non-Patent Citations (2)
Title |
---|
ZHANG L等: "Erythrocyte membrane cloaked metal- organic framework nanoparticle as biomimetic nanoreactor for starvation- activated colon cancer therapy", 《ACS NANO》 * |
杨伟志等: "生物还原剂 SR4233 对人脑胶质瘤细胞的细胞毒作用研究", 《中华放射肿瘤学杂志》 * |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN112957342A (zh) * | 2021-02-05 | 2021-06-15 | 中国科学院化学研究所 | 一种人血清白蛋白负载的四价铂纳米粒子及其制备方法 |
CN114652820A (zh) * | 2022-03-22 | 2022-06-24 | 中国药科大学 | 一种阳离子脂质体纳米粒及其制备方法和应用 |
CN114652820B (zh) * | 2022-03-22 | 2024-02-06 | 中国药科大学 | 一种阳离子脂质体纳米粒及其制备方法和应用 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Huang et al. | Stable black phosphorus/Bi2O3 heterostructures for synergistic cancer radiotherapy | |
Sun et al. | In vitro and in vivo antitumor effects of doxorubicin loaded with bacterial magnetosomes (DBMs) on H22 cells: the magnetic bio-nanoparticles as drug carriers | |
Garc-Olmo et al. | Effects of long-term treatment of colon adenocarcinoma with crocin, a carotenoid from saffron (Crocus sativus L.): an experimental study in the rat | |
Amirani et al. | Effects of chitosan and oligochitosans on the phosphatidylinositol 3-kinase-AKT pathway in cancer therapy | |
CN103961712B (zh) | 一种超顺磁四氧化三铁纳米粒子药物载体及其制备方法和应用 | |
Yuan et al. | In situ-transition nanozyme triggered by tumor microenvironment boosts synergistic cancer radio-/chemotherapy through disrupting redox homeostasis | |
CN105030795A (zh) | 一种纳米载药系统及其制备方法和应用 | |
CN110101848A (zh) | 一种逆转肿瘤细胞顺铂耐药纳米药物及其制备方法和应用 | |
CN114601921B (zh) | 多孔Pt纳米花负载乳酸氧化酶的纳米制剂及其制备和应用 | |
Ge et al. | Effective treatment of cisplatin-resistant ovarian tumors with a MoS2-based sonosensitizer and nanoenzyme capable of reversing the resistant-microenvironment and enhancing ferroptosis and apoptosis | |
CN106344924B (zh) | 一种联合代谢阻断的纳米剂型及其耐药逆转应用 | |
Perumalsamy et al. | Anti-diabetic activity of silver nanoparticles synthesized from the hydroethanolic extract of Myristica fragrans seeds | |
CN110302397A (zh) | pH响应性氧化石墨烯纳米片包覆介孔二氧化硅药物双载复合纳米粒子及制备方法 | |
CN105816883A (zh) | 一种负载抗癌药物姜黄素的益生菌叶酸靶向载体及其制备方法 | |
CN106344539A (zh) | 一种新型多功能靶向纳米胶囊抗癌药物的分子设计与制备技术 | |
Wang et al. | BC@ DNA-Mn3 (PO4) 2 nanozyme for real-time detection of superoxide from living cells | |
Zhang et al. | Engineering biomimetic ATP-responsive Se-containing core-shell cascade nanozyme for efficient tumor combination therapy | |
Paramita et al. | Evaluation of potential anti‐cancer activity of cationic liposomal nanoformulated Lycopodium clavatum in colon cancer cells | |
Moradi et al. | Simulation and computational study of graphene oxide nano-carriers, absorption, and release of the anticancer drug of camptothecin | |
Sun et al. | A multifunctional metal-organic framework nanosystem disrupts redox homeostasis for synergistic therapy | |
Render et al. | Bio-based calcium carbonate (CaCO3) nanoparticles for drug delivery applications | |
CN100506974C (zh) | 粪肠球菌cms-h001及其应用 | |
CN109550050B (zh) | 一种负载黑色素的二氧化钼载药复合物及其制备和应用 | |
Lian et al. | Multi salt strategy based on curcumin pyrimidine derivatives prodrugs: Synthesis, biological activity, in vitro and in vivo imaging, and drug distribution research | |
Wang et al. | Treatment of Parkinson’s disease using focused ultrasound with GDNF retrovirus-loaded microbubbles to open the blood–brain barrier |
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 | ||
WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20190809 |
|
WD01 | Invention patent application deemed withdrawn after publication |