CN117050113B - Preparation method of tetravalent platinum nano-drug particles - Google Patents
Preparation method of tetravalent platinum nano-drug particles Download PDFInfo
- Publication number
- CN117050113B CN117050113B CN202310876447.4A CN202310876447A CN117050113B CN 117050113 B CN117050113 B CN 117050113B CN 202310876447 A CN202310876447 A CN 202310876447A CN 117050113 B CN117050113 B CN 117050113B
- Authority
- CN
- China
- Prior art keywords
- platinum
- nano
- tetravalent platinum
- tetravalent
- drug
- 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.)
- Active
Links
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 title claims abstract description 299
- 229910052697 platinum Inorganic materials 0.000 title claims abstract description 143
- 239000003814 drug Substances 0.000 title claims abstract description 106
- 229940079593 drug Drugs 0.000 title claims abstract description 99
- 239000002245 particle Substances 0.000 title claims abstract description 78
- 238000002360 preparation method Methods 0.000 title claims abstract description 18
- 239000000178 monomer Substances 0.000 claims abstract description 49
- 150000001875 compounds Chemical class 0.000 claims abstract description 21
- 238000007720 emulsion polymerization reaction Methods 0.000 claims abstract description 16
- 239000002994 raw material Substances 0.000 claims abstract description 12
- 239000003999 initiator Substances 0.000 claims abstract description 11
- 238000003756 stirring Methods 0.000 claims abstract description 6
- -1 alkenyl compound Chemical class 0.000 claims description 26
- 229920001223 polyethylene glycol Polymers 0.000 claims description 24
- 238000006243 chemical reaction Methods 0.000 claims description 13
- 238000012377 drug delivery Methods 0.000 claims description 13
- 239000002202 Polyethylene glycol Substances 0.000 claims description 11
- 239000002105 nanoparticle Substances 0.000 claims description 10
- 239000003381 stabilizer Substances 0.000 claims description 9
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 claims description 6
- 239000002246 antineoplastic agent Substances 0.000 claims description 6
- 229940041181 antineoplastic drug Drugs 0.000 claims description 6
- 230000001590 oxidative effect Effects 0.000 claims description 6
- 239000007800 oxidant agent Substances 0.000 claims description 5
- ATXASKQIXAJYLM-UHFFFAOYSA-N 1-hydroxypyrrolidine-2,5-dione;prop-2-enoic acid Chemical compound OC(=O)C=C.ON1C(=O)CCC1=O ATXASKQIXAJYLM-UHFFFAOYSA-N 0.000 claims description 4
- CERQOIWHTDAKMF-UHFFFAOYSA-M Methacrylate Chemical compound CC(=C)C([O-])=O CERQOIWHTDAKMF-UHFFFAOYSA-M 0.000 claims description 4
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 4
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 4
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 4
- 230000035484 reaction time Effects 0.000 claims description 4
- 229920002818 (Hydroxyethyl)methacrylate Polymers 0.000 claims description 3
- JAHNSTQSQJOJLO-UHFFFAOYSA-N 2-(3-fluorophenyl)-1h-imidazole Chemical compound FC1=CC=CC(C=2NC=CN=2)=C1 JAHNSTQSQJOJLO-UHFFFAOYSA-N 0.000 claims description 3
- NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 claims description 3
- WOBHKFSMXKNTIM-UHFFFAOYSA-N Hydroxyethyl methacrylate Chemical compound CC(=C)C(=O)OCCO WOBHKFSMXKNTIM-UHFFFAOYSA-N 0.000 claims description 3
- STVZJERGLQHEKB-UHFFFAOYSA-N ethylene glycol dimethacrylate Chemical compound CC(=C)C(=O)OCCOC(=O)C(C)=C STVZJERGLQHEKB-UHFFFAOYSA-N 0.000 claims description 3
- FPYJFEHAWHCUMM-UHFFFAOYSA-N maleic anhydride Chemical compound O=C1OC(=O)C=C1 FPYJFEHAWHCUMM-UHFFFAOYSA-N 0.000 claims description 3
- LVHBHZANLOWSRM-UHFFFAOYSA-N methylenebutanedioic acid Natural products OC(=O)CC(=C)C(O)=O LVHBHZANLOWSRM-UHFFFAOYSA-N 0.000 claims description 3
- 239000004372 Polyvinyl alcohol Substances 0.000 claims description 2
- 229920002451 polyvinyl alcohol Polymers 0.000 claims description 2
- 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 abstract description 18
- 238000000034 method Methods 0.000 abstract description 16
- 230000009467 reduction Effects 0.000 abstract description 12
- 210000004881 tumor cell Anatomy 0.000 abstract description 12
- 229960003180 glutathione Drugs 0.000 abstract description 9
- 239000000126 substance Substances 0.000 abstract description 9
- 238000009826 distribution Methods 0.000 abstract description 8
- 230000002147 killing effect Effects 0.000 abstract description 8
- 230000015572 biosynthetic process Effects 0.000 abstract description 6
- 238000003786 synthesis reaction Methods 0.000 abstract description 6
- 108010024636 Glutathione Proteins 0.000 abstract description 5
- 238000010276 construction Methods 0.000 abstract description 5
- 230000008569 process Effects 0.000 abstract description 4
- 230000004044 response Effects 0.000 abstract description 4
- 238000001308 synthesis method Methods 0.000 abstract description 4
- 239000012467 final product Substances 0.000 abstract 1
- 229960004316 cisplatin Drugs 0.000 description 23
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 23
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 19
- 239000000243 solution Substances 0.000 description 19
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 15
- 206010028980 Neoplasm Diseases 0.000 description 14
- 235000019441 ethanol Nutrition 0.000 description 14
- 239000000047 product Substances 0.000 description 13
- OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical compound N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- 150000002148 esters Chemical class 0.000 description 11
- 238000011068 loading method Methods 0.000 description 11
- NIXOWILDQLNWCW-UHFFFAOYSA-N 2-Propenoic acid Natural products OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 9
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- DDRJAANPRJIHGJ-UHFFFAOYSA-N creatinine Chemical compound CN1CC(=O)NC1=N DDRJAANPRJIHGJ-UHFFFAOYSA-N 0.000 description 8
- 230000000694 effects Effects 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- 238000012360 testing method Methods 0.000 description 8
- 241000700159 Rattus Species 0.000 description 7
- 230000002209 hydrophobic effect Effects 0.000 description 7
- 210000004369 blood Anatomy 0.000 description 6
- 239000008280 blood Substances 0.000 description 6
- 210000004027 cell Anatomy 0.000 description 6
- 238000002347 injection Methods 0.000 description 6
- 239000007924 injection Substances 0.000 description 6
- 239000002244 precipitate Substances 0.000 description 6
- 239000004698 Polyethylene Substances 0.000 description 5
- 238000000338 in vitro Methods 0.000 description 5
- 238000009616 inductively coupled plasma Methods 0.000 description 5
- 239000003960 organic solvent Substances 0.000 description 5
- 229920000573 polyethylene Polymers 0.000 description 5
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- 241000699670 Mus sp. Species 0.000 description 4
- ROOXNKNUYICQNP-UHFFFAOYSA-N ammonium persulfate Chemical compound [NH4+].[NH4+].[O-]S(=O)(=O)OOS([O-])(=O)=O ROOXNKNUYICQNP-UHFFFAOYSA-N 0.000 description 4
- 229940109239 creatinine Drugs 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- 230000003907 kidney function Effects 0.000 description 4
- 230000003908 liver function Effects 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- 238000002156 mixing Methods 0.000 description 4
- 239000002539 nanocarrier Substances 0.000 description 4
- 238000007920 subcutaneous administration Methods 0.000 description 4
- 238000010998 test method Methods 0.000 description 4
- 206010018910 Haemolysis Diseases 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- 238000012512 characterization method Methods 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 239000008367 deionised water Substances 0.000 description 3
- 229910021641 deionized water Inorganic materials 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 230000008588 hemolysis Effects 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 239000011261 inert gas Substances 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- 229960001756 oxaliplatin Drugs 0.000 description 3
- DWAFYCQODLXJNR-BNTLRKBRSA-L oxaliplatin Chemical compound O1C(=O)C(=O)O[Pt]11N[C@@H]2CCCC[C@H]2N1 DWAFYCQODLXJNR-BNTLRKBRSA-L 0.000 description 3
- 238000003860 storage Methods 0.000 description 3
- 239000006228 supernatant Substances 0.000 description 3
- 231100000331 toxic Toxicity 0.000 description 3
- 230000002588 toxic effect Effects 0.000 description 3
- 210000003462 vein Anatomy 0.000 description 3
- DPNXHTDWGGVXID-UHFFFAOYSA-N 2-isocyanatoethyl prop-2-enoate Chemical compound C=CC(=O)OCCN=C=O DPNXHTDWGGVXID-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 239000004342 Benzoyl peroxide Substances 0.000 description 2
- OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical compound C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 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
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- 108010087230 Sincalide Proteins 0.000 description 2
- 230000001154 acute effect Effects 0.000 description 2
- 229910001870 ammonium persulfate Inorganic materials 0.000 description 2
- 230000001093 anti-cancer Effects 0.000 description 2
- 229940045985 antineoplastic platinum compound Drugs 0.000 description 2
- 229910052786 argon Inorganic materials 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 235000019400 benzoyl peroxide Nutrition 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 229960004562 carboplatin Drugs 0.000 description 2
- YAYRGNWWLMLWJE-UHFFFAOYSA-L carboplatin Chemical compound O=C1O[Pt](N)(N)OC(=O)C11CCC1 YAYRGNWWLMLWJE-UHFFFAOYSA-L 0.000 description 2
- 238000010609 cell counting kit-8 assay Methods 0.000 description 2
- 238000005119 centrifugation Methods 0.000 description 2
- 230000001186 cumulative effect Effects 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 238000000502 dialysis Methods 0.000 description 2
- 238000002296 dynamic light scattering Methods 0.000 description 2
- 239000001963 growth medium Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 239000013067 intermediate product Substances 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- 201000007270 liver cancer Diseases 0.000 description 2
- 210000005229 liver cell Anatomy 0.000 description 2
- 208000014018 liver neoplasm Diseases 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 150000003058 platinum compounds Chemical class 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- USHAGKDGDHPEEY-UHFFFAOYSA-L potassium persulfate Chemical compound [K+].[K+].[O-]S(=O)(=O)OOS([O-])(=O)=O USHAGKDGDHPEEY-UHFFFAOYSA-L 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 230000004043 responsiveness Effects 0.000 description 2
- 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 2
- 239000000758 substrate Substances 0.000 description 2
- 239000003981 vehicle Substances 0.000 description 2
- WVXMNBDPVYOPLX-UHFFFAOYSA-N 2-isocyanoethyl prop-2-enoate Chemical class C=CC(=O)OCC[N+]#[C-] WVXMNBDPVYOPLX-UHFFFAOYSA-N 0.000 description 1
- CYUZOYPRAQASLN-UHFFFAOYSA-N 3-prop-2-enoyloxypropanoic acid Chemical compound OC(=O)CCOC(=O)C=C CYUZOYPRAQASLN-UHFFFAOYSA-N 0.000 description 1
- 102100036475 Alanine aminotransferase 1 Human genes 0.000 description 1
- 108010082126 Alanine transaminase Proteins 0.000 description 1
- 108010003415 Aspartate Aminotransferases Proteins 0.000 description 1
- 102000004625 Aspartate Aminotransferases Human genes 0.000 description 1
- 238000011725 BALB/c mouse Methods 0.000 description 1
- 206010010356 Congenital anomaly Diseases 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- CERQOIWHTDAKMF-UHFFFAOYSA-N Methacrylic acid Chemical compound CC(=C)C(O)=O CERQOIWHTDAKMF-UHFFFAOYSA-N 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 238000003917 TEM image Methods 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- XSMVECZRZBFTIZ-UHFFFAOYSA-M [2-(aminomethyl)cyclobutyl]methanamine;2-oxidopropanoate;platinum(4+) Chemical compound [Pt+4].CC([O-])C([O-])=O.NCC1CCC1CN XSMVECZRZBFTIZ-UHFFFAOYSA-M 0.000 description 1
- PNNCWTXUWKENPE-UHFFFAOYSA-N [N].NC(N)=O Chemical compound [N].NC(N)=O PNNCWTXUWKENPE-UHFFFAOYSA-N 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 239000012300 argon atmosphere Substances 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- GRHLMSBCOPRFNA-UHFFFAOYSA-M azanide 2-oxidoacetate platinum(4+) Chemical compound N[Pt]1(N)OCC(=O)O1 GRHLMSBCOPRFNA-UHFFFAOYSA-M 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 230000005880 cancer cell killing Effects 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 230000003833 cell viability Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000010668 complexation reaction Methods 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000006735 deficit Effects 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 1
- 238000010556 emulsion polymerization method Methods 0.000 description 1
- 210000003743 erythrocyte Anatomy 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 1
- 210000003494 hepatocyte Anatomy 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 229950008991 lobaplatin Drugs 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000010907 mechanical stirring Methods 0.000 description 1
- RBQRWNWVPQDTJJ-UHFFFAOYSA-N methacryloyloxyethyl isocyanate Chemical compound CC(=C)C(=O)OCCN=C=O RBQRWNWVPQDTJJ-UHFFFAOYSA-N 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 210000000865 mononuclear phagocyte system Anatomy 0.000 description 1
- 229950007221 nedaplatin Drugs 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 238000000643 oven drying Methods 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000001706 oxygenating effect Effects 0.000 description 1
- IIMIOEBMYPRQGU-UHFFFAOYSA-L picoplatin Chemical compound N.[Cl-].[Cl-].[Pt+2].CC1=CC=CC=N1 IIMIOEBMYPRQGU-UHFFFAOYSA-L 0.000 description 1
- 229950005566 picoplatin Drugs 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 239000002954 polymerization reaction product Substances 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 239000010414 supernatant solution Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 238000004627 transmission electron microscopy Methods 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
Classifications
-
- 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
- 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
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
-
- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
- A61K9/5107—Excipients; Inactive ingredients
- A61K9/5123—Organic compounds, e.g. fats, sugars
-
- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
- A61K9/5107—Excipients; Inactive ingredients
- A61K9/513—Organic macromolecular compounds; Dendrimers
- A61K9/5146—Organic macromolecular compounds; Dendrimers obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyamines, polyanhydrides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- 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
-
- 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
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F283/00—Macromolecular compounds obtained by polymerising monomers on to polymers provided for in subclass C08G
- C08F283/06—Macromolecular compounds obtained by polymerising monomers on to polymers provided for in subclass C08G on to polyethers, polyoxymethylenes or polyacetals
- C08F283/065—Macromolecular compounds obtained by polymerising monomers on to polymers provided for in subclass C08G on to polyethers, polyoxymethylenes or polyacetals on to unsaturated polyethers, polyoxymethylenes or polyacetals
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Nanotechnology (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- Organic Chemistry (AREA)
- Physics & Mathematics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Biomedical Technology (AREA)
- Optics & Photonics (AREA)
- General Chemical & Material Sciences (AREA)
- Crystallography & Structural Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Medical Informatics (AREA)
- Inorganic Chemistry (AREA)
- Polymers & Plastics (AREA)
- Biophysics (AREA)
- Biotechnology (AREA)
- General Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Condensed Matter Physics & Semiconductors (AREA)
- General Physics & Mathematics (AREA)
- Manufacturing & Machinery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention discloses a preparation method of tetravalent platinum nano-drug particles, which comprises the following steps: sequentially adding hydrophilic monomer and initiator into platinum-containing monomer compound, and performing emulsion polymerization under stirring and anaerobic conditions to obtain the final product. The tetravalent platinum nano-drug particles prepared by the method have the advantages of adjustable particle size, narrow particle size distribution, good stability, high drug load and good biocompatibility, and based on the characteristic of the tetravalent platinum complex reduction response, the tetravalent platinum nano-drug particles can selectively release active drugs under the environment of high reduction substances (glutathione) of tumor cells, thereby playing a role in killing the tumor cells. In addition, the emulsion polymerization synthesis method has wide selection range of raw material monomers, simple synthesis process, simple post-treatment method and good batch-to-batch stability, and can realize the construction of nano delivery systems of various platinum drugs.
Description
Technical Field
The invention relates to the technical field of biological medicine, in particular to a preparation method of tetravalent platinum nano-drug particles.
Background
Since the 60 s of the 20 th century, the American scholars Rosenberg discovered the anticancer activity of cisplatin for the first time, and platinum-based drugs became a hotspot for the development of anticancer drugs. Several platinum-based anticancer drugs are currently approved for the treatment of various tumors in clinic and are widely used worldwide. Such as cisplatin, carboplatin and oxaliplatin, which are representative of the first, second and third generation platinum group drugs, respectively. However, the serious toxic side effects of bivalent platinum anti-cancer drugs and the problem of congenital/acquired tumor resistance greatly limit the practical clinical application effects of these platinum drugs in cancer treatment.
Nano-delivery is an emerging field of material science, engineering, medicine, and chemical crossover. The construction of nano-drug delivery systems by incorporating drugs into nanocarriers using physical entrapment or chemical bonding is very promising for tumor therapy. Compared with small molecular drugs, the nano drug delivery system has the advantages of improving the stability of the drugs, prolonging the internal circulation time, increasing the biosafety and realizing targeted delivery, and has great potential in improving the tissue distribution of the drugs and further improving the bioavailability. Currently, there have been many reported nano-delivery systems for platinum drug delivery, and common nano-carriers are liposomes, polymer nano-carriers, inorganic nano-carriers, and the like. However, a large number of reports indicate that the drug loading of various types of nano-drug delivery systems is low (often less than 10%), and there are related reports that, after intravenous administration, most of the existing nano-drug delivery systems are recognized by mononuclear macrophages in the reticuloendothelial system of the body, and accumulate in non-targeted organs, and less than 1% of anticancer nano-drug particles can reach the target site. Thus, low drug loading and low delivery efficiency are challenges that need to be overcome in the development of nano-drug delivery systems.
Disclosure of Invention
The present invention aims to solve at least one of the above technical problems in the prior art. Therefore, the invention aims to provide a preparation method of tetravalent platinum nano-drug particles. The particle size of the tetravalent platinum nano-drug particles prepared by the preparation method is adjustable in a specific range, the particle size distribution is narrow, the stability is good, the drug loading is high, the biocompatibility is good, and based on the characteristic of the tetravalent platinum complex reduction response, active drugs can be selectively released under the environment of high reduction substances (glutathione) of tumor cells, so that the killing effect of the tumor cells is exerted. In addition, the emulsion polymerization synthesis method has wide selection range of raw material monomers, simple synthesis process, simple post-treatment method and good batch-to-batch stability, and can realize the construction of nano delivery systems of various platinum drugs.
In a first aspect of the present invention, there is provided a platinum-containing monomer compound having a structure as shown in formula (I):
formula (I).
In some embodiments of the invention, the platinum-containing monomer compound has hydrophobicity.
In some embodiments of the invention, the platinum-containing monomer compound has a double bond structure axial ligand structure.
In a second aspect of the present invention, there is provided a method for producing a platinum-containing monomer compound according to the first aspect of the present invention, comprising the steps of:
(1) Oxidizing the bivalent platinum drug by using an oxidant to obtain a tetravalent platinum intermediate with dihydroxyl axial coordination;
(2) And adding an alkenyl compound into the tetravalent platinum intermediate, and carrying out light-proof reaction for 6-24 hours under the anaerobic and anhydrous conditions to obtain the platinum-containing monomer compound.
In some embodiments of the invention, the oxidizing agent comprises hydrogen peroxide.
In some embodiments of the invention, the oxidation is for a period of time ranging from 12 to 24h to ensure that a dihydroxyl axial coordination structure is formed.
In some embodiments of the invention, in step (1), the divalent platinum drug is oxidized with an oxidizing agent followed by recrystallization, filtration, washing of the precipitate with acetone and diethyl ether, and yielding a tetravalent platinum intermediate with axial complexation of the dihydroxyl groups.
In some embodiments of the invention, the divalent platinum drug comprises cisplatin, carboplatin, heptaplatin, nedaplatin, oxaliplatin, lobaplatin, miltiplatin, picoplatin.
In some embodiments of the invention, the polymer has a dihydroxy groupThe tetravalent platinum intermediate of axial coordination isc,c,t-Pt(NH 3 ) 2 Cl 2 (OH) 2 。
In some embodiments of the invention, the alkenyl compounds include, but are not limited to, 2-isocyanatoethyl acrylate, isocyanatoethyl methacrylate, 4-nitrophenyl- (ethyl methacrylate) ethylcarbonate, 2-carboxyethyl acrylate.
In some embodiments of the invention, the alkenyl compound is used in an amount of 2 times or more equivalent to the tetravalent platinum intermediate. Of course, the amount of alkenyl compound used can be adjusted reasonably by those skilled in the art to effect the reaction, depending on the actual experimental conditions and the specific choice of raw materials.
In some embodiments of the invention, the alkenyl compound is used in an amount of 2 equivalents of tetravalent platinum intermediate.
In some embodiments of the present invention, in step (2), an organic solvent is also added to ensure anhydrous conditions of the reaction system.
In some embodiments of the invention, the organic solvent comprises dimethylformamide.
In some embodiments of the invention, an inert gas is used to maintain an oxygen-free system. The inert gas includes argon.
In some embodiments of the present invention, in the step (2), stirring is further performed during the light-shielding reaction under the condition of no oxygen and no water, and the reaction temperature is 25-100 ℃.
In some embodiments of the present invention, the preparation method specifically comprises: oxidizing bivalent platinum medicine 12-24-h by using a proper amount or excessive oxidant to obtain tetravalent platinum intermediate with axial coordination of double hydroxyl; and then adding alkenyl compound with the equivalent weight of two times or more into the tetravalent platinum intermediate, adding organic solvent in argon atmosphere, and carrying out light-shielding reaction for 6-24 hours at 25-100 ℃ to obtain the platinum-containing monomer compound.
In a third aspect, the invention provides the use of the platinum-containing monomer compound according to the first aspect of the invention in any one of the following (1) to (3);
(1) The application in preparing antitumor drugs;
(2) Use in the preparation of a drug delivery vehicle or system;
(3) The application of the intermediate in preparing tetravalent platinum compounds.
In the invention, the inventor finds that the tetravalent platinum nano-particles prepared based on the platinum-containing monomer compound of the first aspect of the invention can effectively overcome the defects of low drug load and low delivery efficiency of the traditional nano-delivery system, have adjustable particle size, narrow particle size distribution, good stability and good biocompatibility, can selectively release active drugs in the environment of high-reduction substances of tumor cells, and can be used as a novel drug or an intermediate product (substrate) for developing the novel drug to play a role in killing the tumor cells.
In a fourth aspect of the present invention, there is provided a tetravalent platinum nano product, wherein the tetravalent platinum nano product carries tetravalent platinum, the tetravalent platinum nano product is spherical nano particles, and the particle size is 20-5000 nm.
In some embodiments of the present invention, the particle size of the tetravalent platinum nano product is 115-250 nm.
In some embodiments of the invention, the tetravalent platinum type nano product has an average particle size of about 175 nm.
In some embodiments of the invention, the tetravalent platinum-based nano product comprises a drug, a drug delivery carrier, and a drug delivery system constituent unit.
In some embodiments of the invention, the effective drug loading (DLC%) of the tetravalent platinum type nano product is 21.54 ±0.74%.
In some embodiments of the present invention, the tetravalent platinum-based nano product is prepared from the platinum-containing monomer compound as a raw material.
In some embodiments of the present invention, the preparation raw materials of the tetravalent platinum type nano product further comprise: at least one of a solvent, a hydrophilic monomer, a stabilizer, and an initiator.
In some embodiments of the invention, the hydrophilic monomer comprises poly (ethylene glycol) methacrylate, poly (ethylene glycol) acrylate, polyethylene glycol methyl ether methacrylate, polyethylene glycol methyl ether acrylate, polyethylene glycol dimethacrylate, N-hydroxysuccinimide acrylate, hydroxyethyl methacrylate, maleic anhydride, itaconic acid.
In some embodiments of the invention, the hydrophilic monomer is present in the system at a molar concentration of 0.001 to 5 mol/L.
In some embodiments of the invention, the solvent comprises dimethyl sulfoxide, dimethylformamide, water, ethanol, glycerol, and propylene glycol.
In some embodiments of the invention, the stabilizer comprises at least one of polyvinylpyrrolidone, polyvinyl alcohol, polyethylene glycol.
In some embodiments of the invention, the initiator comprises azobisisobutyronitrile, benzoyl peroxide, ammonium persulfate, and potassium persulfate.
In some embodiments of the invention, the initiator is used in the system in an amount of 0.01 g/L to 10 g/L.
In a fifth aspect, the present invention provides a method for preparing a tetravalent platinum nano product according to the fourth aspect of the present invention, comprising the steps of:
hydrophilic monomer and initiator are added into the platinum-containing monomer compound in the first aspect of the invention in sequence, and emulsion polymerization reaction is carried out under the conditions of stirring and anaerobic condition, thus obtaining tetravalent platinum nanometer products.
In some embodiments of the present invention, the hydrophilic monomer is selected from at least one of poly (ethylene glycol) methacrylate, poly (ethylene glycol) acrylate, polyethylene glycol methyl ether methacrylate, polyethylene glycol methyl ether acrylate, polyethylene glycol dimethacrylate, N-hydroxysuccinimide acrylate, hydroxyethyl methacrylate, maleic anhydride, itaconic acid.
In some embodiments of the invention, the hydrophilic monomer is also pre-mixed with a stabilizer upon addition.
In some embodiments of the invention, the stabilizer is selected from at least one of azobisisobutyronitrile, benzoyl peroxide, ammonium persulfate, and potassium persulfate.
In some embodiments of the invention, the reaction temperature of the emulsion polymerization reaction is 50-100 ℃ and the reaction time is 1-48 hours.
In some embodiments of the invention, the reaction time is 8 to 24 hours.
In some embodiments of the invention, the emulsion polymerization reaction product is recycled washed with a polar solution after the emulsion polymerization reaction.
In some embodiments of the invention, the polar solution is selected from the group consisting of water, ethanol, glycerol, and propylene glycol.
In some embodiments of the present invention, the preparation method specifically comprises:
(1) Dissolving the platinum-containing monomer compound according to the first aspect of the present invention in an organic solvent (at least one of dimethyl sulfoxide and dimethylformamide) to obtain a platinum-containing monomer compound solution; mixing hydrophilic monomer and stabilizer in polar solution (at least one of water, ethanol, glycerol and propylene glycol) to obtain hydrophilic monomer solution;
(2) Mixing a platinum-containing monomer compound solution, a hydrophilic monomer solution and an initiator, introducing inert gas under the condition of stirring to isolate oxygen, and initiating emulsion polymerization reaction at 50-100 ℃ for 8-24 hours to obtain a crude product;
(3) And (3) circularly washing the crude product by using water and absolute ethyl alcohol, re-suspending by using water, and freeze-drying to obtain the product.
In the invention, the emulsion polymerization synthesis method (initiated under the action of an initiator and mechanical stirring) used by the method has the advantages of wide selection range of available monomers, simple synthesis process, simple post-treatment method and good batch-to-batch stability, and can realize the construction of nano delivery systems of various platinum drugs.
In a sixth aspect, the invention provides an application of the tetravalent platinum nano product in any one of the following (1) - (3);
(1) The application in preparing antitumor drugs;
(2) Use in the preparation of a drug delivery vehicle or system;
(3) The application in preparing tetravalent platinum compounds.
In the invention, the inventor verifies through various experiments that the tetravalent platinum nano-particles prepared in the invention can effectively overcome the defects of low drug load and low delivery efficiency of the traditional nano-delivery system, have adjustable particle size, narrow particle size distribution, good stability and good biocompatibility, can selectively release active drugs in the environment of high-reduction substances of tumor cells, and can be used as a novel drug or an intermediate product (substrate) for developing the novel drug to play a role in killing tumor cells.
The beneficial effects of the invention are as follows:
1. the invention provides a novel synthesis strategy of platinum nano-drug particles, which is used for solving the problems of low drug load and low delivery efficiency of the traditional nano-delivery system.
2. The synthesized tetravalent platinum nano-drug particles have the characteristics of adjustable particle size, narrow particle size distribution, good stability, high drug loading and good biocompatibility, and can selectively release active drugs in the environment of high-reduction substances of tumor cells based on the characteristic of the tetravalent platinum complex reduction response, thereby playing a role in killing tumor cells.
3. The emulsion polymerization synthesis method used in the invention has wide selection range of available monomers, simple synthesis process, simple post-treatment method and better batch stability, and can realize the construction of nano delivery systems of various platinum drugs.
Drawings
FIG. 1 is a scanning electron microscope photograph of tetravalent platinum nano-drug particles DDNP1 synthesized in example 1 of the present invention.
Fig. 2 is a release profile of the tetravalent platinum nanoparticle DDNP1 synthesized in example 1 of the present invention under in vitro reduction conditions.
Fig. 3 is a transmission electron micrograph of tetravalent platinum nano-drug particles DDNP1 synthesized in example 1 of the present invention before and after reduction, wherein a is before reduction and B is after reduction.
FIG. 4 shows the killing effect of the tetravalent platinum nanoparticle DDNP1 synthesized in example 1 of the present invention on liver cancer cells Hep 3B (A) and normal liver cells L02 (B) under in vitro conditions.
Fig. 5 is a pharmacokinetic profile of tetravalent platinum group nanoparticle DDNP1 synthesized in example 1 of the present invention.
Fig. 6 shows the delivery efficiency of the tetravalent platinum nano-drug particles DDNP1 synthesized in example 1 of the present invention in H22 subcutaneous transplantation tumor-bearing mouse tumor.
FIG. 7 shows the storage stability of the tetravalent platinum nanoparticle DDNP1 synthesized in example 1 of the present invention, wherein A is the dimensional change, and B is the PDI.
FIG. 8 shows the acute liver and kidney function injury results of tetravalent platinum nano-drug particles DDNP1 synthesized in example 1 of the present invention, A corresponds to AST (glutamic oxaloacetic transaminase); b corresponds to ALT (glutamic pyruvic transaminase); c corresponds to BUN (blood urea nitrogen); d corresponds to CRE (creatinine).
Fig. 9 shows the blood compatibility of the tetravalent platinum group nano-drug particles DDNP1 synthesized in example 1 of the present invention.
Detailed Description
The present invention will be described in further detail with reference to specific examples. The starting materials, reagents or apparatus used in the examples and comparative examples were either commercially available from conventional sources or may be obtained by prior art methods unless specifically indicated. Unless otherwise indicated, assays or testing methods are routine in the art.
Preparation of tetravalent platinum nano-drug particles
The preparation method of the tetravalent platinum nanometer drug particles in the embodiment comprises the following steps:
(1) Preparation of hydrophobic monomer DB-DDP:
cisplatin (1.0 g,3.333 mmol) was dissolved in 5 mL deionized water, transferred to a round bottom flask and 25 mL 30% H was added 2 O 2 The solution was stirred well in the dark for 24 h. For cisplatin-H at 4 DEG C 2 O 2 And (3) carrying out in-situ recrystallization on the mixed solution, and carrying out vacuum suction filtration to obtain a pale yellow precipitate. Repeatedly washing pale yellow precipitate with acetone and diethyl ether twice, and oven drying to obtain pale yellow powder, namely tetravalent platinum intermediatec,c,t-Pt(NH 3 ) 2 Cl 2 (OH) 2 The yield was 90%.
Taking the tetravalent platinum intermediate obtained in the stepsc,c,t-Pt(NH 3 ) 2 Cl 2 (OH) 2 (334.0 mg,1 mmol) was placed in a round bottom flask, 2 equivalents of 2-isocyanatoethyl acrylate (564.5 mg,2 mmol) was added, the gaseous atmosphere in the flask was replaced three times with argon, then 10 mL anhydrous Dimethylformamide (DMF) was injected inward using a syringe and the reaction was stirred at 45℃for 12 h.
After reaction 12 h, the solvent was removed under reduced pressure, the residual bottom oil was dispersed using 5 mL methanol, and then 100 mL diethyl ether was added for settling to give a white precipitate. The precipitate was filtered out using a sand core funnel, repeatedly washed twice with diethyl ether, and the washed white precipitate was dried in a vacuum oven to obtain a white powder, namely, tetravalent platinum complex DB-DDP (hereinafter referred to as hydrophobic monomer DB-DDP) having an axial ligand with a double bond structure, in a yield of about 95%.
The structural formula of the hydrophobic monomer DB-DDP is as follows:
；
the nuclear magnetic resonance hydrogen spectrum data are as follows: 1 H NMR（600MHz，DMSO-d6）δ6.72（d，2H），6.67（s，6H），6.36（d，2H），6.16（dd，2H），5.95（d，2H），4.12（m，4H），3.18（dd，4H）。
mass spectrum data are: ESI-MS: m/z [ M+H ] + ], 616.1.
(2) Preparation of tetravalent platinum nano-drug particles:
the hydrophobic monomer DB-DDP (20 mg,0.032 mmol) prepared in the above step (1) was dissolved in 0.5 mL of DMSO to obtain a hydrophobic monomer solution. The hydrophilic monomer poly (ethylene glycol) methacrylate (20 μl,0.044 mmol) was dissolved in 40 mL absolute ethanol containing 2% pvp (polyvinylpyrrolidone) to give a hydrophilic monomer solution. Mixing the obtained hydrophobic monomer solution and hydrophilic monomer solution in a round-bottom flask, adding an initiator azodiisobutyronitrile (120 mg,0.730 mmol), introducing nitrogen for protection, stirring at 70 ℃, refluxing, and performing emulsion polymerization reaction for 24h to obtain a tetravalent platinum nano drug particle crude product.
Transferring the crude product of the tetravalent platinum nano-drug particles into a 50 mL centrifuge tube, and performing water-absolute ethyl alcohol circulation centrifugal washing to remove redundant monomers, stabilizers and initiators in the system. The specific operation of water-absolute ethyl alcohol circulating centrifugal washing is as follows: adding absolute ethyl alcohol into a centrifuge tube, centrifuging, removing supernatant, re-suspending by using absolute ethyl alcohol, repeating for three times, re-suspending by using deionized water, and centrifuging to obtain tetravalent platinum nano-drug particles DDNP1. Wherein, the centrifugation conditions are 13000 rpm and 10 min.
Of course, tetravalent platinum nano-drug particles having the same effect as in the present example can also be prepared according to the other raw materials shown in table 1.
TABLE 1 tetravalent platinum nano-drug particles of different combinations
| <b>Examples</b> | Example 1 | Example 2 | Example 3 | Example 4 | Example 5 | Example 6 |
| <b>Bivalent platinum medicine</b> | Cisplatin (cisplatin) | Cisplatin (cisplatin) | Cisplatin (cisplatin) | Cisplatin (cisplatin) | Cisplatin (cisplatin) | Oxaliplatin |
| <b>Alkenyl compounds</b> <b>（</b><b>mg</b> <b>，</b><b>mmol</ b><b>）</b> | Acrylic acid 2- Isocyanoethyl The ester is used as a solvent for the oil, 564.5，2 | acrylic acid 2- Isocyanoethyl The ester is used as a solvent for the oil, 564.5，2 | acrylic acid 2- Isocyanoethyl The ester is used as a solvent for the oil, 564.5，2 | acrylic acid 2- Isocyanoethyl The ester is used as a solvent for the oil, 564.5，2 | acrylic acid 2-isocyanoethyl ester Esters 564.5,2 | Acrylic acid 2- Isocyanoethyl The ester is used as a solvent for the oil, 564.5，2 |
| <b>hydrophobic monomer</b><b >（</b><b>mg</b><b >，</b><b>mmol</b> <b>）</b> | DB-DDP， 20，0.032 | DB-DDP， 40，0.064 | DB-DDP， 60，0.096 | DB-DDP， 60，0.096 | DB-DDP，60，0.096 | DB-OXA， 60，0.084 |
| <b>Hydrophilic monomers</b><b >（</b><b>μL/mg</b ><b>，</b><b>mmol </b><b>）</b> | Poly (ethylene glycol) Alcohol) methyl group Acrylic acid The amount of the ester, 20, 0.044 | poly (ethylene glycol) Alcohol) methyl group Acrylic acid The amount of the ester, 20, 0.044 | poly (ethylene glycol) Alcohol) methyl group Acrylic acid The amount of the ester, 20, 0.044 | poly (ethylene glycol) Alcohol) dipropyl alcohol An ester of an alkenoate with a reactive group, 100， 0.444 | poly (ethylene glycol) methacrylic acid Acid esters, 20,0.044, N-hydroxy Succinimide acrylic acid Esters 5,0.030 | Poly (ethylene glycol) Alcohol) methyl group Acrylic acid The amount of the ester, 20, 0.044 |
| <b>organic solvents</b><b >（</b><b>mL</b><b >）</b> | Dimethyl methylene Sulfone, 0.5 | Dimethyl methylene Sulfone, 1 | Dimethyl methylene Sulfone, 1.5 | Dimethyl methylene Sulfone, 1.5 | Dimethyl sulfoxide, 1.5 | Dimethyl methylene Sulfone, 1.5 |
| <b>Stabilizer [ ]</b><b >%w/v</b><b>）</b> | Polyethylene pyri Pyrrolidone, 2 | Polyethylene pyri Pyrrolidone, 2 | Polyethylene pyri Pyrrolidone, 2 | Polyethylene pyri Pyrrolidone, 2 | Polyvinylpyrrolidone, 2 | Polyethylene pyri Pyrrolidone, 2 |
| <b>Polar solvent</b>< b>mL</b><b>）</b> | Anhydrous ethanol Alcohols, 40 | Anhydrous ethanol Alcohols, 40 | Anhydrous ethanol Alcohols, 40 | Anhydrous ethanol Alcohols, 40 | Absolute ethanol, 40 | Anhydrous ethanol Alcohols, 40 |
| <b>Initiator [ (]</b><b> mg</b><b>，</b><b> mmol</b><b>）</b> | Azo diiso Butyronitrile is used as the raw material, 120， 0.730 | azo diiso Butyronitrile is used as the raw material, 120， 0.730 | azo diiso Butyronitrile is used as the raw material, 120， 0.730 | azo diiso Butyronitrile is used as the raw material, 120， 0.730 | azobisisobutyronitrile, 120, 0.730 | azo diiso Butyronitrile is used as the raw material, 120， 0.730 |
| <b>reaction temperature [ ]</b>< b>℃</b><b>）</b> | 70 | 70 | 70 | 70 | 70 | 70 |
| <b>Reaction time [ (]</b>< b>h</b><b>）</b> | 24 | 24 | 24 | 24 | 24 | 24 |
| <b>Tetravalent platinum nano medicine Particle size [ ]</b><b> nm</b><b>）</b> | 119.82 ± 7.82 | 158.32 ± 10.23 | 214.59 ± 13.57 | 249.23 ± 6.75 | 243.67 ± 9.71 | 143.75 ± 9.66 |
Characterization of tetravalent platinum nano-drug particles DDNP1
SEM characterization was performed on the tetravalent platinum nano-drug particles DDNP1 prepared in the above example using a scanning electron microscope, and the results are shown in fig. 1.
It can be found that the tetravalent platinum nano-drug particles DDNP1 synthesized by the emulsion polymerization method are characterized by narrow particle size distribution and good monodispersity through SEM, and the average particle size is about 175 nm.
The drug loading (cisplatin) of the tetravalent platinum nano drug particles DDNP1 prepared in the above example was detected using an inductively coupled plasma mass spectrometer.
As a result, it was found that the effective drug loading (DLC%) of the tetravalent platinum nano-drug particles DDNP1 prepared in the above examples was 21.54.+ -. 0.74%, which is far higher than that of the conventional platinum-based drug carriers of the prior art by about 10%.
In vitro release effect of tetravalent platinum nano-drug particles DDNP1
The in vitro release effect of the tetravalent platinum nano-drug particles DDNP1 prepared in the above examples was tested by the following method.
The method comprises the following specific steps:
PBS solutions with Glutathione (GSH) concentrations of 0 and 10 mM were prepared, respectively. The tetravalent platinum nano-drug particles DDNP1 prepared in the above example were placed in dialysis bags (mwco=3500 Da), sealed and immersed in PBS solution containing 0 or 10 mM GSH prepared in 50 mL, respectively, and then oscillated at constant temperature (vibration rate 70 rpm) at 37 ℃. At this time, the time point was recorded as 0. At hours 0, 0.5, 1, 3, 6, 12, 24, 48, 72, 96 and 120, 600. Mu.L of the solution was taken out of the solution outside the dialysis bag as the test sample (600. Mu.L of the corresponding solution was added after the taking out to ensure that the original volume was unchanged). Platinum content in the test samples at different time points was measured using an inductively coupled plasma mass spectrometer, the cumulative platinum release rate was calculated, and a drug release curve based on "platinum cumulative release rate versus time" was plotted.
The results are shown in FIG. 2.
It can be found that in the environment simulating high reduction substances in tumor cells (namely, the PBS solution containing 10 mM GSH), the DDNP1 drug release efficiency of the tetravalent platinum nano-drug particles prepared in the embodiment is higher than that of a control group (namely, the PBS solution containing 0 mM GSH), which indicates that the tetravalent platinum nano-drug particles synthesized by emulsion polymerization have good glutathione reduction substance responsiveness.
Further transmission electron microscopy observation was performed on tetravalent platinum nano-drug particles DDNP1 before and after the test, and the results are shown in FIG. 3.
It can be found that the tetravalent platinum nano-drug particles DDNP1 with reduction response are confirmed to be disintegrated after TEM characterization, and further the tetravalent platinum nano-drug particles synthesized by emulsion polymerization have good glutathione reducing substance responsiveness.
In vitro killing effect of tetravalent platinum nano-drug particles DDNP1 on cancer cells
In this example, hepatoma cell Hep 3B and normal hepatocytes L02 were used as test subjects to verify the cancer cell killing effect and safety of the tetravalent platinum nano-drug particle DDNP1 prepared in the above example.
The specific test method comprises the following steps:
preparing single cell suspension of liver cancer cell Hep 3B and normal liver cell L02 with corresponding culture medium containing 10% FBS, and preparing into 4.5X10 3 Is inoculated in 96-well plates and cultured in 12 h. Then, corresponding drug-containing culture media containing cisplatin, DB-DDP and DDNP1 with different concentration gradients are respectively added, and 5 compound holes are arranged at each concentration. After 48. 48h incubation, the medium in the 96-well plate was removed, 110. Mu.L of the corresponding medium containing CCK-8 reagent (medium to CCK-8 reagent ratio 100:10) was added to each well and incubated in the incubator at 2 h in the absence of light. The OD value of each well at wavelength 450 nm was measured using a microplate reader, and cell viability was calculated using PBS as a control group.
The results are shown in FIG. 4.
It can be found that the killing effect of the tetravalent platinum nano-drug particles DDNP1 prepared in the above examples is superior to DB-DDP without emulsion polymerization for tumor cells Hep 3B. And the DB-DDP and the DDNP1 prepared in the embodiment of the invention have no influence on the proliferation of normal cells L02, which proves that the toxic effect of cisplatin on normal cells is obviously reduced, and the safety of the medicament and the toxic and side effects on a subject are improved.
Pharmacokinetics of tetravalent platinum nano-drug particles DDNP1
In this example, the pharmacokinetics of tetravalent platinum nano-drug particles DDNP1 prepared in the above example was tested using SD rats as test subjects.
The specific test method comprises the following steps:
SD rats were randomly divided into three groups and cisplatin, DB-DDP and DDNP1 were administered by tail vein at a dose of 4 mg Pt/kg rat body weight based on Pt content, with an injection time of 0. At 0.5, 3, 6, 12, 24, 48, 72, 96 and 120 hours after injection, rats were subjected to orbital blood collection using microcapillary tubes, and rat whole blood was collected at about 0.5 mL and centrifuged (centrifugation conditions: 4 ℃,3000 rpm,15 min) to obtain plasma. Plasma samples were assayed for platinum content using an inductively coupled plasma mass spectrometer and a "plasma concentration-time" curve was drawn. Based on the obtained curve data, each pharmacokinetic parameter is obtained by utilizing pharmacokinetic analysis software DAS 2.0.
The results are shown in FIG. 5.
It can be found that the blood concentration of DDNP1 is obviously increased after administration compared with cisplatin and DB-DDP, and the half-life of the medicine in vivo is obviously prolonged.
In vivo delivery drug effect of tetravalent platinum nano drug particles DDNP1
In this example, the in vivo drug delivery efficiency of tetravalent platinum nano drug particles DDNP1 prepared in the above example was tested using H22 subcutaneous tumor-bearing mice as test subjects.
The specific test method comprises the following steps:
tumor volume of 200 mm is obtained 3 Left and right H22 subcutaneous tumor-bearing mice were randomly divided into 3 groups, and cisplatin, DB-DDP and DDNP1 were administered by tail vein injection at a dose of 4 mg Pt/kg rat body weight based on Pt content, and at an injection time of 0. At 1, 6 and 12 hours after injection, part of tumor-bearing mice in each group were sacrificed by cervical dislocation, subcutaneous tumor tissues of the tumor-bearing mice were taken, placed in a vacuum oven at 60 ℃, dried 48h, and the dry weights of organs and tissues were recorded. Platinum content in the taken tissue samples was measured using an inductively coupled plasma mass spectrometer and drug delivery efficiency in the tissue was calculated.
The results are shown in FIG. 6.
It can be found that the tetravalent platinum nano-drug particles DDNP1 prepared in the above examples have higher delivery efficiency compared to cisplatin and DB-DDP.
Stability of tetravalent platinum nano-drug particles DDNP1
The storage stability of the tetravalent platinum nano-drug particles DDNP1 prepared in the above examples was tested by the following method, and the specific steps are as follows:
equal mass of DDNP1 was dispersed in PBS buffer and left at 4℃for 30 days. On days 0, 1, 5, 10, 15, 20, 25 and 30, the particle size distribution and dispersion coefficient PDI of DDNP1 were examined using a dynamic light scattering instrument.
The results are shown in FIG. 7.
It can be found that the particle size of the tetravalent platinum nano-drug particles DDNP1 prepared in the embodiment is not changed remarkably under the storage condition of 1-30 days, and the tetravalent platinum nano-drug particles have good stability.
Meanwhile, the inventors also tested the batch-to-batch stability of the tetravalent platinum nano-drug particles DDNP1 prepared in the above examples, and the specific test method is as follows:
according to the completely same formula composition and synthesis conditions, 3 batches of tetravalent platinum nano-drug particles DDNP1 are continuously synthesized, the particle size and the morphology of the nano-particles are detected by using a dynamic light scattering instrument, and the drug loading capacity and the drug loading efficiency are detected by using an inductively coupled plasma mass spectrometer.
The results are shown in Table 2.
TABLE 2 parameters relating to tetravalent platinum nanoparticle DDNP1 between different batches
It can be found that the tetravalent platinum particles DDNP1 among 3 batches have no obvious difference in particle size, potential, drug loading rate and drug loading efficiency, which indicates that the tetravalent platinum nano-drug particles DDNP1 prepared in the above embodiment have better batch-to-batch stability.
Biocompatibility of tetravalent platinum nano-drug particles DDNP1
The biocompatibility of the tetravalent platinum nano-drug particles DDNP1 prepared in the above examples was tested by the following method, and the specific steps are as follows:
(1) Acute toxicity experiment:
healthy BALB/c mice were randomly divided into 4 groups, and PBS, cisplatin, DB-DDP and DDNP1 were injected via tail veins in an amount of 4 mg Pt/kg body weight of the rats based on the Pt content, and serum was collected 24 hours after injection, and liver function (AST, ALT) and kidney function-related indicators (BUN, CRE) were detected by an ELISA.
The results are shown in FIG. 8.
It was found that the liver function indexes AST, ALT and kidney function indexes BUN and CRE in the DDNP1 group were slightly deviated (not significant) from the PBS control group after 24-h treatment, indicating that the administration of DDNP1 had no acute impairment of liver and kidney functions.
(2) Hemolysis experiment:
taking 0.5 mL of 2% erythrocyte suspension, respectively adding DDP (cisplatin), DB-DDP and DDNP1 with equal volume concentration of 10-40 mug Pt/mL, taking equal volume PBS buffer solution and deionized water as negative control and positive control, uniformly mixing each group, placing the mixture in a 37 ℃ incubator for incubation for 3 h, centrifuging (centrifuging condition: room temperature, 3000 rpm,15 min), observing supernatant, detecting absorbance of the supernatant at 540 nm by using an enzyme-labeled instrument, and calculating the hemolysis rate of each sample.
The results are shown in FIG. 9.
It was found that the supernatant solution of the test group using the tetravalent platinum nano-drug particle DDNP1 prepared in the above example was colorless and clear, indicating that DDNP1 did not cause a hemolysis reaction.
In conclusion, the tetravalent platinum nano-drug particles DDNP1 prepared in the embodiment have good tissue and blood compatibility, and can be safely applied to tumor treatment.
The above examples are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above examples, and any other changes, modifications, substitutions, combinations, and simplifications that do not depart from the spirit and principle of the present invention should be made in the equivalent manner, and the embodiments are included in the protection scope of the present invention.
Claims (6)
1. The tetravalent platinum nano product is characterized in that tetravalent platinum is loaded on the tetravalent platinum nano product, the tetravalent platinum nano product is spherical nano particles, and the particle size is 115-250 nm;
the tetravalent platinum nanometer product is prepared from a platinum-containing monomer compound serving as a raw material by a preparation method comprising the following steps:
sequentially adding a hydrophilic monomer and an initiator into the platinum-containing monomer compound, and performing emulsion polymerization under stirring and anaerobic conditions to obtain a tetravalent platinum nano product;
the platinum-containing monomer compound has a structure as shown in formula (I):
the platinum-containing monomer compound has hydrophobicity.
2. The tetravalent platinum type nano product according to claim 1, wherein said preparation method of platinum containing monomer compound comprises the steps of:
(1) Oxidizing the bivalent platinum drug by using an oxidant to obtain a tetravalent platinum intermediate with dihydroxyl axial coordination;
(2) Adding an alkenyl compound into the tetravalent platinum intermediate, and carrying out light-proof reaction for 6-24 hours under the anaerobic and anhydrous conditions to obtain the platinum-containing monomer compound.
3. The tetravalent platinum nano product according to claim 1, wherein said hydrophilic monomer is at least one selected from the group consisting of poly (ethylene glycol) methacrylate, poly (ethylene glycol) acrylate, polyethylene glycol methyl ether methacrylate, polyethylene glycol methyl ether acrylate, polyethylene glycol dimethacrylate, N-hydroxysuccinimide acrylate, hydroxyethyl methacrylate, maleic anhydride, itaconic acid.
4. The tetravalent platinum type nano-product according to claim 1, wherein said hydrophilic monomer is further pre-mixed with a stabilizer at the time of addition, said stabilizer being at least one selected from the group consisting of polyvinylpyrrolidone, polyvinyl alcohol, polyethylene glycol.
5. The tetravalent platinum nano-product according to claim 1, wherein the reaction temperature of the emulsion polymerization is 50 to 100 ℃ and the reaction time is 1 to 48 hours.
6. Use of the tetravalent platinum-based nano product of any one of claims 1 to 5 in any one of the following (1) to (2);
(1) The application in preparing antitumor drugs;
(2) Use in the preparation of a drug delivery vehicle or system.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310876447.4A CN117050113B (en) | 2023-07-17 | 2023-07-17 | Preparation method of tetravalent platinum nano-drug particles |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310876447.4A CN117050113B (en) | 2023-07-17 | 2023-07-17 | Preparation method of tetravalent platinum nano-drug particles |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN117050113A CN117050113A (en) | 2023-11-14 |
| CN117050113B true CN117050113B (en) | 2024-03-19 |
Family
ID=88656227
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202310876447.4A Active CN117050113B (en) | 2023-07-17 | 2023-07-17 | Preparation method of tetravalent platinum nano-drug particles |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN117050113B (en) |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105713046A (en) * | 2016-02-01 | 2016-06-29 | 复旦大学 | Anti-tumor platinum pro-drug and nanometer hydrogel drug and preparation method thereof |
| CN107445997A (en) * | 2017-07-03 | 2017-12-08 | 上海交通大学 | A kind of photochemical treatment platinum class prodrug and preparation method thereof, application |
| CN109678909A (en) * | 2019-01-10 | 2019-04-26 | 中国科学院化学研究所 | A kind of preparation method and applications of platinum class derivative and containing platinum nano-particle |
| CN112957342A (en) * | 2021-02-05 | 2021-06-15 | 中国科学院化学研究所 | Human serum albumin loaded tetravalent platinum nano particle and preparation method thereof |
-
2023
- 2023-07-17 CN CN202310876447.4A patent/CN117050113B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105713046A (en) * | 2016-02-01 | 2016-06-29 | 复旦大学 | Anti-tumor platinum pro-drug and nanometer hydrogel drug and preparation method thereof |
| CN107445997A (en) * | 2017-07-03 | 2017-12-08 | 上海交通大学 | A kind of photochemical treatment platinum class prodrug and preparation method thereof, application |
| CN109678909A (en) * | 2019-01-10 | 2019-04-26 | 中国科学院化学研究所 | A kind of preparation method and applications of platinum class derivative and containing platinum nano-particle |
| CN112957342A (en) * | 2021-02-05 | 2021-06-15 | 中国科学院化学研究所 | Human serum albumin loaded tetravalent platinum nano particle and preparation method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN117050113A (en) | 2023-11-14 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Na et al. | Reactive oxygen species (ROS)-responsive ferrocene-polymer-based nanoparticles for controlled release of drugs | |
| JP3465260B2 (en) | Nanoparticles based on block copolymers of polyoxyethylene and polylactic acid | |
| TWI306869B (en) | Amphiphilic block copolymers and nano particles comprising the same | |
| CN107550921B (en) | Nanoparticle-polymer injectable composite hydrogel double-drug-loading system and preparation method thereof | |
| US20070154397A1 (en) | Thermosensitive nanostructure for hyperthermia treatment | |
| CN114377149B (en) | Mn-based degradable MOF nano-reactor and preparation method and application thereof | |
| Ju et al. | A biodegradable polyphosphoester-functionalized poly (disulfide) nanocarrier for reduction-triggered intracellular drug delivery | |
| CN104231155A (en) | Cholesterol modified amphiphilic pH response pennicuius copolymer as well as preparation and micelle of copolymer | |
| CN109678909B (en) | Preparation method and application of platinum derivative and platinum-containing nano particle | |
| US20220378712A1 (en) | Hybrid membrane camouflaged nanomedicine loaded with oxidative phosphorylation inhibitor and preparing method thereof | |
| Xu et al. | Facile construction of noncovalent graft copolymers with triple stimuli-responsiveness for triggered drug delivery | |
| Zhong et al. | Galactose-based polymer-containing phenylboronic acid as carriers for insulin delivery | |
| Peng et al. | Nanogels loading curcumin in situ through microemulsion photopolymerization for enhancement of antitumor effects | |
| CN109134870B (en) | pH response polymer carrier, micelle prepared from pH response polymer carrier, preparation method and application | |
| CN117050113B (en) | Preparation method of tetravalent platinum nano-drug particles | |
| Hochreiner et al. | Polymerization‐induced self‐assembly for drug delivery: A critical appraisal | |
| CN107693505B (en) | Oil-water double-soluble ROS sensitive nanoparticle and preparation method thereof | |
| Lu et al. | Hydrogels containing core cross-linked block co-polymer micelles | |
| CN109260176B (en) | Tumor-specific cleavable PEG (polyethylene glycol) nanoparticle as well as preparation method and application thereof | |
| CN107011515B (en) | Triblock polymer and preparation method thereof | |
| CN107049950B (en) | Preparation method of cyclodextrin polymer drug-loaded vesicle | |
| CN114426656B (en) | Polymer nanohydrogels, drug delivery systems comprising the same, and methods of making the same | |
| CN114605600B (en) | Esterase-response amphiphilic linear polymer and preparation method and application thereof | |
| CN107412159B (en) | Preparation method and application of triblock polymer micelle | |
| CN112661961B (en) | Amphiphilic polyoxazoline copolymer, and preparation method and application thereof |
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 |