CN106177979B - 一种具有多药协同作用的抗肿瘤高分子键合药及其制备方法 - Google Patents
一种具有多药协同作用的抗肿瘤高分子键合药及其制备方法 Download PDFInfo
- Publication number
- CN106177979B CN106177979B CN201610566950.XA CN201610566950A CN106177979B CN 106177979 B CN106177979 B CN 106177979B CN 201610566950 A CN201610566950 A CN 201610566950A CN 106177979 B CN106177979 B CN 106177979B
- Authority
- CN
- China
- Prior art keywords
- drug
- group
- antitumor
- monomethyl ether
- glycol monomethyl
- 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.)
- Expired - Fee Related
Links
- 239000003814 drug Substances 0.000 title claims abstract description 68
- 229940079593 drug Drugs 0.000 title claims abstract description 44
- 229920000642 polymer Polymers 0.000 title claims abstract description 41
- 230000000259 anti-tumor effect Effects 0.000 title claims abstract description 23
- 230000002195 synergetic effect Effects 0.000 title claims abstract description 17
- 238000002360 preparation method Methods 0.000 title abstract description 13
- 239000002246 antineoplastic agent Substances 0.000 claims abstract description 24
- 229940041181 antineoplastic drug Drugs 0.000 claims abstract description 21
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 15
- JJTUDXZGHPGLLC-UHFFFAOYSA-N lactide Chemical compound CC1OC(=O)C(C)OC1=O JJTUDXZGHPGLLC-UHFFFAOYSA-N 0.000 claims abstract description 9
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 claims abstract description 7
- -1 bromo caprolactone Chemical compound 0.000 claims abstract description 6
- 238000006116 polymerization reaction Methods 0.000 claims abstract description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 6
- 229920001223 polyethylene glycol Polymers 0.000 claims description 45
- 239000002202 Polyethylene glycol Substances 0.000 claims description 41
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 38
- 229920001577 copolymer Polymers 0.000 claims description 32
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical group O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 claims description 29
- 229930012538 Paclitaxel Natural products 0.000 claims description 18
- 229960001592 paclitaxel Drugs 0.000 claims description 18
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical group O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 claims description 18
- 238000000034 method Methods 0.000 claims description 10
- 229940009456 adriamycin Drugs 0.000 claims description 9
- OTLNPYWUJOZPPA-UHFFFAOYSA-M 4-nitrobenzoate Chemical compound [O-]C(=O)C1=CC=C([N+]([O-])=O)C=C1 OTLNPYWUJOZPPA-UHFFFAOYSA-M 0.000 claims description 8
- 238000012650 click reaction Methods 0.000 claims description 7
- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical group C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 claims description 6
- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical group C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 claims description 6
- 150000001875 compounds Chemical class 0.000 claims description 6
- OMQFCTMVUFQKDS-UHFFFAOYSA-N 3-bromooxepan-2-one Chemical compound BrC1CCCCOC1=O OMQFCTMVUFQKDS-UHFFFAOYSA-N 0.000 claims description 5
- 238000007151 ring opening polymerisation reaction Methods 0.000 claims description 5
- AOJJSUZBOXZQNB-VTZDEGQISA-N 4'-epidoxorubicin Chemical group O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-VTZDEGQISA-N 0.000 claims description 4
- KLWPJMFMVPTNCC-UHFFFAOYSA-N Camptothecin Natural products CCC1(O)C(=O)OCC2=C1C=C3C4Nc5ccccc5C=C4CN3C2=O KLWPJMFMVPTNCC-UHFFFAOYSA-N 0.000 claims description 4
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical group O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 claims description 4
- 125000002947 alkylene group Chemical group 0.000 claims description 4
- 229940127093 camptothecin Drugs 0.000 claims description 4
- VSJKWCGYPAHWDS-UHFFFAOYSA-N dl-camptothecin Natural products C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)C5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-UHFFFAOYSA-N 0.000 claims description 4
- 229960003668 docetaxel Drugs 0.000 claims description 4
- 230000000977 initiatory effect Effects 0.000 claims description 4
- NXLNNXIXOYSCMB-UHFFFAOYSA-N (4-nitrophenyl) carbonochloridate Chemical compound [O-][N+](=O)C1=CC=C(OC(Cl)=O)C=C1 NXLNNXIXOYSCMB-UHFFFAOYSA-N 0.000 claims description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 3
- 229910052794 bromium Inorganic materials 0.000 claims description 3
- 238000006482 condensation reaction Methods 0.000 claims description 3
- 239000002253 acid Substances 0.000 claims description 2
- 238000007112 amidation reaction Methods 0.000 claims description 2
- 125000003277 amino group Chemical group 0.000 claims description 2
- 229960001904 epirubicin Drugs 0.000 claims description 2
- 238000005886 esterification reaction Methods 0.000 claims description 2
- 229960004857 mitomycin Drugs 0.000 claims description 2
- 125000003518 norbornenyl group Chemical group C12(C=CC(CC1)C2)* 0.000 claims description 2
- UUNIOFWUJYBVGQ-UHFFFAOYSA-N 2-amino-4-(3,4-dimethoxyphenyl)-10-fluoro-4,5,6,7-tetrahydrobenzo[1,2]cyclohepta[6,7-d]pyran-3-carbonitrile Chemical compound C1=C(OC)C(OC)=CC=C1C1C(C#N)=C(N)OC2=C1CCCC1=CC=C(F)C=C12 UUNIOFWUJYBVGQ-UHFFFAOYSA-N 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 abstract description 18
- 230000000694 effects Effects 0.000 abstract description 14
- 238000002512 chemotherapy Methods 0.000 abstract description 7
- 230000001093 anti-cancer Effects 0.000 abstract description 5
- JFNLZVQOOSMTJK-KNVOCYPGSA-N norbornene Chemical compound C1[C@@H]2CC[C@H]1C=C2 JFNLZVQOOSMTJK-KNVOCYPGSA-N 0.000 abstract description 4
- 231100000331 toxic Toxicity 0.000 abstract description 4
- 230000002588 toxic effect Effects 0.000 abstract description 4
- 238000007086 side reaction Methods 0.000 abstract description 2
- 229920002521 macromolecule Polymers 0.000 abstract 2
- 229920000428 triblock copolymer Polymers 0.000 abstract 2
- QHFKWIKCUHNXAU-UHFFFAOYSA-N (4-nitrophenyl) carbamate Chemical compound NC(=O)OC1=CC=C([N+]([O-])=O)C=C1 QHFKWIKCUHNXAU-UHFFFAOYSA-N 0.000 abstract 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 abstract 1
- 229920000151 polyglycol Polymers 0.000 abstract 1
- 239000010695 polyglycol Substances 0.000 abstract 1
- 230000019491 signal transduction Effects 0.000 abstract 1
- 238000009826 distribution Methods 0.000 description 15
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- 239000001257 hydrogen Substances 0.000 description 12
- 229910052739 hydrogen Inorganic materials 0.000 description 12
- 238000001228 spectrum Methods 0.000 description 12
- 206010028980 Neoplasm Diseases 0.000 description 10
- 238000010586 diagram Methods 0.000 description 10
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- 210000004881 tumor cell Anatomy 0.000 description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- 229960004679 doxorubicin Drugs 0.000 description 5
- 239000000693 micelle Substances 0.000 description 5
- 229920000747 poly(lactic acid) Polymers 0.000 description 5
- 238000011160 research Methods 0.000 description 5
- BDNKZNFMNDZQMI-UHFFFAOYSA-N 1,3-diisopropylcarbodiimide Chemical compound CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-UHFFFAOYSA-N 0.000 description 4
- 102000029749 Microtubule Human genes 0.000 description 4
- 108091022875 Microtubule Proteins 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 108090000704 Tubulin Proteins 0.000 description 4
- 102000004243 Tubulin Human genes 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 4
- 239000003937 drug carrier Substances 0.000 description 4
- 210000004688 microtubule Anatomy 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 4
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 229910052786 argon Inorganic materials 0.000 description 3
- 201000011510 cancer Diseases 0.000 description 3
- 230000030833 cell death Effects 0.000 description 3
- 238000005119 centrifugation Methods 0.000 description 3
- 229940044683 chemotherapy drug Drugs 0.000 description 3
- 238000011068 loading method Methods 0.000 description 3
- 229940002612 prodrug Drugs 0.000 description 3
- 239000000651 prodrug Substances 0.000 description 3
- 230000010076 replication Effects 0.000 description 3
- 238000001291 vacuum drying Methods 0.000 description 3
- DGVVWUTYPXICAM-UHFFFAOYSA-N β‐Mercaptoethanol Chemical compound OCCS DGVVWUTYPXICAM-UHFFFAOYSA-N 0.000 description 3
- KDXYEWRAWRZXFT-UHFFFAOYSA-N 2-bromocyclohexan-1-one Chemical compound BrC1CCCCC1=O KDXYEWRAWRZXFT-UHFFFAOYSA-N 0.000 description 2
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 2
- DKIDEFUBRARXTE-UHFFFAOYSA-N 3-mercaptopropanoic acid Chemical compound OC(=O)CCS DKIDEFUBRARXTE-UHFFFAOYSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 2
- 230000002159 abnormal effect Effects 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- ISAOCJYIOMOJEB-UHFFFAOYSA-N benzoin Chemical compound C=1C=CC=CC=1C(O)C(=O)C1=CC=CC=C1 ISAOCJYIOMOJEB-UHFFFAOYSA-N 0.000 description 2
- 235000019400 benzoyl peroxide Nutrition 0.000 description 2
- 229920001400 block copolymer Polymers 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 230000022131 cell cycle Effects 0.000 description 2
- 230000000973 chemotherapeutic effect Effects 0.000 description 2
- 229960001701 chloroform Drugs 0.000 description 2
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 description 2
- ZSWFCLXCOIISFI-UHFFFAOYSA-N cyclopentadiene Chemical compound C1C=CC=C1 ZSWFCLXCOIISFI-UHFFFAOYSA-N 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- 230000012010 growth Effects 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 description 2
- 229920001610 polycaprolactone Polymers 0.000 description 2
- 239000002861 polymer material Substances 0.000 description 2
- 230000004043 responsiveness Effects 0.000 description 2
- 229940126586 small molecule drug Drugs 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 238000013518 transcription Methods 0.000 description 2
- 230000035897 transcription Effects 0.000 description 2
- 230000004614 tumor growth Effects 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- IEXRKQFZXJSHOB-UHFFFAOYSA-N (4-nitrophenyl) formate Chemical group [O-][N+](=O)C1=CC=C(OC=O)C=C1 IEXRKQFZXJSHOB-UHFFFAOYSA-N 0.000 description 1
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
- 239000005695 Ammonium acetate Substances 0.000 description 1
- 238000006220 Baeyer-Villiger oxidation reaction Methods 0.000 description 1
- OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical compound C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 description 1
- 102000003915 DNA Topoisomerases Human genes 0.000 description 1
- 108090000323 DNA Topoisomerases Proteins 0.000 description 1
- 230000005778 DNA damage Effects 0.000 description 1
- 231100000277 DNA damage Toxicity 0.000 description 1
- 238000005698 Diels-Alder reaction Methods 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- HTIJFSOGRVMCQR-UHFFFAOYSA-N Epirubicin Natural products COc1cccc2C(=O)c3c(O)c4CC(O)(CC(OC5CC(N)C(=O)C(C)O5)c4c(O)c3C(=O)c12)C(=O)CO HTIJFSOGRVMCQR-UHFFFAOYSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 230000010337 G2 phase Effects 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 230000018199 S phase Effects 0.000 description 1
- 244000028419 Styrax benzoin Species 0.000 description 1
- 235000000126 Styrax benzoin Nutrition 0.000 description 1
- 235000008411 Sumatra benzointree Nutrition 0.000 description 1
- 229920003232 aliphatic polyester Polymers 0.000 description 1
- 229940043376 ammonium acetate Drugs 0.000 description 1
- 235000019257 ammonium acetate Nutrition 0.000 description 1
- 229920000469 amphiphilic block copolymer Polymers 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 230000000118 anti-neoplastic effect Effects 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229960002130 benzoin Drugs 0.000 description 1
- 229920002988 biodegradable polymer Polymers 0.000 description 1
- 239000004621 biodegradable polymer Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000012876 carrier material Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 1
- 229960004316 cisplatin Drugs 0.000 description 1
- 229940000425 combination drug Drugs 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 229920000359 diblock copolymer Polymers 0.000 description 1
- 239000000890 drug combination Substances 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 238000002651 drug therapy Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- DNJIEGIFACGWOD-UHFFFAOYSA-N ethyl mercaptane Natural products CCS DNJIEGIFACGWOD-UHFFFAOYSA-N 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 238000007306 functionalization reaction Methods 0.000 description 1
- 235000019382 gum benzoic Nutrition 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000003999 initiator Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 229920001427 mPEG Polymers 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- PSGAAPLEWMOORI-PEINSRQWSA-N medroxyprogesterone acetate Chemical compound C([C@@]12C)CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2CC[C@]2(C)[C@@](OC(C)=O)(C(C)=O)CC[C@H]21 PSGAAPLEWMOORI-PEINSRQWSA-N 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 239000011859 microparticle Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000003607 modifier Substances 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 231100000956 nontoxicity Toxicity 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000000737 periodic effect Effects 0.000 description 1
- 239000004626 polylactic acid Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 230000005180 public health Effects 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 238000004062 sedimentation Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000004654 survival pathway Effects 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 231100000167 toxic agent Toxicity 0.000 description 1
- 239000003440 toxic substance Substances 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 150000003672 ureas Chemical class 0.000 description 1
- 239000013598 vector Substances 0.000 description 1
- 229920003169 water-soluble polymer Polymers 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
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
-
- 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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
-
- 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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
- A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
-
- 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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G63/00—Macromolecular compounds obtained by reactions forming a carboxylic ester link in the main chain of the macromolecule
- C08G63/02—Polyesters derived from hydroxycarboxylic acids or from polycarboxylic acids and polyhydroxy compounds
- C08G63/06—Polyesters derived from hydroxycarboxylic acids or from polycarboxylic acids and polyhydroxy compounds derived from hydroxycarboxylic acids
- C08G63/08—Lactones or lactides
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G63/00—Macromolecular compounds obtained by reactions forming a carboxylic ester link in the main chain of the macromolecule
- C08G63/78—Preparation processes
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G63/00—Macromolecular compounds obtained by reactions forming a carboxylic ester link in the main chain of the macromolecule
- C08G63/91—Polymers modified by chemical after-treatment
- C08G63/912—Polymers modified by chemical after-treatment derived from hydroxycarboxylic acids
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Polymers & Plastics (AREA)
- Organic Chemistry (AREA)
- Molecular Biology (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
本发明公开了一种具有多药协同作用的抗肿瘤高分子键合药及其制备方法;以聚乙二醇单甲醚依次引发含降冰片烯的丙交酯及α溴代己内酯聚合,得到三嵌段共聚物,在三嵌段共聚物上修饰对硝基苯基甲酸酯侧基和羧基侧基,得到高分子载体,高分子载体与含羟基的抗肿瘤药物和含氨基的抗肿瘤药物键合,即得;该制备方法操作简单,反应条件温和,副反应少,产率高,载药量大且可控,产物纯度高;制得的抗肿瘤高分子键合药通过多种信号通路作用(协同作用)提高了抗癌活性,同时又因为多种药物的联合作用可降低每种药物的剂量从而降低了化疗的毒副作用。
Description
技术领域
本发明涉及一种抗肿瘤药物,特别涉及一种具有多药协同作用的抗肿瘤高分子键合药及其制备方法;属于生物医药高分子材料领域。
背景技术
肿瘤是一个全球性的公共健康问题。近三十年来,世界癌症发病率以每年3-5%的速度增加,二十一世纪,肿瘤已成为导致人类死亡的第一诱因。化疗作为肿瘤三大治疗手段之一,是目前肿瘤治疗的重要手段。尽管化疗在治疗肿瘤方面已经取得了长足的进步,然而在临床应用中仍存在一些障碍。如传统的肿瘤化疗采取的是单一化疗药物,其主要缺陷是单一药物的治疗往往会激活和强化肿瘤细胞其他方面的存活路径,从而导致耐药性的出现并最终导致化疗失败。同时为了达到治疗效果,需要更高的药物剂量,导致难以接受的药物毒副作用。为了解决这一难题,近年来,利用多个药物的协同作用使用联合给药的方法成为抗肿瘤药物药剂学领域的一个研究热点。
目前,临床使用的抗肿瘤药物以紫杉醇、阿霉素、喜树碱、顺铂为主。这类抗肿瘤药物因其抗癌机理的不同而作用于肿瘤细胞的不同周期。如紫杉醇作用于微管/微管蛋白系统,可影响微管蛋白的装配和解聚,从而导致微管束的排列异常,形成星状体,使纺锤体失去正常功能,导致细胞死亡,作用于细胞周期的G2和M期;阿霉素通过嵌入癌细胞的DNA碱基片段中,阻碍DNA的转录和复制,从而抑制肿瘤细胞生长,属周期非特异性药物;喜树碱能稳定拓扑异构酶Ⅰ和DNA的共价化合物,形成了三元可解离复合物,通过复制冲突模型造成DNA损伤,最终导致细胞死亡,作用于细胞周期的S期。联合用药是基于不同的化疗药物对应于肿瘤细胞的不同信号通路,在肿瘤细胞的不同生长周期产生抑制作用,从而实现治疗目的。
然而小分子药物的联合存在不同药物的代谢性质、组织和器官分布、穿透各级膜的能力的不同的问题,很难控制到达最终靶点的多种药物仍保持注射时的最初浓度。其次,小分子药物的联合,往往会带来更大的副作用和毒性。因此,使用聚合物前药或纳米药物载体成为联合用药的最佳策略。众所周知,纳米药物载体具有可通过合适的尺寸和结构设计来改变药物的药代动力学和体内分布以及通过EPR效应实现被动靶向的优点。作为载体给药系统的一员,从两亲性嵌段共聚物发展而来的聚合物胶束深受青睐。当投入到水性介质中时,在体系自由能降低的驱动下,胶束的疏水段自发聚集在一起形成微粒的内核。它既可以作为很多难溶性药物的微储库,又能避免药物在生物体内环境中失活。自组装形成的载药胶束是热力学、动力学稳定的体系,具有稳定、长效、安全等许多优良的性质,使得聚合物胶束成为难溶性药物理想的输送系统,且在药物释放、基因载体和诊断制剂等很多方面得到广泛地应用。
聚合物修饰剂的选择是药物分子修饰的关键,现有研究表明脂肪族聚酯如聚乳酸(PLA),聚乳酸-羟基乙酸共聚物(PLGA)和聚ε-己内酯(PCL)属于生物可降解聚合物。它们的分子量在相当宽的范围可以随意控制,所以在聚合物药物载体的研究中得到了广泛的应用。特别是在与水溶性聚合物形成嵌段共聚物后,不仅具有生物可降解性,而且大大地改善了材料与人体的生物相容性,作为药物载体材料时,延长了药物在体内的循环时间,提高了药效,降低了免疫响应性,已经成为生物医药高分子材料领域的研究热点。
发明内容
针对传统的肿瘤化疗采取的是单一化疗药,或一些联合给药的药物载体大多都是不可降解的高分子聚合物,且其键合方式都是物理包裹,导致人体对药物的生物利用度低,抗癌活性差等缺陷;本发明的目的是在于提供一种以可生物降解高分子为载体,同时负载多种抗肿瘤药物构成的高分子键合药,该高分子键合药通过多药协同作用提高抗癌活性,同时降低化疗的毒副作用,且该高分子键合药生物相容性好,载药量高且可控,可以应用于临床研究。
本发明的另一个目的是在于提供一种经济、高效和无毒的制备上述可生物降解的具有多药协同作用的抗肿瘤药高分子键合药的方法。
为了实现上述技术目的,本发明提供了一种具有多药协同作用的抗肿瘤高分子键合药,具有式1结构:
其中,
A为含有羟基的抗肿瘤药物基团;
B为含有氨基的抗肿瘤药物基团;
n为45~454,x为1~20,y为1~20;
R1和R2独立地选自C1~C4的亚烷基。
优选的方案,A为紫杉醇基团、多西紫杉醇基团、喜树碱基团、丝裂霉素C基团中的至少一种。
优选的方案,B为阿霉素基团、表阿霉素基团、吡喃阿霉素基团中的至少一种。
本发明还提供了一种制备所述的具有多药协同作用的抗肿瘤高分子键合药的方法,该方法包括以下步骤:
1)以聚乙二醇单甲醚引发含降冰片烯基团的丙交酯进行开环聚合,聚合产物再引发α溴代己内酯进行开环聚合,得到聚乙二醇单甲醚-b-聚丙交酯-b-聚α溴代己内酯共聚物;
2)所述聚乙二醇单甲醚-b-聚丙交酯-b-聚α溴代己内酯共聚物与含巯基的醇类化合物进行巯基-溴点击反应,得到含羟基侧基的聚乙二醇单甲醚-b-聚丙交酯-b-聚α溴代己内酯共聚物;所述含羟基侧基的聚乙二醇单甲醚-b-聚丙交酯-b-聚α溴代己内酯共聚物与对硝基苯基氯甲酸酯进行缩合反应,得到含对硝基苯基甲酸酯侧基的聚乙二醇单甲醚-b-聚丙交酯-b-聚α溴代己内酯共聚物;所述含对硝基苯基甲酸酯侧基的聚乙二醇单甲醚-b-聚丙交酯-b-聚α溴代己内酯共聚物与含巯基的酸类化合物进行巯基-烯光点击反应,得到式2载体聚合物;
3)含羟基的抗肿瘤药物和含氨基的抗肿瘤药物与式2载体聚合物分别进行酯化反应和酰胺化反应,即得;
其中,
n为45~454;
x为1~20;
y为1~20;
R1和R2各自独立地选自C1~C4的亚烷基。
优选的方案,含有氨基的抗肿瘤药物为阿霉素、表阿霉素、吡喃阿霉素中的至少一种。
优选的方案,含有羟基的抗肿瘤药物为紫杉醇、多西紫杉醇、喜树碱、丝裂霉素C中的至少一种。
本发明的聚乙二醇单甲醚-b-聚丙交酯-b-聚α溴代己内酯聚合物的制备方法:
将丙交酯和N-溴代丁二酰亚胺(NBS),以四氯化碳或苯为溶液,以过氧化二苯甲酰(BPO)做催化剂,在60~90℃下发生取代反应,得到溴代丙交酯;得到的溴代丙交酯以二氯甲烷溶剂中,在三乙胺的作用下,0~5℃下发生消去反应得到双键丙交酯;得到的双键丙交酯和新蒸环戊二烯在四氯化碳或苯溶液中,氩气保护,60~90℃下,通过Diels-Alder反应后,得到含降冰片烯侧基的丙交酯;
将环己酮和N-溴代丁二酰亚胺(NBS)以无水乙醚为溶剂,醋酸铵(NH4AcO)做催化剂,室温下反应得到溴代环己酮;溴代环己酮通过Baeyer-Villiger氧化反应与间氯过氧苯甲酸(m-CPBA)生成了α位溴代己内酯;
以聚乙二醇单甲醚为大分子引发剂,TBD或DBU为催化剂,二氯甲烷为溶剂,-20~40℃下引发含降冰片烯侧基的丙交酯进行开环聚合得到聚乙二醇单甲醚-b-聚丙交酯聚合物,再以聚乙二醇单甲醚-b-聚丙交酯聚合物为大分子引发剂,同样的聚合条件将α溴代己内酯引发聚合,得到聚乙二醇单甲醚-b-聚丙交酯-b-聚α溴代己内酯聚合物。
本发明的聚合物官能化的制备方法:将聚乙二醇单甲醚-b-聚丙交酯-b-聚α溴代己内酯聚合物采用巯基-溴点击化学反应和巯基-烯光点击化学反应,反应点击效率高,无副产物。
本发明的含羟基的抗肿瘤药物与高分子载体进行DIC缩合反应,其副产物易除去,避免了传统DCC缩合后剧毒物质DCU的产生。含氨基的抗肿瘤药物与对硝基苯基甲酸酯活化的高分子载体键合,其键合效率高,生成的酰胺键稳定。
本发明的具有多药协同作用的抗肿瘤高分子键合药的合成路线如下:
以抗肿瘤药物紫杉醇(paclitaxel)和阿霉素(doxorubicin)为例:
相对现有技术,本发明的技术方案带来的有益效果:
1)与现有的高分子抗肿瘤高分子键合药相比,本发明的抗肿瘤高分子键合药最大的优势在于通过将抗肿瘤药物阿霉素和紫杉醇等同时键合到高分子载体上,不同的抗肿瘤药物对应于肿瘤细胞的不同信号通路,在肿瘤细胞的不同生长周期产生抑制作用,提高治疗效果。如阿霉素通过嵌入癌细胞的DNA碱基片段中,阻碍DNA的转录和复制,从而抑制肿瘤细胞生长;而紫杉醇作用于微管/微管蛋白系统,可影响微管蛋白的装配和解聚,从而导致微管束的排列异常,形成星状体,使纺锤体失去正常功能,导致细胞死亡。
2)本发明的高分子抗肿瘤高分子键合药另一优势在于可降低化疗药物的毒副作用,因为药物联合作用导致每种药物的给药剂量减少,同时抗癌活性不受影响,提高了药物的利用度,可以降低化疗成本。
3)本发明的高分子抗肿瘤高分子键合药在端基引入分子量较小的聚乙二醇单甲醚,聚乙二醇单甲醚不但具有较好的生物相容性及生物可降解性,并且在水相中易于自组装形成纳米胶束粒子,延长了药物在体内的循环时间,提高了药效,降低了免疫响应性。
4)本发明的高分子抗肿瘤高分子键合药的制备方法操作简单、反应条件温和、副反应少、产率高和安全无毒,且易于调控高分子键合药的载药量,满足工业生产要求。
附图说明
【图1】为聚乙二醇单甲醚-b-聚丙交酯两嵌段共聚物的核磁氢谱图;
【图2】为聚乙二醇单甲醚-b-聚丙交酯-b-聚α溴代己内酯共聚物的核磁氢谱图;【图3】为实施例1的步骤1中各聚合物的分子量分布图:A为聚乙二醇单甲醚的分子量分布图,B为聚乙二醇单甲醚-b-聚丙交酯共聚物的分子量分布图,C为聚乙二醇单甲醚-b-聚丙交酯-b-聚α溴代己内酯共聚物的分子量分布图;
【图4】为聚乙二醇单甲醚-b-聚丙交酯-b-聚α溴代己内酯共聚物与巯基乙醇反生巯基-溴点击反应得到的含羟基侧基的聚乙二醇单甲醚-b-聚丙交酯-b-聚α溴代己内酯共聚物核磁氢谱图;
【图5】为含对硝基苯基甲酸酯侧基的聚乙二醇单甲醚-b-聚丙交酯-b-聚α溴代己内酯共聚物的核磁氢谱图;
【图6】为含对硝基苯基甲酸酯侧基的聚乙二醇单甲醚-b-聚丙交酯-b-聚α溴代己内酯共聚物与巯基丙酸反生巯基-烯光点击反应得到的载体聚合物的核磁氢谱图;
【图7】为含紫杉醇的抗肿瘤高分子键合药的核磁氢谱图;
【图8】为含紫杉醇和阿霉素高分子键合药的核磁氢谱图;
【图9】为实施例1中步骤2~4中各聚合物的分子量分布图:A为聚乙二醇单甲醚-b-聚丙交酯-b-聚α溴代己内酯共聚物与巯基乙醇反生巯基-溴点击反应得到的含羟基侧基的聚乙二醇单甲醚-b-聚丙交酯-b-聚α溴代己内酯共聚物的分子量分布图,B为含对硝基苯基甲酸酯侧基的聚乙二醇单甲醚-b-聚丙交酯-b-聚α溴代己内酯共聚物的分子量分布图,C为含对硝基苯基甲酸酯侧基的聚乙二醇单甲醚-b-聚丙交酯-b-聚α溴代己内酯共聚物与巯基丙酸反生巯基-烯光点击反应得到的含羧基侧基的聚乙二醇单甲醚-b-聚丙交酯-b-聚α溴代己内酯共聚物分子量分布图。
具体实施方式
以下实施例旨在是对本发明内容进一步说明,而不是限制本发明权利要求的保护范围。
实施例1
1、聚乙二醇单甲醚-b-聚丙交酯-b-聚α溴代己内酯共聚物的制备:
首先,在已真空烤过3次的安培瓶中,于氮气保护下加入0.80g的降冰片烯侧基的丙交酯和1.00g聚乙二醇单甲醚(mPEG),之后加入1mL的精制的DCM使其完全溶解,注射由精制DCM配制好的含引发剂TBD溶液1mL,常温反应48h后,用无水乙醚沉降3次,离心后真空干燥,得到聚乙二醇单甲醚-b-聚丙交酯两嵌段聚合物,结构表征如图1所示,分子量分布为图3。然后,再以其为大分子引发剂,同样聚合条件下引发α溴代己内酯聚合,得到聚乙二醇单甲醚-b-聚丙交酯-b-聚α溴代己内酯共聚物,其结构表征如图2,分子量分布见图3,说明该聚合物已成功合成。
2、含羟基侧基的聚乙二醇单甲醚-b-聚丙交酯-b-聚α溴代己内酯共聚物的制备:
称取上述聚乙二醇单甲醚-b-聚丙交酯-b-聚α溴代己内酯共聚物0.5g(0.06mmol),2-巯基乙醇0.054g(0.73mmol),溶于10mL的乙腈,加入0.05mL三乙胺做催化剂,在氩气保护下反应2h。反应结束后用水透析24h,除去季铵盐,再用无水乙醚沉降,离心后真空干燥,得到纯的含羟基侧基的聚乙二醇单甲醚-b-聚丙交酯-b-聚α溴代己内酯共聚物。其结构表征见核磁氢谱图(图4),分子量分布见图9A,说明该聚合物已成功合成。
3、含对硝基苯基甲酸酯侧基的聚乙二醇单甲醚-b-聚丙交酯-b-聚α溴代己内酯共聚物的制备:
称取含羟基侧基的聚乙二醇单甲醚-b-聚丙交酯-b-聚α溴代己内酯聚合物0.4g(0.049mmol),溶于10mL二氯甲烷,在氩气保护下缓慢滴加0.21g对硝基苯基氯甲酸酯和0.05mL三乙胺,0℃反应24小时,反应结束后用无水乙醚沉降3次,离心后真空干燥。其结构表征见核磁氢谱图6,分子量分布见图9B。
4、载体聚合物的制备:
在氮气的保护下,将0.3g(0.45mmol)上述聚合物溶解在10mL精制的四氢呋喃(THF)中,加入0.030g(0.029mmol)3-巯基丙酸,3mg安息香二甲醚(DMPA)光引发剂,在紫外灯光照下反应0.5h。反应结束后,用无水乙醚沉降3次,离心后真空干燥,得到载体聚合物。其结构表征见核磁氢谱图6,分子量分布见图9C,说明该聚合物已成功合成。
5、含紫杉醇的高分子键合药的制备
称取载体聚合物0.1g(0.008mmol),紫杉醇0.029g(0.03mmol),N,N-二异丙基碳二亚胺(DIC)0.004g(0.03mmol)。将紫杉醇溶于10mL三氯甲烷,加入催化量的DMAP,在氮气保护下缓慢滴加溶于2mL三氯甲烷的聚合物和DIC,冰浴搅拌1h后,在45℃下反应24h。反应结束后用甲醇透析24h,除掉脲盐,然后用无水乙醚沉降3次,离心,真空干燥。其结构表征见核磁氢谱图7。
6、含紫杉醇和阿霉素的高分子键合药的制备:
称取上述紫杉醇前药0.5g,盐酸盐阿霉素0.025g,将盐酸盐阿霉素溶于干燥的DMF,加入0.01mL三乙胺,抽真空充氮气三次,反应2小时脱掉盐酸盐,再加入紫杉醇前药,避光,室温反应48h。反应结束后,用DMF透析48h,乙腈透析掉DMF,无水乙醚沉降,离心,真空干燥。其结构表征见核磁氢谱图8。
Claims (6)
1.一种具有多药协同作用的抗肿瘤高分子键合药,其特征在于:具有式1结构:
其中,
A为含有羟基的抗肿瘤药物基团;
B为含有氨基的抗肿瘤药物基团;
n为45~454,x为1~20,y为1~20;
R1和R2独立地选自C1~C4的亚烷基。
2.如权利要求1所述的具有多药协同作用的抗肿瘤高分子键合药,其特征在于:所述的A为紫杉醇基团、多西紫杉醇基团、喜树碱基团、丝裂霉素C基团中的至少一种。
3.如权利要求1所述的具有多药协同作用的抗肿瘤高分子键合药,其特征在于:所述的B为阿霉素基团、表阿霉素基团、吡喃阿霉素基团中的至少一种。
4.制备权利要求1~3任一项所述的具有多药协同作用的抗肿瘤高分子键合药的方法,其特征在于:包括以下步骤:
1)以聚乙二醇单甲醚引发含降冰片烯基团的丙交酯进行开环聚合,聚合产物再引发α溴代己内酯进行开环聚合,得到聚乙二醇单甲醚-b-聚丙交酯-b-聚α溴代己内酯共聚物;
2)所述聚乙二醇单甲醚-b-聚丙交酯-b-聚α溴代己内酯共聚物与含巯基的醇类化合物进行巯基-溴点击反应,得到含羟基侧基的聚乙二醇单甲醚-b-聚丙交酯-b-聚α溴代己内酯共聚物;所述含羟基侧基的聚乙二醇单甲醚-b-聚丙交酯-b-聚α溴代己内酯共聚物与对硝基苯基氯甲酸酯进行缩合反应,得到含对硝基苯基甲酸酯侧基的聚乙二醇单甲醚-b-聚丙交酯-b-聚α溴代己内酯共聚物;所述含对硝基苯基甲酸酯侧基的聚乙二醇单甲醚-b-聚丙交酯-b-聚α溴代己内酯共聚物与含巯基的酸类化合物进行巯基-烯光点击反应,得到式2载体聚合物;
3)含羟基的抗肿瘤药物和含氨基的抗肿瘤药物与式2载体聚合物分别进行酯化反应和酰胺化反应,即得;
其中,
n为45~454;
x为1~20;
y为1~20;
R1和R2各自独立地选自C1~C4的亚烷基。
5.如权利要求4所述的制备具有多药协同作用的抗肿瘤高分子键合药的方法,其特征在于:含有氨基的抗肿瘤药物为阿霉素、表阿霉素、吡喃阿霉素中的至少一种。
6.如权利要求4所述的制备具有多药协同作用的抗肿瘤高分子键合药的方法,其特征在于:含有羟基的抗肿瘤药物为紫杉醇、多西紫杉醇、喜树碱、丝裂霉素C中的至少一种。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201610566950.XA CN106177979B (zh) | 2016-07-18 | 2016-07-18 | 一种具有多药协同作用的抗肿瘤高分子键合药及其制备方法 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201610566950.XA CN106177979B (zh) | 2016-07-18 | 2016-07-18 | 一种具有多药协同作用的抗肿瘤高分子键合药及其制备方法 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN106177979A CN106177979A (zh) | 2016-12-07 |
CN106177979B true CN106177979B (zh) | 2019-03-08 |
Family
ID=57493914
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201610566950.XA Expired - Fee Related CN106177979B (zh) | 2016-07-18 | 2016-07-18 | 一种具有多药协同作用的抗肿瘤高分子键合药及其制备方法 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN106177979B (zh) |
Families Citing this family (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN107670049B (zh) * | 2017-11-23 | 2020-04-07 | 湘潭大学 | 一种具有多药协同作用的全降解高分子抗肿瘤药物及其制备方法 |
CN107899019B (zh) * | 2017-11-23 | 2020-04-21 | 湘潭大学 | 一种键合细胞穿透肽的智能型高分子键合药及其制备方法 |
CN109054028B (zh) * | 2018-06-27 | 2021-01-29 | 湘潭大学 | 一种温度可控型易降解温敏性聚合物及其制备方法 |
CN109771657B (zh) * | 2019-03-27 | 2022-06-24 | 湘潭大学 | 一种键合血管阻断剂和免疫调节剂的高分子抗肿瘤药物及其制备方法 |
CN113081960B (zh) * | 2021-04-08 | 2023-02-03 | 湘潭大学 | 一种可生物降解且具有温敏性的抗肿瘤键合前药及其制备方法 |
CN113105614A (zh) * | 2021-04-08 | 2021-07-13 | 湘潭大学 | 一种易降解响应型可核心交联的两亲性嵌段聚合物及其制备方法和作为药物载体的应用 |
CN115010910B (zh) * | 2022-05-31 | 2023-04-28 | 湘潭大学 | 一种具有氧化还原双重响应的替拉扎明抗肿瘤前药及其制备方法 |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103275312B (zh) * | 2013-05-16 | 2015-01-21 | 湘潭大学 | 含侧羟基或侧羧基官能团的聚丙交酯及其制备方法 |
CN104327018B (zh) * | 2013-12-01 | 2016-07-13 | 复旦大学 | 一种含二硫键可聚合紫杉醇单体及其合成方法 |
CN107670049B (zh) * | 2017-11-23 | 2020-04-07 | 湘潭大学 | 一种具有多药协同作用的全降解高分子抗肿瘤药物及其制备方法 |
-
2016
- 2016-07-18 CN CN201610566950.XA patent/CN106177979B/zh not_active Expired - Fee Related
Also Published As
Publication number | Publication date |
---|---|
CN106177979A (zh) | 2016-12-07 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN106177979B (zh) | 一种具有多药协同作用的抗肿瘤高分子键合药及其制备方法 | |
CN107670049B (zh) | 一种具有多药协同作用的全降解高分子抗肿瘤药物及其制备方法 | |
CN105251013B (zh) | 一种具有氧化还原响应性可降解水溶性抗肿瘤聚合物前药及其制备方法 | |
CN106831805B (zh) | 一种喜树碱-阿霉素前药及其制备方法和应用 | |
Zhang et al. | Synthesis and characterization of a new multifunctional polymeric prodrug paclitaxel–polyphosphoester–folic acid for targeted drug delivery | |
Quaglia et al. | Nanoscopic core-shell drug carriers made of amphiphilic triblock and star-diblock copolymers | |
CN104548124B (zh) | 一种水溶性可降解的抗肿瘤前药及其制备方法 | |
CN107669626B (zh) | 一种高载药量的还原敏感的药物传递系统的制备方法及其应用 | |
CN107596380B (zh) | 基于聚乙二醇-聚碳酸酯的还原敏感性喜树碱前药及其制备方法和应用 | |
CN109303780B (zh) | 一种还原响应型7-乙基-10-羟基喜树碱的两亲性聚合物药物前体及其制备方法 | |
CN109771657B (zh) | 一种键合血管阻断剂和免疫调节剂的高分子抗肿瘤药物及其制备方法 | |
CN103893769B (zh) | 含聚乙丙交酯靶向高分子药物载体及其制备方法 | |
Li et al. | Synthesis and characterization of amphiphilic block polymer poly (ethylene glycol)-poly (propylene carbonate)-poly (ethylene glycol) for drug delivery | |
CN113081961A (zh) | 一种键合免疫调节剂且具有pH响应的核心交联型胶束抗肿瘤前药及其制备方法 | |
CN104922689B (zh) | 一种可生物降解且具有pH响应性的抗肿瘤高分子键合药及其制备方法 | |
CA2950312C (en) | Cyclic carbonate monomer containing double-sulfur five-membered ring functional group, and preparation method thereof | |
CN106177978B (zh) | 一种具有靶向和示踪功能的抗肿瘤高分子键合药及其制备方法 | |
Chang et al. | Ring-opening polymerization of ε-caprolactone initiated by the antitumor agent doxifluridine | |
EP3004202B1 (en) | Copolymer and nanoparticles obtained therefrom for drug delivery | |
CN107899019B (zh) | 一种键合细胞穿透肽的智能型高分子键合药及其制备方法 | |
CN102552930B (zh) | 一种具有细胞靶向作用的水溶性紫杉醇衍生物及其制备 | |
CN107744514B (zh) | 一种具有酶靶向性的星状给药纳米粒的制备方法 | |
CN113908289B (zh) | 一种具有精确调控药物比例的抗肿瘤多元载药体系及其制备方法 | |
KR20200139737A (ko) | 개선된 물리적 안정성 및 향상된 항종양 효능을 위한 미셀에서의 올리고락트산 접합체의 입체복합체 | |
CN113081960B (zh) | 一种可生物降解且具有温敏性的抗肿瘤键合前药及其制备方法 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant | ||
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20190308 |
|
CF01 | Termination of patent right due to non-payment of annual fee |