CN117004006A - Amphiphilic block copolymer and preparation method and application thereof - Google Patents
Amphiphilic block copolymer and preparation method and application thereof Download PDFInfo
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- CN117004006A CN117004006A CN202310984284.1A CN202310984284A CN117004006A CN 117004006 A CN117004006 A CN 117004006A CN 202310984284 A CN202310984284 A CN 202310984284A CN 117004006 A CN117004006 A CN 117004006A
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- block copolymer
- amphiphilic block
- pdlla
- mpeg
- boc
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- 229920000469 amphiphilic block copolymer Polymers 0.000 title claims abstract description 42
- 238000002360 preparation method Methods 0.000 title claims abstract description 32
- 239000003814 drug Substances 0.000 claims abstract description 52
- 239000000693 micelle Substances 0.000 claims abstract description 47
- 229940079593 drug Drugs 0.000 claims abstract description 45
- ZYJPUMXJBDHSIF-NSHDSACASA-N (2s)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-3-phenylpropanoic acid Chemical compound CC(C)(C)OC(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 ZYJPUMXJBDHSIF-NSHDSACASA-N 0.000 claims abstract description 34
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 96
- 229920001244 Poly(D,L-lactide) Polymers 0.000 claims description 66
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 42
- 238000006243 chemical reaction Methods 0.000 claims description 22
- 238000001914 filtration Methods 0.000 claims description 22
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 21
- 238000002390 rotary evaporation Methods 0.000 claims description 20
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 19
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 14
- 239000012043 crude product Substances 0.000 claims description 12
- 238000006116 polymerization reaction Methods 0.000 claims description 12
- 239000002904 solvent Substances 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 11
- 239000000203 mixture Substances 0.000 claims description 10
- JJTUDXZGHPGLLC-IMJSIDKUSA-N 4511-42-6 Chemical compound C[C@@H]1OC(=O)[C@H](C)OC1=O JJTUDXZGHPGLLC-IMJSIDKUSA-N 0.000 claims description 9
- 239000000047 product Substances 0.000 claims description 9
- KSBAEPSJVUENNK-UHFFFAOYSA-L tin(ii) 2-ethylhexanoate Chemical compound [Sn+2].CCCCC(CC)C([O-])=O.CCCCC(CC)C([O-])=O KSBAEPSJVUENNK-UHFFFAOYSA-L 0.000 claims description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 8
- 229930012538 Paclitaxel Natural products 0.000 claims description 8
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 8
- 239000003960 organic solvent Substances 0.000 claims description 8
- 229960001592 paclitaxel Drugs 0.000 claims description 8
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 claims description 8
- JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 claims description 7
- RGUKYNXWOWSRET-UHFFFAOYSA-N 4-pyrrolidin-1-ylpyridine Chemical compound C1CCCN1C1=CC=NC=C1 RGUKYNXWOWSRET-UHFFFAOYSA-N 0.000 claims description 7
- 238000002425 crystallisation Methods 0.000 claims description 7
- 230000008025 crystallization Effects 0.000 claims description 7
- 229910052757 nitrogen Inorganic materials 0.000 claims description 7
- 238000005303 weighing Methods 0.000 claims description 7
- 239000002202 Polyethylene glycol Substances 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- 229920001400 block copolymer Polymers 0.000 claims description 6
- 229920001223 polyethylene glycol Polymers 0.000 claims description 6
- -1 polyethylene Polymers 0.000 claims description 5
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 4
- 239000011230 binding agent Substances 0.000 claims description 4
- JJTUDXZGHPGLLC-UHFFFAOYSA-N lactide Chemical compound CC1OC(=O)C(C)OC1=O JJTUDXZGHPGLLC-UHFFFAOYSA-N 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- PGZVFRAEAAXREB-UHFFFAOYSA-N 2,2-dimethylpropanoyl 2,2-dimethylpropanoate Chemical compound CC(C)(C)C(=O)OC(=O)C(C)(C)C PGZVFRAEAAXREB-UHFFFAOYSA-N 0.000 claims description 3
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 claims description 3
- 239000004698 Polyethylene Substances 0.000 claims description 3
- 238000001035 drying Methods 0.000 claims description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 3
- 229920000573 polyethylene Polymers 0.000 claims description 3
- AOJJSUZBOXZQNB-VTZDEGQISA-N 4'-epidoxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-VTZDEGQISA-N 0.000 claims description 2
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 claims description 2
- 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 claims description 2
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 claims description 2
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 claims description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-diisopropylethylamine Substances CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 2
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound 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 2
- KMSKQZKKOZQFFG-HSUXVGOQSA-N Pirarubicin Chemical compound O([C@H]1[C@@H](N)C[C@@H](O[C@H]1C)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]1CCCCO1 KMSKQZKKOZQFFG-HSUXVGOQSA-N 0.000 claims description 2
- BMQGVNUXMIRLCK-OAGWZNDDSA-N cabazitaxel Chemical compound O([C@H]1[C@@H]2[C@]3(OC(C)=O)CO[C@@H]3C[C@@H]([C@]2(C(=O)[C@H](OC)C2=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=3C=CC=CC=3)C[C@]1(O)C2(C)C)C)OC)C(=O)C1=CC=CC=C1 BMQGVNUXMIRLCK-OAGWZNDDSA-N 0.000 claims description 2
- 229960001573 cabazitaxel Drugs 0.000 claims description 2
- 229960004397 cyclophosphamide Drugs 0.000 claims description 2
- 229960003668 docetaxel Drugs 0.000 claims description 2
- 229960004679 doxorubicin Drugs 0.000 claims description 2
- 229960001904 epirubicin Drugs 0.000 claims description 2
- 229960002949 fluorouracil Drugs 0.000 claims description 2
- 230000000887 hydrating effect Effects 0.000 claims description 2
- 229960000485 methotrexate Drugs 0.000 claims description 2
- 229960001221 pirarubicin Drugs 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 230000006340 racemization Effects 0.000 claims description 2
- 238000007670 refining Methods 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 claims description 2
- 229920000642 polymer Polymers 0.000 abstract description 12
- 239000000463 material Substances 0.000 abstract description 8
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract description 4
- 239000002246 antineoplastic agent Substances 0.000 abstract description 3
- 229940041181 antineoplastic drug Drugs 0.000 abstract description 3
- 238000000338 in vitro Methods 0.000 abstract 1
- 238000001727 in vivo Methods 0.000 abstract 1
- 229920001427 mPEG Polymers 0.000 description 62
- 238000003756 stirring Methods 0.000 description 27
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 25
- 238000004090 dissolution Methods 0.000 description 20
- 239000007787 solid Substances 0.000 description 15
- 238000005227 gel permeation chromatography Methods 0.000 description 13
- 238000001816 cooling Methods 0.000 description 11
- 229920001577 copolymer Polymers 0.000 description 11
- 238000001291 vacuum drying Methods 0.000 description 11
- 230000008014 freezing Effects 0.000 description 10
- 238000007710 freezing Methods 0.000 description 10
- 230000005311 nuclear magnetism Effects 0.000 description 10
- 230000002209 hydrophobic effect Effects 0.000 description 9
- 239000002245 particle Substances 0.000 description 9
- 230000018044 dehydration Effects 0.000 description 5
- 238000006297 dehydration reaction Methods 0.000 description 5
- 239000012065 filter cake Substances 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 230000036571 hydration Effects 0.000 description 5
- 238000006703 hydration reaction Methods 0.000 description 5
- 239000000376 reactant Substances 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 238000005538 encapsulation Methods 0.000 description 4
- 238000011068 loading method Methods 0.000 description 4
- 238000001514 detection method Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 229920000747 poly(lactic acid) Polymers 0.000 description 3
- 239000004626 polylactic acid Substances 0.000 description 3
- 238000012512 characterization method Methods 0.000 description 2
- 238000012377 drug delivery Methods 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 229940124602 FDA-approved drug Drugs 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 229940024606 amino acid Drugs 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 230000021615 conjugation Effects 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 125000001165 hydrophobic group Chemical group 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 229960005190 phenylalanine Drugs 0.000 description 1
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 1
- 239000002861 polymer material Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 238000011287 therapeutic dose Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
Classifications
-
- 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
- C08G63/66—Polyesters containing oxygen in the form of ether groups
- C08G63/664—Polyesters containing oxygen in the form of ether groups derived from hydroxy carboxylic acids
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- 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
- A61K31/66—Phosphorus compounds
- A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
- A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- 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
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
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- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Molecular Biology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Polymers & Plastics (AREA)
- General Chemical & Material Sciences (AREA)
- Inorganic Chemistry (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Biophysics (AREA)
- Dispersion Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention relates to an amphiphilic block copolymer, a preparation method and application thereof, wherein the amphiphilic block copolymer has a structural general formula shown in (I), the amphiphilic block copolymer provided by the invention has the advantages that the end hydroxyl of a polymer is blocked by Boc-phenylalanine, the in-vivo and in-vitro stability of a formed micelle is obviously improved, and the amphiphilic block copolymer can be prepared into a drug carrying system with an anti-tumor drug and pharmaceutically acceptable auxiliary materials, so that the amphiphilic block copolymer has a relatively high application prospect.
Description
Technical Field
The invention belongs to the field of synthesis of biological high polymer materials, and particularly relates to a preparation method of an amphiphilic block copolymer and a micelle thereof, and the amphiphilic block copolymer is applied to a medicament for treating tumor diseases.
Background
The polymer micelle is a nano drug controlled release system which mainly aims at insoluble drugs and is developed in recent years. The polymer micelle drug delivery system can obviously improve the solubility of the drug and reduce the toxic and side effects of the drug, thereby improving the therapeutic dose, and the drug is wrapped in the core, so that the degradation and inactivation of the drug can be avoided. The most important materials for forming micelles to date remain amphiphilic block copolymers. However, to date, in FDA approved drug delivery systems, synthetic polymeric excipients that have been truly tested by humans and demonstrated to be highly safe remain very limited, essentially only two classes of polyethylene glycol (PEG) and lactide/glycolide copolymers (PLGA). These two types of polymers and their copolymers are also used as adjuvants in other, largely ongoing clinical trials.
At present, polymer micelles taking mPEG-PDLLA as a carrier are mature, and copolymers with different structures and molecular weights can be formed according to different molecular weights of PEG and mPEG/PLA ratios. The copolymer has amphipathy, when micelle is formed in solution, the periphery of the micelle is a hydrophilic mPEG chain segment, the inner core is a hydrophobic PLA chain segment, and some insoluble medicines can be solubilized by utilizing the property of the copolymer material. However, the problems in the prior art are: firstly, as the end hydroxyl in the mPEG-PDLLA has certain hydrophilicity and is difficult to form stronger acting force with hydrophobic drugs, the micelle is influenced to encapsulate the drugs; secondly, the intermolecular force between the drug molecules and the hydrophobic chain of the copolymer is weak, so that the drug is easy to dissolve out in the core of the micelle; thirdly, the formed copolymer drug micelle has poor stability.
Disclosure of Invention
In order to solve the technical problems, the invention aims to provide an amphiphilic block copolymer, wherein the end hydroxyl of the tail end of mPEG-PDLLA is blocked by Boc-L-phenylalanine, so that acting force of a hydrophobic chain segment and a drug in the copolymer is increased, and the drug-loading micelle stability is improved.
In order to achieve the above purpose, the invention adopts the following technical scheme: an amphiphilic block copolymer, namely a tert-butyloxycarbonyl phenylalanine end-capped methoxy polyethylene glycol-poly (racemization lactide) block copolymer (called mPEG-PDLLA-Phe (Boc) for short), has the following structural general formula:
wherein m=44-45; n=6-12.
The molecular formula of the amphiphilic block copolymer is CH 3 O(C 2 H 4 O) m (C 6 O 4 H 8 ) n C 14 H 18 NO 4 The method comprises the steps of carrying out a first treatment on the surface of the The average molecular weight is 2600-6000, wherein the molecular weight of polyethylene glycol monomethyl ether section is 2000, and polylactic acid section is 800-4000.
A method for preparing an amphiphilic block copolymer, comprising the steps of:
1) Taking polyethylene glycol monomethyl ether (mPEG) and D, L-lactide, adding a catalyst stannous octoate, and carrying out melt polymerization reaction for 4-24 hours at 110-180 ℃ under the protection of nitrogen, pouring the obtained product into an organic solvent for crystallization, and drying to obtain an intermediate mPEG-PDLLA.
Preferably, the adding amount of the catalyst stannous octoate is 1-10 per mill of the weight of the D, L-lactide.
Preferably, the organic solvent is selected from one or more of absolute ethyl alcohol, dichloromethane, ethyl acetate, n-hexane and absolute ethyl ether.
2) And (3) dissolving Boc-L-phenylalanine in ethyl acetate, reacting with pivaloyl chloride in the presence of an acid binding agent, reacting for 5-48 hours at 0-50 ℃, filtering, and performing rotary evaporation to obtain tert-butoxycarbonyl-L-phenylalanine pivaloyl anhydride.
Preferably, the acid binding agent is selected from the group consisting of triethylamine, N-diisopropylethylamine, tripropylamine, pyridine, potassium carbonate, sodium carbonate and sodium hydroxide.
Preferably, the mole ratio of the tert-butoxycarbonyl-L-phenylalanine pivaloanhydride to the intermediate mPEG-PDLLA= (1-10) 1.
3) Taking the intermediate mPEG-PDLLA obtained in the step 1) and the tert-butoxycarbonyl-L-phenylalanine pivalic anhydride obtained in the step 2), adding triethylamine and 4-pyrrolidinyl pyridine into the solvent, and carrying out end-capping reaction at 0-5 ℃, and refining the obtained crude product by using an organic solvent to obtain the amphiphilic block copolymer.
Preferably, the organic solvent is selected from one or more than two of absolute ethyl alcohol, ethyl acetate, n-hexane, absolute ethyl ether and methyl tertiary butyl ether.
The synthetic process route is as follows:
the invention provides application of an amphiphilic block copolymer serving as a carrier in preparation of drug-loaded micelles.
The preparation method of the amphiphilic block copolymer drug-loaded micelle comprises the following steps: weighing the medicine and the amphiphilic block copolymer, dissolving in ethyl acetate, removing the ethyl acetate by rotary evaporation at 30 ℃, vacuum drying at 45 ℃, adding water, and hydrating at 45-50 ℃ and 200rpm to obtain medicine carrying micelle solution.
Preferably, the drug is selected from the group consisting of paclitaxel, docetaxel, cabazitaxel, methotrexate, 5-fluorouracil, cyclophosphamide, doxorubicin, epirubicin, and pirarubicin.
The beneficial effects of the invention are as follows:
1. according to the invention, the hydroxyl at the tail end of the mPEG-PDLLA is blocked by grafting hydrophobic Boc-L-phenylalanine, so that the hydrophobicity of a hydrophobic chain segment is increased, and the acting force of the hydrophobic chain segment and a drug in the copolymer is increased through blocking, so that the drug-coating capacity of a high polymer auxiliary material when a micelle is formed by a water phase is improved, and the stability of the drug-carrying micelle is improved. The stability is improved, so that the scale of the preparation is enlarged when the micelle is prepared by adopting a film hydration process, the quality of the product can be effectively controlled, and the EPR effect of the micelle in the body can be exerted, thereby improving the targeting property of the medicine and finally improving the medicine effect.
2. The invention has the advantages of no harsh process conditions, reasonable and effective process, reproducibility and reliability, and can ensure that the product quality meets the requirements.
3. The amphiphilic chimeric copolymer provided by the invention is mixed with an anti-tumor drug to prepare the micelle, so that the solubility of the anti-tumor drug is greatly improved, and the prepared micelle has small particle size, high encapsulation efficiency, good stability and good application prospect.
4. The invention improves the compatibility of the drug molecules and the hydrophobic chain segments in the segmented copolymer, and increases the intermolecular acting force of the drug molecules and the hydrophobic chain, so that the drug is not easy to dissolve in the core of the micelle.
5. According to the invention, boc-L-phenylalanine is introduced, a benzene ring in an introduced hydrophobic group and a benzene ring in a drug can generate molecular pi-pi conjugation, and an amide bond in Boc-L-phenylalanine can also form a hydrogen bond with a carbonyl in the drug, so that the acting force is favorable for limiting the drug in the core of the micelle, and the stability of the micelle is improved. And phenylalanine is taken as an amino acid necessary for human body, and has little influence on biocompatibility after being combined with the mPEG-PDLLA copolymer.
6. The amphiphilic block copolymer tert-butoxycarbonyl phenylalanine end-capped methoxy polyethylene glycol-poly racemized lactide block copolymer provided by the invention is a biodegradable material and has high biosafety.
Drawings
FIG. 1 is an amphiphilic block copolymer mPEG prepared in example 1 2000 -PDLLA 800 -nuclear magnetic hydrogen spectrum of Phe (Boc).
FIG. 2 is an amphiphilic block copolymer mPEG prepared in example 1 2000 -PDLLA 800 Molecular weight and molecular weight distribution System of Phe (Boc).
FIG. 3 is an implementationAmphiphilic Block copolymer mPEG prepared in example 1 2000 -PDLLA 800 -granularity map of Phe (Boc).
Detailed Description
The invention will be further illustrated with reference to the following specific examples; it is to be understood that these examples are illustrative of the present invention and are not intended to limit the scope of the present invention.
Example 1 amphiphilic Block copolymer mPEG 2000 -PDLLA 800 -Phe(Boc)
The preparation method comprises the following steps:
1. preparation of intermediate mPEG 2000 -PDLLA 800
10.0g of mPEG was weighed out 2000 In a 100mL polymerization reaction bottle, after dehydration for 3h under vacuum stirring at 130 ℃, 5.0g of D, L-lactide and 5mg of stannous octoate are added under the protection of nitrogen, the reaction vessel is closed under the vacuum degree of minus 0.095Mpa, reactants are stirred in an oil bath at 130 ℃ to carry out melt polymerization for 18h, and the reaction is stopped. Cooling to room temperature, adding 100mL of absolute ethanol for dissolution, cooling for crystallization, filtering to obtain white solid, and vacuum drying at room temperature for 24h to obtain 10.03g of intermediate mPEG 2000 -PDLLA 800 。
Nuclear magnetism calculation mPEG 2000 -PDLLA 800 Molecular weight 2839, gel permeation chromatography (Gel Permeation Chromatography, GPC) to determine mPEG 2000 -PDLLA 800 The number average molecular weight and the molecular weight distribution coefficient of (2) were 4088 and 1.11, respectively.
2. Preparation of Boc-L-phenylalanine pivaloanhydride
Into a 100mL three-necked round bottom flask, boc-L-phenylalanine/anhydrous ethyl acetate solution (2.16 g of Boc-L-phenylalanine was dissolved in 20mL of anhydrous ethyl acetate) and 0.83g of triethylamine were added, and after stirring and dissolution, the mixture was cooled to-10 to 0 ℃. Dripping 1.0g of pivaloyl chloride, stirring at 0-10 ℃ for 2h, continuing stirring at room temperature for 1h, filtering to remove insoluble substances, decompressing the filtrate at 35-40 ℃ and removing the solvent by rotary evaporation at-0.09 MPa to obtain white solid which is tert-butoxycarbonyl-L-phenylalanine pivaloanhydride (Boc-Phe-OCOC (CH) 3 ) 3 )。
3. Capping reactions
5.33g mPEG was added to a 100mL three neck round bottom flask 2000 -PDLLA 800 And 60mL of methylene chloride, and after stirring and dissolving, boc-Phe-OCOC (CH) obtained in step 2 was added 3 ) 3 The system was cooled to 0-5 ℃, 1.35g of triethylamine and 0.20g of 4-pyrrolidinylpyridine were added, the resulting mixture was stirred at 0-5 ℃ for 1 hour, then the reaction was continued at room temperature for 24 hours, the solvent was removed by rotary evaporation under reduced pressure, and the obtained polymer was mPEG-PDLLA-Phe (Boc) crude product.
Adding 25mL of absolute ethyl alcohol into the obtained crude product for dissolution, freezing and crystallizing at the temperature of minus 10 ℃ for filtration, adding 25mL of absolute ethyl alcohol for dissolution, freezing and crystallizing at the temperature of minus 10 ℃ for filtration, and vacuum drying the obtained filter cake for 24 hours at room temperature to obtain 3.77g of white solid, namely the amphiphilic block copolymer mPEG 2000 -PDLLA 800 Phe (Boc) finished product.
Nuclear magnetism calculation mPEG 2000 -PDLLA 800 Phe (Boc) molecular weight 3122, mPEG determined by GPC 2000 -PDLLA 800 Phe (Boc) has a number average molecular weight and a molecular weight distribution coefficient of 4445 and 1.09, respectively.
(II) characterization
The nuclear magnetic spectrum is shown in FIG. 1, H1-NMR (DCCl 3 )：1.38-1.41(-C-CH 3 )，1.55-1.56(CH-CH 3 )，3.38(0-CH 3 )，3.55-3.76(O-CH 2 -C)；4.26-4.30(O-CH 2 CH 2 -O)；5.16-5.22(O＝C-CH(C)-O)7.16-7.28(≡CH)。
GPC chart is shown in FIG. 2, and the detection results are as follows: mp=4628, mn=4445, mw=4827, mz=5268, mz+1:5791, pdi=1.09.
The granularity diagram is shown in fig. 3, and the detection result is as follows: average particle size=20.1 nm, dispersion coefficient pdi=0.142, d50=18.7nm, d90=30.4 nm.
Example 2 amphiphilic Block copolymer mPEG 2000 -PDLLA 1200 -Phe(Boc)
The preparation method comprises the following steps:
1. preparation of intermediate mPEG 2000 -PDLLA 1200
8.50g mPEG was weighed out 2000 Polymerization reaction at 100mLIn a flask, after vacuum stirring and dehydration for 3h at 130 ℃, 6.80g of D, L-lactide and 7mg of stannous octoate are added under the protection of nitrogen, a reaction vessel is closed under the vacuum degree of minus 0.095Mpa, reactants are stirred in an oil bath at 130 ℃ and are subjected to melt polymerization for 18h, and the reaction is stopped. Cooling to room temperature, adding 85mL absolute ethanol for dissolution, cooling for crystallization, filtering to obtain white solid, and vacuum drying at room temperature for 24h to obtain 9.91g intermediate mPEG 2000 -PDLLA 1200 。
Nuclear magnetism calculation mPEG 2000 -PDLLA 1200 Molecular weight 3186, mPEG by GPC 2000 -PDLLA 1200 The number average molecular weight and the molecular weight distribution coefficient of (2) were 4608 and 1.09, respectively.
2. Preparation of Boc-L-phenylalanine pivaloanhydride
Into a 100mL three-necked round bottom flask, boc-L-phenylalanine/anhydrous ethyl acetate solution (3.04 g of Boc-L-phenylalanine was dissolved in 20mL of anhydrous ethyl acetate) and 1.16g of triethylamine were added, followed by stirring and dissolution, and then cooling to-10 to 0 ℃. Dripping 1.39g of pivaloyl chloride, stirring at 0-10 ℃ for 2h, continuing stirring at room temperature for 1h, filtering to remove insoluble substances, decompressing the filtrate at 35-40 ℃ and removing the solvent by rotary evaporation at-0.09 MPa to obtain white solid which is tert-butoxycarbonyl-L-phenylalanine pivaloanhydride (Boc-Phe-OCOC (CH) 3 ) 3 )。
3. Capping reactions
9.20g mPEG was added to a 100mL three neck round bottom flask 2000 -PDLLA 1200 And 50mL of methylene chloride, and after stirring and dissolving, boc-Phe-OCOC (CH) obtained in step 2 was added 3 ) 3 The system was cooled to 0-5 ℃, 1.16g of triethylamine and 0.20g of 4-pyrrolidinylpyridine were added, the resulting mixture was stirred at 0-5 ℃ for 1 hour, then the stirring reaction was continued at room temperature for 24 hours, the solvent was removed by rotary evaporation under reduced pressure, and the obtained polymer was mPEG-PDLLA-Phe (Boc) crude product.
Adding 75mL of absolute ethyl alcohol into the obtained crude product for dissolution, freezing and crystallizing at the temperature of minus 10 ℃ for filtration, adding 75mL of absolute ethyl alcohol for dissolution, freezing and crystallizing at the temperature of minus 10 ℃ for filtration, and vacuum drying the obtained filter cake for 24 hours at room temperature to obtain 9.10g of white solid which is the amphiphileSex block copolymer mPEG 2000 -PDLLA 1200 Phe (Boc) finished product.
Nuclear magnetism calculation mPEG 2000 -PDLLA 1200 Phe (Boc) molecular weight 3433, mPEG determined by GPC 2000 -PDLLA 1200 Phe (Boc) has a number average molecular weight and a molecular weight distribution coefficient of 4825 and 1.09, respectively.
Example 3 amphiphilic Block copolymer mPEG 2000 -PDLLA 1500 -Phe(Boc)
The preparation method comprises the following steps:
1. preparation of intermediate mPEG 2000 -PDLLA 1500
10.0g of mPEG was weighed out 2000 In a 100mL polymerization reaction bottle, after dehydration for 3h under vacuum stirring at 130 ℃, 11.0g of D, L-lactide and 11mg of stannous octoate are added under the protection of nitrogen, the reaction vessel is closed under the vacuum degree of minus 0.095Mpa, reactants are stirred in an oil bath at 130 ℃ to carry out melt polymerization for 18h, and the reaction is stopped. Cooling to room temperature, adding 100mL of absolute ethanol for dissolution, cooling for crystallization, filtering to obtain white solid, and vacuum drying at room temperature for 24h to obtain 12.38g of intermediate mPEG 2000 -PDLLA 1500 。
Nuclear magnetism calculation mPEG 2000 -PDLLA 1500 Molecular weight 3491, mPEG by GPC 2000 -PDLLA 1500 Phe (Boc) has a number average molecular weight and a molecular weight distribution coefficient of 4460 and 1.10, respectively.
2. Preparation of Boc-L-phenylalanine pivaloanhydride
A100 mL three-necked round bottom flask was charged with a Boc-L-phenylalanine/anhydrous ethyl acetate solution (2.16 g of Boc-L-phenylalanine was dissolved in 20mL of anhydrous ethyl acetate) and 0.83g of triethylamine, and after stirring and dissolution, the mixture was cooled to-10 to 0 ℃. Dripping 1.0g of pivaloyl chloride, stirring at 0-10 ℃ for 2h, continuing stirring at room temperature for 1h, filtering to remove insoluble substances, decompressing the filtrate at 35-40 ℃ and removing the solvent by rotary evaporation at-0.09 MPa to obtain white solid which is tert-butoxycarbonyl-L-phenylalanine pivaloanhydride (Boc-Phe-OCOC (CH) 3 ) 3 )。
3. Capping reactions
In a 100mL three-necked round bottom flask, addInto 5.0g mPEG 2000 -PDLLA 1500 And 50mL of methylene chloride, and after stirring and dissolving, boc-Phe-OCOC (CH) obtained in step 2 was added 3 ) 3 The system was cooled to 0-5 ℃, 0.63g of triethylamine and 0.093g of 4-pyrrolidinylpyridine were added, the resulting mixture was stirred at 0-5 ℃ for 1 hour, then the reaction was continued at room temperature for 24 hours, the solvent was removed by rotary evaporation under reduced pressure, and the obtained polymer was mPEG-PDLLA-Phe (Boc) crude product.
Adding 50mL of absolute ethyl alcohol into the obtained crude product for dissolution, freezing and crystallizing at the temperature of minus 10 ℃ for filtration, adding 50mL of absolute ethyl alcohol for dissolution, freezing and crystallizing at the temperature of minus 10 ℃ for filtration, and vacuum drying the obtained filter cake for 24 hours at room temperature to obtain 4.72g of white solid, namely the amphiphilic block copolymer mPEG 2000 -PDLLA 1500 Phe (Boc) finished product.
Nuclear magnetism calculation mPEG 2000 -PDLLA 1500 Phe (Boc) molecular weight 3845, mPEG determined by GPC 2000 -PDLLA 1500 Phe (Boc) has a number average molecular weight and a molecular weight distribution coefficient of 4896 and 1.07, respectively.
Example 4 amphiphilic Block copolymer mPEG 2000 -PDLLA 1700 -Phe(Boc)
The preparation method comprises the following steps:
1. preparation of intermediate mPEG 2000 -PDLLA 1700
10.0g of mPEG was weighed out 2000 In a 100mL polymerization reaction bottle, after dehydration for 3h under vacuum stirring at 130 ℃, 12.0g of D, L-lactide and 12mg of stannous octoate are added under the protection of nitrogen, a reaction vessel is closed under the vacuum degree of minus 0.095Mpa, reactants are stirred in an oil bath at 130 ℃ to carry out melt polymerization for 18h, and the reaction is stopped. Cooling to room temperature, adding 100mL of absolute ethanol for dissolution, cooling for crystallization, filtering to obtain white solid, and vacuum drying at room temperature for 24h to obtain 3.1g of intermediate mPEG 2000 -PDLLA 1700 The yield thereof was found to be 59.61%.
Nuclear magnetism calculation mPEG 2000 -PDLLA 1700 Molecular weight 3654, mPEG by GPC 2000 -PDLLA 1700 The number average molecular weight and the molecular weight distribution coefficient of (a) were 4710 and 1.09, respectively.
2. Preparation of Boc-L-phenylalanine pivaloanhydride
A100 mL three-necked round bottom flask was charged with a Boc-L-phenylalanine/anhydrous ethyl acetate solution (2.16 g of Boc-L-phenylalanine was dissolved in 20mL of anhydrous ethyl acetate) and 0.83g of triethylamine, and after stirring and dissolution, the mixture was cooled to-10 to 0 ℃. Dripping 1.0g of pivaloyl chloride, stirring at 0-10 ℃ for 2h, continuing stirring at room temperature for 1h, filtering to remove insoluble substances, decompressing the filtrate at 35-40 ℃ and removing the solvent by rotary evaporation at-0.09 MPa to obtain white solid which is tert-butoxycarbonyl-L-phenylalanine pivaloanhydride (Boc-Phe-OCOC (CH) 3 ) 3 )。
3. Capping reactions
5.01g mPEG was added to a 100mL three neck round bottom flask 2000 -PDLLA 1700 And 50mL of methylene chloride, and after stirring and dissolving, boc-Phe-OCOC (CH) obtained in step 2 was added 3 ) 3 The system was cooled to 0-5 ℃, 0.63g of triethylamine and 0.093g of 4-pyrrolidinylpyridine were added, the resulting mixture was stirred at 0-5 ℃ for 1 hour, then the reaction was continued at room temperature for 24 hours, the solvent was removed by rotary evaporation under reduced pressure, and the obtained polymer was mPEG-PDLLA-Phe (Boc) crude product.
Adding 50mL of absolute ethyl alcohol into the obtained crude product for dissolution, freezing and crystallizing at the temperature of minus 10 ℃ for filtration, adding 50mL of absolute ethyl alcohol for dissolution, freezing and crystallizing at the temperature of minus 10 ℃ for filtration, and vacuum drying the obtained filter cake for 24 hours at room temperature to obtain 4.53g of white solid, namely the amphiphilic block copolymer mPEG 2000 -PDLLA 1700 Phe (Boc) finished product.
Nuclear magnetism calculation mPEG 2000 -PDLLA 1700 Phe (Boc) molecular weight 4078, mPEG by GPC 2000 -PDLLA 1700 Phe (Boc) has a number average molecular weight and a molecular weight distribution coefficient of 5208 and 1.07, respectively.
Example 5 amphiphilic Block copolymer mPEG 2000 -PDLLA 2600 -Phe(Boc)
The preparation method comprises the following steps:
1. preparation of intermediate mPEG 2000 -PDLLA 2600
Weigh 5.0g mPEG 2000 In a 100mL polymerization flask, inAfter vacuum stirring and dehydration for 3h at 130 ℃, 10.3g of D, L-lactide and 10mg of stannous octoate are added under the protection of nitrogen, a reaction vessel is closed under the vacuum degree of minus 0.095Mpa, reactants are stirred in an oil bath at 130 ℃ for melt polymerization for 18h, and the reaction is stopped. Cooling to room temperature, adding 100mL of absolute ethanol for dissolution, cooling for crystallization, filtering to obtain white solid, and vacuum drying at room temperature for 22h to obtain 11.4g of intermediate mPEG 2000 -PDLLA 2600 The yield thereof was found to be 74.53%.
Nuclear magnetism calculation mPEG 2000 -PDLLA 2600 Molecular weight 4656, GPC measurement mPEG 2000 -PDLLA 2600 The number average molecular weight and the molecular weight distribution coefficient of (3) were 5606 and 1.09, respectively.
2. Preparation of Boc-L-phenylalanine pivaloanhydride
A100 mL three-necked round bottom flask was charged with a Boc-L-phenylalanine/anhydrous ethyl acetate solution (2.16 g of Boc-L-phenylalanine was dissolved in 20mL of anhydrous ethyl acetate) and 0.83g of triethylamine, and after stirring and dissolution, the mixture was cooled to-10 to 0 ℃. Dripping 1.0g of pivaloyl chloride, stirring at 0-10 ℃ for 2h, continuing stirring at room temperature for 1h, filtering to remove insoluble substances, decompressing the filtrate at 35-40 ℃ and removing the solvent by rotary evaporation at-0.09 MPa to obtain white solid which is tert-butoxycarbonyl-L-phenylalanine pivaloanhydride (Boc-Phe-OCOC (CH) 3 ) 3 )。
3. Capping reactions
5.01g mPEG was added to a 100mL three neck round bottom flask 2000 -PDLLA 2600 And 50mL of methylene chloride, and after stirring and dissolving, boc-Phe-OCOC (CH) obtained in step 2 was added 3 ) 3 The system was cooled to 0-5 ℃, 0.63g of triethylamine and 0.09g of 4-pyrrolidinylpyridine were added, the resulting mixture was stirred at 0-5 ℃ for 1 hour, then the stirring reaction was continued at room temperature for 24 hours, the solvent was removed by rotary evaporation under reduced pressure, and the obtained polymer was mPEG-PDLLA-Phe (Boc) crude product.
Adding 50mL of absolute ethyl alcohol into the obtained crude product for dissolution, freezing and crystallizing at the temperature of minus 10 ℃ for filtration, adding 50mL of absolute ethyl alcohol for dissolution, freezing and crystallizing at the temperature of minus 10 ℃ for filtration, and vacuum drying the obtained filter cake for 24 hours at room temperature to obtain 4.78g of white solid which is the amphiphileSex block copolymer mPEG 2000 -PDLLA 2600 Phe (Boc) finished product.
Nuclear magnetism calculation mPEG 2000 -PDLLA 2600 Phe (Boc) molecular weight 4926, mPEG by GPC 2000 -PDLLA 2600 Phe (Boc) has a number average molecular weight and a molecular weight distribution coefficient of 6059 and 1.06, respectively.
Example 6 amphiphilic Block copolymer drug-loaded micelle
The preparation method comprises the following steps:
weighing 0.25g of paclitaxel and 1.25g of mPEG prepared in example 2 2000 -PDLLA 1200 After 50mL of ethyl acetate was added and stirred to dissolve completely, ethyl acetate was removed by rotary evaporation at 30℃for 30min, the vacuum was opened to the minimum, dried at 45℃for 2h under vacuum, 35mL of water was added, and hydrated at 200rpm at 45℃for 4.5min to give a drug-loaded micelle solution, the results of which are shown in Table 1.
Example 7 amphiphilic Block copolymer drug-loaded micelle
The preparation method comprises the following steps:
weighing 0.25g of paclitaxel and 1.25g of mPEG prepared in example 1 2000 -PDLLA 800 Phe (Boc), 50mL of ethyl acetate was added and stirred to dissolve completely, the ethyl acetate was removed by rotary evaporation at 30℃and the vacuum was opened to the minimum after 30min, dried at 45℃for 2h under vacuum, 50mL of water was added and hydrated at 200rpm for 5.5min at 50℃to give drug-loaded micelle solutions, the results of which are shown in Table 1.
Example 8 amphiphilic Block copolymer drug-loaded micelle
The preparation method comprises the following steps:
weighing 0.25g of paclitaxel and 1.25g of mPEG prepared in example 2 2000 -PDLLA 1200 Phe (Boc), 50mL of ethyl acetate was added and stirred to dissolve completely, the ethyl acetate was removed by rotary evaporation at 30℃and the vacuum was opened to the minimum after 30min, dried in vacuo at 45℃for 2h, 50mL of water was added and hydrated at 200rpm for 4.5min at 50℃to give drug-loaded micelle solutions, the results of which are shown in Table 1.
Example 9 amphiphilic Block copolymer drug-loaded micelle
The preparation method comprises the following steps:
weighing 0.25g of paclitaxel and 1.25g of example3 mPEG prepared 2000 -PDLLA 1500 Phe (Boc), 50mL of ethyl acetate was added and stirred to dissolve completely, the ethyl acetate was removed by rotary evaporation at 30℃and the vacuum was opened to the minimum after 30min, dried in vacuo at 45℃for 2h, 50mL of water was added and hydrated at 200rpm at 50℃for 21min to give a drug-loaded micelle solution, the results of which are shown in Table 1.
Example 10 amphiphilic Block copolymer drug-loaded micelle
The preparation method comprises the following steps:
0.25g of paclitaxel and 1.25g of mPEG prepared in example 4 were weighed out 2000 -PDLLA 1700 Phe (Boc), 50mL of ethyl acetate was added and stirred to dissolve completely, the ethyl acetate was removed by rotary evaporation at 30℃and the vacuum was opened to the minimum after 30min, dried in vacuo at 45℃for 2h, 50mL of water was added and hydrated at 200rpm at 50℃for 47min to give a drug-loaded micelle solution, the results of which are shown in Table 1.
Example 11 amphiphilic Block copolymer drug-loaded micelle
The preparation method comprises the following steps:
weighing 0.25g of paclitaxel and 1.25g of mPEG prepared in example 5 2000 -PDLLA 2600 Phe (Boc), 50mL of ethyl acetate was added and stirred to dissolve completely, the ethyl acetate was removed by rotary evaporation at 30℃for 30min, the vacuum was opened to the minimum, dried at 45℃for 2h under vacuum, 50mL of water was added and hydrated at 200rpm for 70min at 50℃to give a drug-loaded micelle solution, the hydration of this example was incomplete for 70min, and the hydration was too poor and left unset, the results of which are shown in Table 1.
TABLE 1 particle size and drug loading detection results
Table 1 is summarized below:
(1) As can be seen from comparison of example 6 and example 8, the micelle prepared by using the capping auxiliary material mPEG-PDLLA-Phe (Boc) in example 8 has no obvious change in particle size distribution, encapsulation efficiency and drug loading within 24 hours at 37 ℃; in example 6, the micelle prepared by using the non-end-capping auxiliary material mPEG-PDLLA has obviously changed particle size distribution after being placed at 37 ℃ for 8 hours, which is shown by obviously increased PDI, widened characterization particle size distribution range and reduced particle uniformity. Therefore, the micelle prepared from the polymer auxiliary material mPEG-PDLLA-Phe (Boc) subjected to end capping treatment has better stability.
(2) From examples 7 to 11, when the molecular weight of mPEG-PDLLA-Phe (Boc) is 3100-3900, the prepared drug-loaded micelle has the advantages of narrow particle size distribution range, high encapsulation efficiency and relatively short hydration time, and the particle size distribution, encapsulation efficiency and drug loading capacity are basically unchanged after the drug-loaded micelle is placed at 37 ℃ for 24 hours, thus showing that the formed micelle has better stability; the hydration time is longer when the molecular weight is more than 4000, and the micelle stability is poor.
Claims (10)
1. The amphiphilic block copolymer is characterized by being a tert-butyloxycarbonyl phenylalanine end-capped methoxy polyethylene glycol-poly (racemization lactide) block copolymer, and has a structural general formula shown in (I):
wherein m=44-45; n=6-12.
2. The method for preparing the amphiphilic block copolymer as claimed in claim 1, wherein the method comprises the following steps:
1) Taking polyethylene glycol monomethyl ether and D, L-lactide, adding a catalyst stannous octoate, carrying out melt polymerization reaction for 4-24 hours at 110-180 ℃ under the protection of nitrogen, pouring the obtained product into an organic solvent for crystallization, and drying to obtain an intermediate mPEG-PDLLA;
2) Dissolving Boc-L-phenylalanine in ethyl acetate, reacting with pivaloyl chloride in the presence of an acid binding agent, reacting for 5-48 hours at 0-50 ℃, filtering, and performing rotary evaporation to obtain tert-butoxycarbonyl-L-phenylalanine pivaloyl anhydride;
3) Taking the intermediate mPEG-PDLLA obtained in the step 1) and the tert-butoxycarbonyl-L-phenylalanine pivalic anhydride obtained in the step 2), adding triethylamine and 4-pyrrolidinyl pyridine into the solvent, and carrying out end-capping reaction at 0-5 ℃, and refining the obtained crude product by using an organic solvent to obtain the amphiphilic block copolymer.
3. The preparation method according to claim 2, wherein in the step 1), the stannous octoate is added in an amount of 1 to 10% by weight of D, L-lactide.
4. The method according to claim 2, wherein in step 1), the organic solvent is selected from one or a mixture of two or more of absolute ethyl alcohol, methylene chloride, ethyl acetate, n-hexane and absolute ethyl ether.
5. The method according to claim 2, wherein in step 2), the acid-binding agent is selected from the group consisting of triethylamine, N-diisopropylethylamine, tripropylamine, pyridine, potassium carbonate, sodium carbonate and sodium hydroxide.
6. The preparation method according to claim 2, wherein in the step 2), t-butoxycarbonyl-L-phenylalanine pivalic anhydride is an intermediate mPEG-PDLLA= (1-10): 1 in a molar ratio.
7. The method according to claim 2, wherein in step 3), the organic solvent is selected from one or more of absolute ethyl alcohol, ethyl acetate, n-hexane, absolute ethyl ether and methyl t-butyl ether.
8. The use of an amphiphilic block copolymer according to claim 1 as a carrier in the preparation of drug-loaded micelles.
9. The preparation method of the amphiphilic block copolymer drug-loaded micelle is characterized by comprising the following steps of: weighing the medicine and the amphiphilic block copolymer as claimed in claim 1, dissolving in ethyl acetate, removing the ethyl acetate by rotary evaporation at 30 ℃, drying in vacuum at 45 ℃, adding water, and hydrating at 45-50 ℃ and 200rpm to obtain a medicine carrying micelle solution.
10. The amphiphilic block copolymer drug-loaded micelle of claim 9, wherein the drug is selected from paclitaxel, docetaxel, cabazitaxel, methotrexate, 5-fluorouracil, cyclophosphamide, doxorubicin, epirubicin, and pirarubicin.
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