CN114634632B - Thermosensitive block copolymer hydrogel and preparation method and application thereof - Google Patents
Thermosensitive block copolymer hydrogel and preparation method and application thereof Download PDFInfo
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- CN114634632B CN114634632B CN202210280181.2A CN202210280181A CN114634632B CN 114634632 B CN114634632 B CN 114634632B CN 202210280181 A CN202210280181 A CN 202210280181A CN 114634632 B CN114634632 B CN 114634632B
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- block copolymer
- block
- groups
- copolymer
- polyethylene glycol
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- 229920001400 block copolymer Polymers 0.000 title claims abstract description 111
- 239000000017 hydrogel Substances 0.000 title claims abstract description 68
- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- 229920001223 polyethylene glycol Polymers 0.000 claims abstract description 80
- 239000002202 Polyethylene glycol Substances 0.000 claims abstract description 56
- 229920000728 polyester Polymers 0.000 claims abstract description 42
- YCIMNLLNPGFGHC-UHFFFAOYSA-N catechol Chemical group OC1=CC=CC=C1O YCIMNLLNPGFGHC-UHFFFAOYSA-N 0.000 claims abstract description 36
- 125000000524 functional group Chemical group 0.000 claims abstract description 31
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 30
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 19
- 230000002209 hydrophobic effect Effects 0.000 claims abstract description 18
- 238000005859 coupling reaction Methods 0.000 claims abstract description 11
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 10
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims abstract description 9
- 238000005886 esterification reaction Methods 0.000 claims abstract description 7
- 229920001577 copolymer Polymers 0.000 claims description 62
- 239000002904 solvent Substances 0.000 claims description 17
- 238000000034 method Methods 0.000 claims description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 9
- 239000000178 monomer Substances 0.000 claims description 8
- NIXOWILDQLNWCW-UHFFFAOYSA-M acrylate group Chemical group C(C=C)(=O)[O-] NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 claims description 6
- 238000012377 drug delivery Methods 0.000 claims description 6
- 150000002148 esters Chemical class 0.000 claims description 6
- 238000007151 ring opening polymerisation reaction Methods 0.000 claims description 6
- 230000008878 coupling Effects 0.000 claims description 5
- 238000010168 coupling process Methods 0.000 claims description 5
- 239000003999 initiator Substances 0.000 claims description 5
- 230000000977 initiatory effect Effects 0.000 claims description 5
- 238000002156 mixing Methods 0.000 claims description 5
- OZJPLYNZGCXSJM-UHFFFAOYSA-N 5-valerolactone Chemical class O=C1CCCCO1 OZJPLYNZGCXSJM-UHFFFAOYSA-N 0.000 claims description 4
- 239000003054 catalyst Substances 0.000 claims description 4
- 238000006555 catalytic reaction Methods 0.000 claims description 4
- 150000005846 sugar alcohols Polymers 0.000 claims description 4
- 238000012719 thermal polymerization Methods 0.000 claims description 4
- 239000007822 coupling agent Substances 0.000 claims description 3
- 230000023597 hemostasis Effects 0.000 claims description 3
- 230000037314 wound repair Effects 0.000 claims description 3
- 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 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Polymers OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 claims description 2
- 229920000954 Polyglycolide Polymers 0.000 claims description 2
- 229920001710 Polyorthoester Polymers 0.000 claims description 2
- 239000004721 Polyphenylene oxide Chemical class 0.000 claims description 2
- 229920001432 poly(L-lactide) Polymers 0.000 claims description 2
- 239000002745 poly(ortho ester) Substances 0.000 claims description 2
- 229920000058 polyacrylate Chemical class 0.000 claims description 2
- 229920001610 polycaprolactone Polymers 0.000 claims description 2
- 229920000515 polycarbonate Chemical class 0.000 claims description 2
- 239000004417 polycarbonate Chemical class 0.000 claims description 2
- 229920006149 polyester-amide block copolymer Chemical class 0.000 claims description 2
- 229920000570 polyether Chemical class 0.000 claims description 2
- PAPBSGBWRJIAAV-UHFFFAOYSA-N ε-Caprolactone Chemical class O=C1CCCCCO1 PAPBSGBWRJIAAV-UHFFFAOYSA-N 0.000 claims description 2
- 229940079593 drug Drugs 0.000 abstract description 10
- 239000003814 drug Substances 0.000 abstract description 10
- 208000031737 Tissue Adhesions Diseases 0.000 abstract description 7
- 239000011159 matrix material Substances 0.000 abstract description 4
- 125000003636 chemical group Chemical group 0.000 abstract description 3
- 238000007385 chemical modification Methods 0.000 abstract description 3
- 238000007306 functionalization reaction Methods 0.000 abstract description 2
- 239000002861 polymer material Substances 0.000 abstract description 2
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 abstract description 2
- 238000003384 imaging method Methods 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 87
- 239000000243 solution Substances 0.000 description 65
- 229920000747 poly(lactic acid) Polymers 0.000 description 40
- 238000006243 chemical reaction Methods 0.000 description 39
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- 229920000642 polymer Polymers 0.000 description 39
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 33
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 30
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 29
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 26
- 230000004048 modification Effects 0.000 description 18
- 238000012986 modification Methods 0.000 description 18
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 16
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- 238000002390 rotary evaporation Methods 0.000 description 13
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 12
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 12
- 238000003756 stirring Methods 0.000 description 12
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 11
- 230000008859 change Effects 0.000 description 10
- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 description 10
- NXLNNXIXOYSCMB-UHFFFAOYSA-N (4-nitrophenyl) carbonochloridate Chemical compound [O-][N+](=O)C1=CC=C(OC(Cl)=O)C=C1 NXLNNXIXOYSCMB-UHFFFAOYSA-N 0.000 description 9
- 238000000518 rheometry Methods 0.000 description 9
- 229910052786 argon Inorganic materials 0.000 description 8
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- 230000018044 dehydration Effects 0.000 description 8
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- 238000003760 magnetic stirring Methods 0.000 description 8
- JJTUDXZGHPGLLC-UHFFFAOYSA-N lactide Chemical compound CC1OC(=O)C(C)OC1=O JJTUDXZGHPGLLC-UHFFFAOYSA-N 0.000 description 7
- 239000000693 micelle Substances 0.000 description 7
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- 230000036760 body temperature Effects 0.000 description 6
- 239000008055 phosphate buffer solution Substances 0.000 description 6
- 230000007704 transition Effects 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 239000012300 argon atmosphere Substances 0.000 description 5
- 238000001727 in vivo Methods 0.000 description 5
- 238000000520 microinjection Methods 0.000 description 5
- 238000001248 thermal gelation Methods 0.000 description 5
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 230000009286 beneficial effect Effects 0.000 description 4
- 239000012267 brine Substances 0.000 description 4
- 230000015556 catabolic process Effects 0.000 description 4
- 238000006731 degradation reaction Methods 0.000 description 4
- 238000000502 dialysis Methods 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 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 description 4
- 210000001519 tissue Anatomy 0.000 description 4
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 3
- CTENFNNZBMHDDG-UHFFFAOYSA-N Dopamine hydrochloride Chemical compound Cl.NCCC1=CC=C(O)C(O)=C1 CTENFNNZBMHDDG-UHFFFAOYSA-N 0.000 description 3
- 229920000469 amphiphilic block copolymer Polymers 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 239000008367 deionised water Substances 0.000 description 3
- 229910021641 deionized water Inorganic materials 0.000 description 3
- 229960001149 dopamine hydrochloride Drugs 0.000 description 3
- 230000036571 hydration Effects 0.000 description 3
- 238000006703 hydration reaction Methods 0.000 description 3
- 229910052740 iodine Inorganic materials 0.000 description 3
- 239000011630 iodine Substances 0.000 description 3
- WXZMFSXDPGVJKK-UHFFFAOYSA-N pentaerythritol Chemical compound OCC(CO)(CO)CO WXZMFSXDPGVJKK-UHFFFAOYSA-N 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 150000005206 1,2-dihydroxybenzenes Chemical class 0.000 description 2
- FALRKNHUBBKYCC-UHFFFAOYSA-N 2-(chloromethyl)pyridine-3-carbonitrile Chemical compound ClCC1=NC=CC=C1C#N FALRKNHUBBKYCC-UHFFFAOYSA-N 0.000 description 2
- 101100083853 Homo sapiens POU2F3 gene Proteins 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- 101100058850 Oryza sativa subsp. japonica CYP78A11 gene Proteins 0.000 description 2
- 101150059175 PLA1 gene Proteins 0.000 description 2
- 102100026466 POU domain, class 2, transcription factor 3 Human genes 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 239000010839 body fluid Substances 0.000 description 2
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- 238000005227 gel permeation chromatography Methods 0.000 description 2
- VANNPISTIUFMLH-UHFFFAOYSA-N glutaric anhydride Chemical compound O=C1CCCC(=O)O1 VANNPISTIUFMLH-UHFFFAOYSA-N 0.000 description 2
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- 238000006116 polymerization reaction Methods 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
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- 238000013268 sustained release Methods 0.000 description 2
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- MHSGOABISYIYKP-UHFFFAOYSA-N (4-nitrophenyl)methyl carbonochloridate Chemical compound [O-][N+](=O)C1=CC=C(COC(Cl)=O)C=C1 MHSGOABISYIYKP-UHFFFAOYSA-N 0.000 description 1
- ZMZGFLUUZLELNE-UHFFFAOYSA-N 2,3,5-triiodobenzoic acid Chemical compound OC(=O)C1=CC(I)=CC(I)=C1I ZMZGFLUUZLELNE-UHFFFAOYSA-N 0.000 description 1
- DZAUWHJDUNRCTF-UHFFFAOYSA-N 3-(3,4-dihydroxyphenyl)propanoic acid Chemical compound OC(=O)CCC1=CC=C(O)C(O)=C1 DZAUWHJDUNRCTF-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
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- TUCIXUDAQRPDCG-UHFFFAOYSA-N benzene-1,2-diol Chemical group OC1=CC=CC=C1O.OC1=CC=CC=C1O TUCIXUDAQRPDCG-UHFFFAOYSA-N 0.000 description 1
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- 125000000896 monocarboxylic acid group Chemical group 0.000 description 1
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- PYWVYCXTNDRMGF-UHFFFAOYSA-N rhodamine B Chemical compound [Cl-].C=12C=CC(=[N+](CC)CC)C=C2OC2=CC(N(CC)CC)=CC=C2C=1C1=CC=CC=C1C(O)=O PYWVYCXTNDRMGF-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
- C08J3/00—Processes of treating or compounding macromolecular substances
- C08J3/02—Making solutions, dispersions, lattices or gels by other methods than by solution, emulsion or suspension polymerisation techniques
- C08J3/03—Making solutions, dispersions, lattices or gels by other methods than by solution, emulsion or suspension polymerisation techniques in aqueous media
- C08J3/075—Macromolecular gels
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- 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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- A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
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- A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
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- A61L26/0061—Use of materials characterised by their function or physical properties
- A61L26/008—Hydrogels or hydrocolloids
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- A—HUMAN NECESSITIES
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- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
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- A61L27/18—Macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
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- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
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- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L27/52—Hydrogels or hydrocolloids
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- 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
- C08G81/00—Macromolecular compounds obtained by interreacting polymers in the absence of monomers, e.g. block polymers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
- A61L2300/412—Tissue-regenerating or healing or proliferative agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
- A61L2300/418—Agents promoting blood coagulation, blood-clotting agents, embolising agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2400/00—Materials characterised by their function or physical properties
- A61L2400/04—Materials for stopping bleeding
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2400/00—Materials characterised by their function or physical properties
- A61L2400/06—Flowable or injectable implant compositions
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
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- C08J2387/00—Characterised by the use of unspecified macromolecular compounds, obtained otherwise than by polymerisation reactions only involving unsaturated carbon-to-carbon bonds
Abstract
The application belongs to the technical field of high polymer materials and medicines, and particularly relates to a thermosensitive block copolymer hydrogel and a preparation method and application thereof. The hydrophobic polyester block in the thermosensitive block copolymer hydrogel disclosed by the application is positioned in the middle of the block copolymer, the hydrophilic polyethylene glycol block is positioned at the outer side of the block copolymer, and the terminal groups are active chemical groups such as hydroxyl, carboxyl or amino, so that the functional groups can be contacted with each other or the functional groups can be contacted with an external matrix. And the free hydroxyl, carboxyl or amino and other active groups at the tail end of the polyethylene glycol block can be used for further chemical modification. Further, functional groups such as propylene double bond, catechol group, phenol group and the like are modified at the terminal active groups of the block copolymer through esterification reaction or coupling reaction to obtain the block copolymer with the hydrophilic terminal modified by functionalization, so that the temperature-sensitive hydrogel tissue adhesion performance, the stronger mechanical strength and the imaging capability are provided.
Description
Technical Field
The application belongs to the technical field of high polymer materials and medicines, and particularly relates to a thermosensitive block copolymer hydrogel and a preparation method and application thereof.
Background
The injectable thermotropic hydrogel formed by the polyethylene glycol/polyester segmented copolymer has good application potential in the aspects of drug delivery, tissue repair, medical contrast, auxiliary surgery and the like due to the advantages of good biocompatibility, adjustable biodegradability, convenient injectability and the like.
While polyethylene glycol/polyester block copolymer thermal hydrogels have been tried in different biomedical fields, there are many times when personalized tailoring of hydrogel properties to different biomedical applications is required through polymer molecular structure design. The common temperature-sensitive polyethylene glycol/polyester block copolymer is obtained by ring-opening polymerization of lactone or lactide monomer initiated by polyethylene glycol with hydroxyl, in the obtained copolymer, the modifiable groups on the molecular chain of the polymer are few, and usually only the tail end of the polyester block is provided with the modifiable hydroxyl groups, and the hydroxyl groups carried by the polyethylene glycol block are consumed by the ring-opening polymerization initiated by the corresponding ester bonds. However, the polyethylene glycol/polyester block copolymer self-assembles in an aqueous medium to form micelles with hydrophobic polyester as the core and polyethylene glycol as the corona. The functional groups modified at the tail ends of the polyester blocks are not beneficial to the contact between the functional groups or between the functional groups and an external matrix because the functional groups are wrapped in the polymer micelle, and no modifiable chemical site exists on the polyethylene glycol blocks exposed on the outer layers of the micelle, so that the development of the functionality of the polyethylene glycol/polyester block copolymer thermal hydrogel is limited to a certain extent due to the copolymer structure with active groups only at the tail ends of the polyester blocks. Therefore, the introduction of groups which are convenient for modification in the polyethylene glycol/polyester block copolymer, especially in the polyethylene glycol block part, has great practical value in expanding the medical application and meeting different application requirements.
The gelation mechanism of polyethylene glycol/polyester block copolymer thermal hydrogel is considered to be that the block copolymer self-assembles in water to form amphiphilic micelle taking a hydrophobic polyester block as a core and a hydrophilic polyethylene glycol block as a corona, and the micelle is aggregated under the drive of temperature to form a percolation physical micelle network. However, the micelles are combined through physical hydrophobic interaction, so that the physical hydrogel has low mechanical strength, and the gel network is often rapidly collapsed under the action of body fluid erosion when the gel is applied in vivo. Premature collapse of the hydrogel network tends to cause severe burst of drug during drug delivery, which not only does not achieve the intended therapeutic effect, but may also cause toxic reactions due to excessive local concentrations of drug. In order to slow down the erosion rate of hydrogel in vivo, it is important to increase the interaction between copolymers by chemical crosslinking, etc. to realize stable degradation of hydrogel in vivo for drug sustained release systems.
Disclosure of Invention
In view of the above, a first object of the present application is to provide a thermosensitive block copolymer hydrogel capable of realizing the modification and modification of the hydrophilic block function of polyethylene glycol/polyester-based thermotropic hydrogel, aiming at the problems existing in the prior art.
In order to achieve the above purpose, the present application adopts the following technical scheme:
a thermosensitive block copolymer hydrogel, wherein the block copolymer comprises a hydrophilic block A with polyethylene glycol as an arm and a hydrophobic block B with polyester as a center, wherein the content of the hydrophilic block A is 20-50wt% and the content of the hydrophobic block B is 40-80 wt%; and the tail end of the hydrophilic block is a free hydroxyl, carboxyl or amino active group.
It is worth noting that the block copolymers in the thermosensitive block copolymer hydrogels disclosed herein include hydrophilic polyethylene glycol blocks and hydrophobic polyester blocks. Wherein the hydrophobic polyester block is positioned in the middle of the block copolymer, the hydrophilic polyethylene glycol block is positioned at the outer side of the block copolymer, and the terminal groups are active chemical groups such as hydroxyl, carboxyl or amino, which is beneficial to the contact between the functional groups or between the functional groups and an external matrix. And the free hydroxyl, carboxyl or amino and other active groups at the tail end of the polyethylene glycol block can be used for further chemical modification.
Further, the polyester is selected from the group consisting of poly D, L-lactide, poly L-lactide, polyglycolide, polyorthoester, poly epsilon-caprolactone, poly epsilon-alkyl substituted caprolactone, poly delta-valerolactone, polyesteramide, polyacrylate, polycarbonate, and polyether ester.
Further, the content of the hydrophilic block A is 30-40wt% and the content of the hydrophobic block B is 50-70wt%.
Further, the average molecular weight of polyethylene glycol in the hydrophilic block a is 400 to 10000, and the average molecular weight of polyester in the hydrophobic block B is 1000 to 20000.
Still further, the block copolymer configuration may be an AB-type two-block, ABA-type three-block, or B- (a) n-type multi-arm star-block copolymer, where n is an integer from 3 to 10.
Further, the segmented copolymer chain segment also comprises an alcohol initiator chain segment, a coupling agent chain segment or a modified functional group with the content of 0.1-10wt%.
The alcohol initiator chain segment is aliphatic linear monohydric alcohol/dihydric alcohol or star polyol, and the coupling agent chain segment is hydrocarbon chain connected by ester bond/amido bond/isocyanate bond/imine bond and other groups.
Still further, the functional groups include one or more of catechol groups, phenol groups, acrylate groups, heavy element-containing groups, fluorescent groups.
Illustratively, the heavy element-containing groups include iodine-containing, bromine-containing groups.
According to the application, the modification group is introduced into the polyethylene glycol block part of the polyethylene glycol/polyester block copolymer, so that the personalized customization of the hydrogel property can be realized simply and rapidly, and a new way is provided for developing the functionality of the polyethylene glycol/polyester block copolymer thermotropic hydrogel. Considering that the type and the number of the modified functional groups can influence the properties of the modified polyethylene glycol/polyester block copolymer, the hydrophilic block terminal of the copolymer can be completely modified with the functional groups, or can be partially modified with the functional groups, and the type of the modified functional groups can be one or more.
In consideration of practical use performance of the hydrogel, the polyethylene glycol-polyester block copolymer in the thermosensitive block copolymer hydrogel disclosed by the application accounts for 10-40wt%, preferably 15-30wt%.
The thermosensitive block copolymer hydrogel disclosed by the application also comprises a solvent in the conventional technology. The solvent is pure water, physiological saline, buffer solution, tissue culture solution, cell culture solution, body fluid of animals, plants or human body, or other aqueous solution or other solvent medium which does not take organic solvent as main body.
The thermosensitive block copolymer hydrogel disclosed by the application can comprise other types of polymer and/or non-polymer components besides the block copolymer and the solvent, and the components can promote the dissolution of the copolymer, or regulate the sol-gel transition temperature of an aqueous solution of the copolymer, or interact with modified functional groups to promote the oxidation-reduction, crosslinking and other reactions of the functional groups.
The thermosensitive block copolymer hydrogel disclosed by the application has injectability, is in a solution state at low temperature, can be converted into a gel state within 1min at 4-37 ℃, and has a preferable gel transition temperature of 25-37 ℃.
The second object of the present application is to provide a method for producing the thermosensitive block copolymer hydrogel.
In order to achieve the above object, the present application provides the following technical solutions:
a preparation method of a thermosensitive block copolymer hydrogel comprises the following steps:
I. initiating ring-opening polymerization or thermal polymerization of ester monomers by using micromolecular monohydric alcohol or polyhydric alcohol under the catalysis of stannous octoate to obtain linear or star-shaped polyester with hydroxyl at the tail end;
II. Connecting polyethylene glycol blocks at the tail end of the polyester through esterification reaction or coupling bonding to obtain a block copolymer with active groups at the tail end of the hydrophilic block;
III, dissolving one or more block copolymers in a solvent at low temperature to prepare a copolymer solution; or alternatively, the first and second heat exchangers may be,
the copolymer solutions were prepared by dissolving the various block copolymers in the solvent, respectively, and then mixing the respective solutions.
It should be noted that, in step II, in order to prevent chain extension or crosslinking reaction during polyethylene glycol connection, the molar amount of polyethylene glycol needs to be kept in excess of that of polyester during reaction, and then the excessive unreacted polyethylene glycol is removed by sedimentation or dialysis.
In some embodiments, step II is:
the polyester prepared by the step I is subjected to esterification reaction with excessive carboxyl-terminated polyethylene glycol under the combined action of N, N' -Dicyclohexylcarbodiimide (DCC)/4-Dimethylaminopyridine (DMAP) or 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI)/DMAP or other dehydrating agents and catalysts to obtain carboxyl-terminated polyester-polyethylene glycol block copolymer; or alternatively, the first and second heat exchangers may be,
the polyester prepared by the step I reacts with excessive succinic anhydride (or glutaric anhydride, diisocyanate, p-nitrobenzyl chloroformate, p-nitrophenyl chloroformate, N' -disuccinimide carbonate and the like) to obtain polyester with a coupling group at the tail end, and then reacts with excessive polyethylene glycol (or polyethylene glycol with amination at the tail end) to obtain the polyester-polyethylene glycol segmented copolymer with hydroxyl or amino at the tail end.
It is worth noting that the low temperature in step III, i.e. below the sol-gel transition temperature of the aqueous copolymer system, is usually referred to as the refrigerator refrigeration temperature (4 ℃).
Further, the step II further includes: the functional group is further modified at the tail end of the hydrophilic block through a coupling reaction, and comprises one or more of catechol group, phenol group, acrylate group, heavy element-containing group and fluorescent group.
The functional groups may be induced to crosslink or undergo redox reaction by introducing a water-soluble initiator, a redox agent, a crosslinking agent, or the like, in an amount of 0.01 to 10% by weight of the copolymer solution.
In some embodiments, the supplementing step of step II may specifically be:
modifying catechol (catechol) group at the end of polyethylene glycol, and enhancing the tissue adhesion performance of copolymer thermotropic hydrogel by using mussel chemistry principle; or alternatively, the first and second heat exchangers may be,
modifying phenol or catechol group at the end of polyethylene glycol, and enhancing the mechanical strength of the copolymer thermotropic hydrogel by inducing enzyme crosslinking or oxidation crosslinking of catechol; or alternatively, the first and second heat exchangers may be,
modifying acrylic ester at the tail end of polyethylene glycol, and initiating polymerization of double bonds to cause crosslinking of the copolymer, so that the mechanical strength of the copolymer thermotropic hydrogel is enhanced; or alternatively, the first and second heat exchangers may be,
modifying the end of polyethylene glycol with radical containing heavy element (such as iodine) to endow copolymer with the developing performance of the copolymer thermotropic hydrogel under X-ray; or alternatively, the first and second heat exchangers may be,
and modifying a fluorescent group at the tail end of polyethylene glycol to endow the copolymer with the fluorescent property of the thermotropic hydrogel.
It is worth to say that the modification rate of the functional groups is 1-100%, and the functional groups modified by the same copolymer are one or more.
The third object of the application is to provide application of the thermosensitive block copolymer hydrogel in the fields of drug delivery, tissue engineering, hemostasis, wound repair and the like.
It is worth noting that the block copolymer thermotropic hydrogel disclosed by the application can be mixed with drugs to form an injectable sustained/controlled release drug delivery system, and the drugs can be hydrophilic drugs, hydrophobic drugs, amphiphilic drugs or mixtures thereof.
The block copolymer thermal hydrogel disclosed by the application can be injected through a syringe subcutaneously, intracavity, abdominal cavity, thoracic cavity, vertebral canal, intratumoral, peritumoral, arterial, lymph node and intramedullary, and can also be used on the skin surface or wound surface by preparing spray or smearing.
Compared with the prior art, the application has the advantages that:
1) The block copolymer in the thermosensitive block copolymer hydrogel disclosed by the application comprises a hydrophilic polyethylene glycol block and a hydrophobic polyester block. Wherein the hydrophobic polyester block is positioned in the middle of the block copolymer, the hydrophilic polyethylene glycol block is positioned at the outer side of the block copolymer, and the terminal groups are active chemical groups such as hydroxyl, carboxyl or amino, which is beneficial to the contact between the functional groups or between the functional groups and an external matrix. And the free hydroxyl, carboxyl or amino and other active groups at the tail end of the polyethylene glycol block can be used for further chemical modification.
2) According to the application, functional groups such as propylene double bond, catechol group, phenol group and the like are modified at the terminal active groups of the block copolymer through esterification reaction or coupling reaction, so that the block copolymer with hydrophilic terminal modified by functionalization is obtained, and the temperature-sensitive hydrogel tissue adhesion performance, stronger mechanical strength, developing performance or fluorescence performance are endowed.
3) The thermosensitive block copolymer hydrogel disclosed by the application has injectability, is in a solution state at low temperature, can be converted into a gel state within 1min at 4-37 ℃, and has good application potential in the fields of drug delivery, tissue engineering, hemostasis, wound repair and the like.
Drawings
In order to more clearly illustrate the embodiments of the present application or the technical solutions in the prior art, the drawings required for the description of the embodiments or the prior art will be briefly described below, it will be apparent that the drawings in the following description are only embodiments of the present application, and other drawings can be obtained from the provided drawings without inventive effort for a person skilled in the art
FIG. 1 is a synthetic route diagram of a thermosensitive amphiphilic block copolymer with free hydroxyl groups at the end of the hydrophilic block in examples 6-10 of the present application.
FIG. 2 is a synthetic scheme of a block copolymer of the hydrophilic block end-modified catechol of example 13 of the present application.
FIG. 3 shows 30wt% of 2-arm PLGA in example 2 of the present application 1250 -PEG 600 -a temperature change dynamic rheology profile of an OH block copolymer solution.
FIG. 4 is 22.5wt% 4-arm PLA in example 6 of the application 1190 -PEG 600 -a temperature change dynamic rheology profile of an OH block copolymer solution.
FIG. 5 is 22.5wt% 4-arm PLA in example 7 of the application 1300 -PEG 600 -a temperature change dynamic rheology profile of an OH block copolymer solution.
FIG. 6 is 22.5wt% 4-arm PLA1 in example 8 of the application 350 -PEG 600 -a temperature change dynamic rheology profile of an OH block copolymer solution.
FIG. 7 is 22.5wt% 4-arm PLA1 in example 9 of the application 350 -PEG 800 -a temperature change dynamic rheology profile of an OH block copolymer solution.
FIG. 8 is 22.5wt% 4-arm PLA in example 10 of the application 1520 -PEG 600 -a temperature change dynamic rheology profile of an OH block copolymer solution.
FIG. 9 is 20wt% 4-arm PLA in example 11 of the application 1350 -PEG 600 -a temperature change dynamic rheology profile of COOH block copolymer solution.
FIG. 10 is 20wt% of 4-arm PLA having a hydrophilic block terminal modified catechol in example 13 of the application 1300 -PEG 600 -a temperature change dynamic rheology profile of the DA block copolymer solution.
FIG. 11 is 20wt% of 4-arm PLA having a hydrophilic block terminal modified catechol in example 13 of the application 1350 -PEG 800 -a temperature change dynamic rheology profile of the DA block copolymer solution.
FIG. 12 is 20wt% of 4-arm PLA having a hydrophilic block terminal modified catechol in example 17 of the application 1350 -PEG 800 Optical photographs of DA block copolymer solutions with varying amounts of sodium periodate added.
FIG. 13 is an in vivo degradation curve of the different block copolymer hydrogels of example 18 of the present application.
FIG. 14 is 20wt% 4-arm PLA in example 19 of the application 1300 -PEG 600 -an optical photograph of the hydrogel formation process of the MA copolymer solution after uv irradiation at 4 ℃.
Detailed Description
The following description of the technical solutions in the embodiments of the present application will be clear and complete, and it is obvious that the described embodiments are only some embodiments of the present application, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the application without making any inventive effort, are intended to be within the scope of the application.
The word "embodiment" as used herein does not necessarily mean that any embodiment described as "exemplary" is preferred or advantageous over other embodiments. Performance index testing in the examples of the present application, unless otherwise specified, was performed using conventional testing methods in the art. It is to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the disclosure.
Unless otherwise defined, technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs; other test methods and techniques not specifically mentioned in the present application are those commonly used by those skilled in the art.
The terms "substantially" and "about" are used herein to describe small fluctuations. For example, they may refer to less than or equal to ±5%, such as less than or equal to ±2%, such as less than or equal to ±1%, such as less than or equal to ±0.5%, such as less than or equal to ±0.2%, such as less than or equal to ±0.1%, such as less than or equal to ±0.05%. Numerical data presented or represented herein in a range format is used only for convenience and brevity and should therefore be interpreted flexibly to include not only the numerical values explicitly recited as the limits of the range, but also to include all the individual numerical values or sub-ranges encompassed within that range. For example, a numerical range of "1 to 5%" should be interpreted to include not only the explicitly recited values of 1% to 5%, but also include individual values and sub-ranges within the indicated range. Thus, individual values, such as 2%, 3.5% and 4%, and subranges, such as 1% to 3%, 2% to 4% and 3% to 5%, etc., are included in this numerical range. The same principle applies to ranges reciting only one numerical value. Moreover, such an interpretation applies regardless of the breadth of the range or the characteristics being described.
Numerous specific details are set forth in the following examples in order to provide a better understanding of the present application. It will be understood by those skilled in the art that the present application may be practiced without some of these specific details. In the examples, some methods, means, instruments, devices, etc. well known to those skilled in the art are not described in detail in order to highlight the gist of the present application.
On the premise of no conflict, the technical features disclosed by the embodiment of the application can be combined at will, and the obtained technical scheme belongs to the disclosure of the embodiment of the application.
The application discloses a thermosensitive block copolymer hydrogel, which comprises a hydrophilic block A with polyethylene glycol as an arm and a hydrophobic block B with polyester as a center, wherein the content of the hydrophilic block A is 20-50wt% and the content of the hydrophobic block B is 40-80 wt%; and the tail end of the hydrophilic block is a free hydroxyl, carboxyl or amino active group.
In other embodiments, the block copolymer further comprises functional groups modified to reactive groups, the functional groups comprising one or more of catechol groups, phenol groups, acrylate groups, heavy element-containing groups, fluorescent groups.
The application also discloses a preparation method of the thermosensitive block copolymer hydrogel, which comprises the following steps:
I. initiating ring-opening polymerization or thermal polymerization of ester monomers by using micromolecular monohydric alcohol or polyhydric alcohol under the catalysis of a catalyst to obtain linear or star-shaped polyester with hydroxyl at the tail end;
II. Connecting polyethylene glycol blocks at the tail end of the polyester through esterification reaction or coupling bonding to obtain a block copolymer with active groups at the tail end of the hydrophilic block;
III, dissolving one or more block copolymers in a solvent at low temperature to prepare a copolymer solution; or alternatively, the first and second heat exchangers may be,
the copolymer solutions were prepared by dissolving the various block copolymers in the solvent, respectively, and then mixing the respective solutions.
In other embodiments, the method of preparation comprises the steps of:
I. initiating ring-opening polymerization or thermal polymerization of ester monomers by using micromolecular monohydric alcohol or polyhydric alcohol under the catalysis of a catalyst to obtain linear or star-shaped polyester with hydroxyl at the tail end;
II. Connecting a polyethylene glycol block at the tail end of the polyester through esterification reaction or coupling bonding to obtain a block copolymer with active groups at the tail end of a hydrophilic block, and then further modifying functional groups at the tail end of the hydrophilic block through coupling reaction, wherein the functional groups comprise one or more of catechol groups, phenol groups, acrylate groups, heavy element-containing groups and fluorescent groups;
III, dissolving one or more block copolymers in a solvent at low temperature to prepare a copolymer solution; or alternatively, the first and second heat exchangers may be,
the copolymer solutions were prepared by dissolving the various block copolymers in the solvent, respectively, and then mixing the respective solutions.
The present application will be further specifically illustrated by the following examples, which are not to be construed as limiting the application, but rather as falling within the scope of the present application, for some non-essential modifications and adaptations of the application that are apparent to those skilled in the art based on the foregoing disclosure.
Example 1
A block copolymer with free hydroxyl at the end of a hydrophilic block is prepared by the following steps:
(1) Amyl alcohol is added into a 250mL three-neck flask, after vacuum dehydration is carried out for 3 hours at 120 ℃, argon is introduced first to cool to 80 ℃, lactide (LA) with the weight corresponding to the target molecular weight and stannous octoate accounting for 0.15-0.20 wt% of the monomer weight are added, after argon is replaced for three times, the temperature is raised to 150 ℃ and the reaction is carried out for 12 hours under stirring, thus obtaining the linear single-arm polylactic acid (PLA).
(2) After the reaction is finished, cooling to room temperature, adding succinic anhydride with 1.5-2 times of the molar weight of hydroxyl groups on the linear polylactic acid, replacing the gas in the reaction bottle with argon for three times, adding a proper amount of anhydrous dichloromethane into the reaction bottle by using a syringe, and dissolving the polymer by magnetic stirring. Then, a methylene dichloride solution containing 1.2-1.5 times of DMAP in molar quantity of polylactic acid hydroxyl groups is slowly dripped into the reaction system under the ice bath condition by a microinjection pump, after the dripping is completed in 2 hours, the ice bath is removed, and the reaction is carried out for 24 hours under the magnetic stirring at room temperature. After the completion of the reaction, the reaction mixture was washed three times with 200mL of an acidic saline solution (pH. Apprxeq.3). The organic phase was concentrated by rotary evaporation and dried over anhydrous sodium sulfate. After removal of sodium sulfate by filtration, most of the dichloromethane solvent was removed by rotary evaporation, and then 10 to 20 times of volume of glacial ethyl ether was allowed to settle overnight in a refrigerator at-20 ℃. The precipitate is filtered and collected, and dried in vacuum at room temperature for 24 hours to obtain linear polylactic acid (PLA-SA) with carboxyl end groups, and the yield is more than 90 percent.
(3) A quantity of PLA-SA polymer is added into a 100mL bottle, about 40mL of toluene is added to dissolve the polymer, and trace moisture possibly existing in the system is removed by a toluene azeotropic water carrying method at 110 ℃. The polymer after water removal was cooled to room temperature under argon atmosphere, 40mL of anhydrous dichloromethane was added, and the polymer was dissolved and stored under magnetic stirring for use. And taking a 250mL branched bottle, adding polyethylene glycol (PEG) with the molar weight being 2-4 times of the molar weight of carboxyl in the PLA-SA polymer, and carrying out reduced pressure (100-400 Pa) water removal for 30min at 120 ℃. After the temperature was lowered to room temperature, EDCI 1.5 times the molar equivalent of the polymer carboxyl groups, DMAP 0.3 times the molar equivalent of the polymer carboxyl groups and 60mL of anhydrous dichloromethane were added under the protection of argon atmosphere. After the system was completely dissolved, the dissolved anhydrous PLA-SA dichloromethane solution was withdrawn by syringe, and the solution was slowly added dropwise to the above reaction system by microinjection pump under ice bath conditions, and it was expected that the dropwise addition was completed within 2 hours. The ice bath was removed and the reaction was left to stand at room temperature with stirring for 48h. After the completion of the reaction, the system was washed with saturated brine to remove excess EDCI, and the solvent was removed by rotary evaporation. The polymer was dissolved in deionized water, and the excess unreacted polyethylene glycol was removed by dialysis, and freeze-dried to give a colorless transparent viscous solid with a yield of about 85%.
Examples 2 to 10
A block copolymer with hydrophilic block and active group is prepared similarly to preparation 1, except that the type and molecular weight of alcohol initiator and polyester and the molecular weight of polyethylene glycol are shown in Table 1.
Example 11
A block copolymer with free carboxyl at the end of a hydrophilic block is prepared by the following steps:
(1) Pentaerythritol is added into a 250mL three-neck flask, after vacuum dehydration is carried out for 3 hours at 120 ℃, argon is introduced, the temperature is cooled to 80 ℃, lactide (LA) with the weight corresponding to the target molecular weight and stannous octoate accounting for 0.15-0.20 wt% of the weight of the monomer are added, after the argon is replaced for three times, the temperature is raised to 150 ℃ and the reaction is carried out for 12 hours under stirring, thus obtaining star-shaped quadrifilar polylactic acid (4-arm PLA).
(2) After the reaction, cooling to room temperature, adding a proper amount of anhydrous dichloromethane into a reaction bottle, and magnetically stirring to dissolve the polymer. Taking a 250mL bottle with a branch mouth, adding end carboxylated polyethylene glycol (HOOC-PEG-COOH) with the molar weight being 2-4 times of the molar weight of hydroxyl on the 4-arm PLA polymer, and carrying out decompression (100-400 Pa) at 120 ℃ for dewatering for 30min. After the temperature was reduced to room temperature, 1.5 times of EDCI and 0.3 times of DMAP as well as 60mL of anhydrous dichloromethane were added to the molar amount of hydroxyl groups on the 4-arm PLA polymer under the protection of argon atmosphere. After the system was completely dissolved, the dissolved anhydrous 4-arm PLA dichloromethane solution was withdrawn by syringe, and the solution was slowly added dropwise to the above system by microinjection pump under ice bath conditions, and it was expected that the dropwise addition was completed within 2 hours. The ice bath was removed and the reaction was left to stand at room temperature with stirring for 48h. After the completion of the reaction, the system was washed with saturated brine to remove excess EDCI, and the solvent was removed by rotary evaporation. The polymer is dissolved in deionized water, the excessive unreacted carboxylated polyethylene glycol is removed by dialysis, and the colorless transparent viscous solid is obtained after freeze drying, and the yield is about 88%.
Example 12
A block copolymer with free amino groups at the tail ends of hydrophilic blocks is prepared by the following steps:
(1) Pentaerythritol is added into a 250mL three-neck flask, after vacuum dehydration is carried out for 3 hours at 120 ℃, argon is introduced, the temperature is cooled to 80 ℃, lactide (LA) with the weight corresponding to the target molecular weight and stannous octoate accounting for 0.15-0.20 wt% of the weight of the monomer are added, after the argon is replaced for three times, the temperature is raised to 150 ℃ and the reaction is carried out for 12 hours under stirring, thus obtaining star-shaped quadrifilar polylactic acid (4-arm PLA).
(2) After the reaction, cooling to room temperature, adding glutaric anhydride with 1.5-2 times of hydroxyl mole amount on 4-arm PLA, replacing the gas in the reaction bottle with argon three times, adding a proper amount of anhydrous dichloromethane into the reaction bottle by a syringe, and dissolving the polymer by magnetic stirring. Subsequently, a methylene dichloride solution containing 1.2-1.5 times of DMAP of the molar quantity of 4-arm PLA hydroxyl groups is slowly dripped into the reaction system under the ice bath condition by a microinjection pump, after the dripping is finished within 2 hours, the ice bath is removed, and the reaction is carried out for 24 hours under the magnetic stirring at room temperature. After the completion of the reaction, the reaction mixture was washed three times with 200mL of an acidic saline solution (pH. Apprxeq.3). The organic phase was concentrated by rotary evaporation and dried over anhydrous sodium sulfate. After removal of sodium sulfate by filtration, most of the dichloromethane solvent was removed by rotary evaporation, and then 10 to 20 times of volume of glacial ethyl ether was allowed to settle overnight in a refrigerator at-20 ℃. The precipitate was filtered and collected and dried in vacuo at room temperature for 24h to give the terminal carboxylated four-arm polylactic acid (4-arm PLA-SA) in a yield of over 90%.
(3) A quantity of 4-arm PLA-SA polymer was added to a 100mL jar, about 40mL of toluene was added to dissolve the polymer, and traces of water that may be present in the system were removed by azeotropic hydration of toluene at 110 ℃. The polymer after water removal was cooled to room temperature under argon atmosphere, 40mL of anhydrous dichloromethane was added, and the polymer was dissolved and stored under magnetic stirring for use. Taking a 250mL bottle with a mouth, adding end-aminated polyethylene glycol (H) with the molar weight being 2-4 times of the molar weight of carboxyl in the PLA-SA polymer 2 N-PEG-NH 2 ) Decompressing at 120 deg.C(100-400 Pa) and dewatering for 30min. After the temperature was lowered to room temperature, EDCI 1.5 times the molar equivalent of the polymer carboxyl groups, DMAP 0.3 times the molar equivalent of the polymer carboxyl groups and 60mL of anhydrous dichloromethane were added under the protection of argon atmosphere. After the system was completely dissolved, the dissolved anhydrous 4-arm PLA-SA dichloromethane solution was withdrawn by syringe, and the solution was slowly added dropwise to the above reaction system by microinjection pump under ice bath conditions, and it was expected that the dropwise addition was completed within 2 hours. The ice bath was removed and the reaction was left to stand at room temperature with stirring for 48h. After the completion of the reaction, the system was washed with saturated brine to remove excess EDCI, and the solvent was removed by rotary evaporation. The polymer obtained was dissolved in deionized water, and the excess unreacted terminal aminated polyethylene glycol was removed by dialysis, and freeze-dried to give a colorless transparent viscous solid with a yield of about 81%.
The types, yields and molecular weights of the individual blocks as determined by nuclear magnetic resonance hydrogen spectroscopy of the copolymers obtained in examples 1-12 are shown in Table 1 (named as single arms, such as PLA obtained by pentaerythritol initiated polymerization is designated as 4-arm PLA, the molecular weights are the molecular weights of the individual arms, and are shown in subscript form, such as 4-arm PLA) 1300 )：
TABLE 1 kinds, molecular weights and corresponding yields of the respective components in examples 1 to 12
The amphiphilic block polymers having hydroxyl groups at the terminal of the hydrophilic block prepared in examples 1 to 12 were subjected to performance test by gel permeation chromatography GPC using polystyrene as a standard, and the weight average molecular weight, the number average molecular weight of the A block, the weight percentage of the A-block and the molar ratio of the B block of the block copolymer were measured, respectively, and the test results are reported in Table 2:
TABLE 2 information on the molecular structure of block polymers in examples 1-12
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Example 13
A thermosensitive block copolymer hydrogel with catechol modified at the end of a hydrophilic block, and the preparation method thereof is as follows:
taking the hydroxyl-terminated copolymer obtained in example 7 as an example, 4-arm PLA of example 7 1300 -PEG 600 the-OH block copolymer was introduced into a 100mL round-bottomed flask with a neck, and the water possibly present in the polymer was removed by azeotropic hydration with toluene. About 20mL of anhydrous methylene chloride was added to redissolve the polymer. About 1mL of anhydrous triethylamine was added to the system and stirring was continued. P-nitrophenyl chloroformate (p-NPC) calculated according to the expected modification rate was accurately weighed, dissolved in a small amount of anhydrous methylene chloride, and slowly added dropwise to the above reaction system under ice bath conditions, after completion of the addition for about 2 hours. The reaction is continued for 24 hours under the magnetic stirring state at normal temperature. The crude product was washed with brine, anhydrous Na 2 SO 4 Drying, settling with glacial ethyl ether, and vacuum drying to obtain the hydrophilic block terminal p-NPC activated copolymer. Dissolving the hydrophilic block terminal p-NPC activated copolymer in anhydrous dichloromethane, dissolving excessive dopamine hydrochloride and triethylamine in DMF and adding the system, stirring at room temperature for reaction for 12 hours, filtering the product, concentrating by rotary evaporation, settling by diethyl ether, and dialyzing to obtain the hydrophilic block terminal catechol modified block copolymer, wherein the catechol modification rate is about 21%. The copolymer is dissolved in phosphate buffer solution at low temperature to prepare a 20wt% block copolymer solution, and after the temperature is raised to the vicinity of the body temperature, the copolymer solution can be converted into temperature-sensitive hydrogel, the thermal gelation temperature is 22 ℃, and the copolymer solution has certain tissue adhesion performance.
Example 14
A thermosensitive block copolymer hydrogel with catechol modified at the end of a hydrophilic block, and the preparation method thereof is as follows:
taking 4-arm PLA of example 9 1350 -PEG 800 the-OH block copolymer was introduced into a 100mL round-bottomed flask with a neck, and the water possibly present in the polymer was removed by azeotropic hydration with toluene. About 20mL of anhydrous methylene chloride was added to redissolve the polymer. About 1mL of anhydrous triethylamine was added to the system and stirring was continued. P-nitrophenyl chloroformate (p-NPC) calculated according to the expected modification rate was accurately weighed, dissolved in a small amount of anhydrous methylene chloride, and slowly added dropwise to the above reaction system under ice bath conditions, after completion of the addition for about 2 hours. The reaction is continued for 24 hours under the magnetic stirring state at normal temperature. The crude product was washed with brine, anhydrous Na 2 SO 4 Drying, settling with glacial ethyl ether, and vacuum drying to obtain the hydrophilic block terminal p-NPC activated copolymer. Dissolving the hydrophilic block terminal p-NPC activated copolymer in anhydrous dichloromethane, dissolving excessive dopamine hydrochloride and triethylamine in DMF and adding the system, stirring at room temperature for reaction for 12 hours, filtering the product, concentrating by rotary evaporation, settling by diethyl ether, and dialyzing to obtain the hydrophilic block terminal catechol modified block copolymer, wherein the catechol modification rate is about 39%. The copolymer is dissolved in phosphate buffer solution at low temperature to prepare a 20wt% segmented copolymer solution, and after the temperature is raised to the vicinity of the body temperature, the copolymer solution can be converted into temperature-sensitive hydrogel, the thermal gelation temperature is 30 ℃, and the copolymer solution has certain tissue adhesion performance.
Example 15
A thermosensitive block copolymer hydrogel with catechol modified at the tail end of a hydrophilic block is prepared by the following method:
4-arm PLGA with carboxyl end obtained in example 11 1350 -PEG 600 For example, the-COOH copolymer was subjected to azeotropic dehydration with toluene by the method of example 13, then dissolved in anhydrous methylene chloride, dopamine hydrochloride and triethylamine were added in the modified ratio, a slightly excessive methylene chloride solution of EDCI/DMAP was added dropwise under ice bath conditions, stirred at room temperature for reaction for 12 hours, and then washed with brine and concentrated by rotary evaporationSettling with diethyl ether, dialyzing to obtain a block copolymer with hydrophilic block terminal modified catechol, wherein the catechol modification rate is about 30%. The copolymer is dissolved in phosphate buffer solution at low temperature to prepare a 20wt% segmented copolymer solution, and after the temperature is raised to the vicinity of the body temperature, the copolymer solution can be converted into temperature-sensitive hydrogel, the thermal gelation temperature is 22 ℃, and the copolymer solution has certain tissue adhesion performance.
Example 16
A thermosensitive block copolymer hydrogel with tissue adhesiveness, prepared by the following method:
4-arm PLA terminated with hydroxyl group obtained in example 9 1350 -PEG 800 For example, the-OH copolymer was subjected to azeotropic dehydration by toluene by the method of example 13, then dissolved in anhydrous methylene dichloride, 3, 4-dihydroxybenzene propionic acid was added according to the modification ratio, a slightly excessive methylene dichloride solution of EDCI/DMAP was added dropwise under the ice bath condition, the mixture was stirred at room temperature for reaction for 12 hours, and then washed with saline solution, concentrated by rotary evaporation, settled with diethyl ether, and dialyzed to obtain a block copolymer of hydrophilic block terminal modified catechol, wherein the catechol modification ratio can reach 100%. The copolymer is dissolved in phosphate buffer solution at low temperature to prepare a 20wt% segmented copolymer solution, and after the temperature is raised to the vicinity of the body temperature, the copolymer solution can be converted into temperature-sensitive hydrogel, the thermal gelation temperature is 40 ℃, and the copolymer solution has certain tissue adhesion performance.
Example 17
A preparation method of a thermo-sensitive block copolymer hydrogel with physicochemical double cross-links comprises the following steps:
preparation of hydrophilic Block end-modified catechol 4-arm PLA according to reference example 14 1350 -PEG 800 DA block copolymer and formulated as a 20wt% copolymer solution, to which a small amount of sodium periodate (NaIO) 4 ) The molecular weight of the amphiphilic block copolymer accounts for 1/2,1/4,1/8 and 0 of the mole number of catechol groups (DA) in the polymer, and the oxidative crosslinking of the catechol groups is induced, so that the temperature-sensitive amphiphilic block copolymer hydrogel with physical/chemical double crosslinking can be obtained, and the chemical crosslinking degree is increased along with the increase of the sodium periodate content.
Example 18
20wt% of 4-arm PLA obtained in example 17 1350 -PEG 800 After mixing the DA block copolymer solution with a small amount of sodium periodate (1/2 of the moles of copolymer DA), subcutaneous injection was performed on the back of female ICR mice, and the mice were euthanized at predetermined time points, the hydrogel was dissected and weighed, and the residual hydrogel mass fraction was recorded as a function of time, with 20wt% of 4-arm PLA in example 8 1350 -PEG 600 -OH and 20wt% Linear PLA 1710 -PEG 1500 -PLA 1710 Hydrogel was used as reference. The results showed that 4-arm PLA 1350 -PEG 800 The in vivo degradation rate of the physical/chemical double crosslinked hydrogel of the DA block copolymer solution mixed with sodium periodate is significantly slower than 20wt% of 4-arm PLA 1350 -PEG 600 -OH hydrogel and PLA 1710 -PEG 1500 -PLA 1710 Hydrogels, and exhibited almost linear degradation behavior in the first three weeks.
Example 19
A preparation method of the thermosensitive block copolymer hydrogel with light response crosslinking comprises the following steps:
4-arm PLA terminated with hydroxyl group obtained in example 7 1300 -PEG 600 For example, the-OH copolymer was subjected to azeotropic dehydration of toluene by the method of example 13, then dissolved in anhydrous methylene chloride, after adding an excessive amount of methacrylic anhydride, dropwise adding a catalytic amount of DMAP in methylene chloride solution in an ice bath, stirring at room temperature for reaction for 12 hours, then filtered, washed with saline solution, concentrated by rotary evaporation, settled with diethyl ether, and dialyzed to obtain a hydrophilic block terminal modified propylene double bond block copolymer 4-arm PLA 1300 -PEG 600 -MA. The copolymer was dissolved in a phosphate buffer at low temperature to prepare a 20wt% block copolymer solution, and after 0.02% photoinitiator D2959 was added, the copolymer solution was converted into a hydrogel after uv irradiation at low temperature.
Example 20
A thermosensitive block copolymer hydrogel with X-ray impermeability is prepared by the following method:
4-arm PLA terminated with hydroxyl group obtained in example 9 1350 -PEG 800 For example, the-OH copolymer was subjected to azeotropic dehydration by toluene by the method of example 13, then dissolved in anhydrous methylene dichloride, 2,3, 5-triiodobenzoic acid was added according to the modification ratio, a slightly excessive methylene dichloride solution of EDCI/DMAP was added dropwise under the ice bath condition, the mixture was stirred at room temperature for reaction for 12 hours, and then washed with brine, concentrated by rotary evaporation, settled with diethyl ether, and dialyzed to obtain a block copolymer with an iodine-containing modified hydrophilic block terminal, wherein the modification ratio can reach 100%. The copolymer is dissolved in phosphate buffer solution at low temperature to prepare a 20wt% block copolymer solution, and after the temperature is raised to the vicinity of the body temperature, the copolymer solution can be converted into temperature-sensitive hydrogel, has X-ray impermeability, and can be used as a medical contrast agent.
Example 21
A thermosensitive block copolymer hydrogel with a hydrophilic end connected with a fluorescent group is prepared by the following method:
4-arm PLA terminated with hydroxyl group obtained in example 9 1350 -PEG 800 For example, the-OH copolymer was subjected to azeotropic dehydration by toluene in the method of example 13, then dissolved in anhydrous methylene chloride, rhodamine B fluorescent dye was added according to the modification ratio, a slightly excessive methylene chloride solution of EDCI/DMAP was added dropwise under the ice bath condition, the mixture was stirred at room temperature for reaction for 12 hours, and then washed with saline solution, concentrated by rotary evaporation, settled with diethyl ether, and fully dialyzed to obtain a block copolymer with a hydrophilic block terminal modified fluorescent group, wherein the modification ratio can be from 5% to 100%. The copolymer is dissolved in phosphate buffer solution at low temperature to prepare a 20wt% block copolymer solution, and after the temperature is raised to the vicinity of the body temperature, the copolymer solution can be converted into temperature-sensitive hydrogel and has fluorescence performance, and fluorescence with the wavelength of 625nm is emitted under the irradiation of excitation light with the wavelength of about 540 nm.
In order to further demonstrate the beneficial effects of the present application for a better understanding of the present application, the properties and application properties of the block polymers disclosed in examples 1 to 12 of the present application are further elucidated by the following measurement tests, but are not to be construed as limiting the present application, and the properties of the products obtained by other measurement tests performed by those skilled in the art based on the above-mentioned summary of the application and the application according to the above-mentioned properties are also considered to fall within the scope of the present application.
Experimental example 1
Polymer solubility
The polymer solutions obtained in examples 1 to 12 were prepared with physiological saline, respectively, at concentrations of 20 to 40%, and specific concentrations were appropriately adjusted according to the solubility of the polymer itself.
Experimental example 2
Phase transition temperature determination
The polymer solutions prepared in the experimental example 1 are respectively taken, the change of rheological properties such as storage modulus, loss modulus and the like of a polymer water system along with temperature is measured by adopting a rotary rheometer, temperature scanning is carried out at a heating rate of 1 ℃/min under a fixed shearing frequency (f= 1.592 Hz), and the storage modulus and the loss modulus have intersection points at the test temperature, so that the polymer solutions can undergo sol-gel phase transition and have the property of thermal gelation, and the phase transition temperature results are recorded in table 3.
TABLE 3 Block Property test in examples 1-12
The previous description of the disclosed embodiments is provided to enable any person skilled in the art to make or use the present application. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the generic principles defined herein may be applied to other embodiments without departing from the spirit or scope of the application. Thus, the present application is not intended to be limited to the embodiments shown herein but is to be accorded the widest scope consistent with the principles and novel features disclosed herein.
Claims (4)
1. Temperature-sensitive block copolymer hydrogelGlue, characterized in that the block copolymer comprises a hydrophilic block a with polyethylene glycol as arm in a content of 20-50wt% and a hydrophobic block B with polyester as centre in a content of 40-80 wt%; and the end of the hydrophilic block is free hydroxyl, carboxyl or amino; and the block copolymer is configured as ABA type triblock or B- (a) n A multi-arm star block copolymer wherein n is an integer from 3 to 10;
the polyester is selected from one or more of poly D, L-lactide, poly L-lactide, polyglycolide, polyorthoester, poly epsilon-caprolactone, poly epsilon-alkyl substituted caprolactone, poly delta-valerolactone, polyesteramide, polyacrylate, polycarbonate and polyether ester;
the content of the hydrophilic block A is 30-40wt%, and the content of the hydrophobic block B is 50-70 wt%;
the average molecular weight of polyethylene glycol in the hydrophilic block A is 400 to 10000, and the average molecular weight of polyester in the hydrophobic block B is 1000 to 20000;
the functional group is further modified at the tail end of the hydrophilic block through a coupling reaction, and comprises one or more of catechol group, phenol group, acrylate group, heavy element-containing group and fluorescent group.
2. The thermosensitive block copolymer hydrogel according to claim 1, wherein the block copolymer segment further comprises an alcohol initiator segment or a coupling agent segment in an amount of 0.1-10 wt%.
3. A method for preparing the thermosensitive block copolymer hydrogel as claimed in claim 1 or 2, comprising the steps of:
I. initiating ring-opening polymerization or thermal polymerization of an ester monomer by using micromolecular polyalcohol under the catalysis of a catalyst to obtain linear or star-shaped polyester with hydroxyl at the tail end;
II. Connecting polyethylene glycol blocks at the tail end of the polyester through esterification reaction or coupling bonding to obtain a block copolymer with active groups at the tail end of the hydrophilic block; further modifying functional groups at the tail end of the hydrophilic block through a coupling reaction, wherein the functional groups comprise one or more of catechol groups, phenol groups, acrylate groups, heavy element-containing groups and fluorescent groups;
III, dissolving one or more block copolymers in a solvent at low temperature to prepare a copolymer solution; or alternatively, the first and second heat exchangers may be,
the copolymer solutions were prepared by dissolving the various block copolymers in the solvent, respectively, and then mixing the respective solutions.
4. Use of the thermosensitive block copolymer hydrogel according to claim 1 or 2 in preparation of preparations in the fields of drug delivery, tissue engineering, hemostasis and wound repair.
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