CN105646891A - Amphiphilic ternary molecular brush polymer and vermicular mono-molecular micelle constructed by same - Google Patents
Amphiphilic ternary molecular brush polymer and vermicular mono-molecular micelle constructed by same Download PDFInfo
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- CN105646891A CN105646891A CN201610144709.8A CN201610144709A CN105646891A CN 105646891 A CN105646891 A CN 105646891A CN 201610144709 A CN201610144709 A CN 201610144709A CN 105646891 A CN105646891 A CN 105646891A
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- Prior art keywords
- polymer
- side chain
- poly
- alkynyl
- polyacrylic acid
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- 229920000642 polymer Polymers 0.000 title claims abstract description 116
- 239000000693 micelle Substances 0.000 title claims abstract description 46
- 238000004132 cross linking Methods 0.000 claims abstract description 21
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 10
- 238000000502 dialysis Methods 0.000 claims abstract description 4
- 238000007334 copolymerization reaction Methods 0.000 claims abstract description 3
- 239000008367 deionised water Substances 0.000 claims abstract 2
- 229910021641 deionized water Inorganic materials 0.000 claims abstract 2
- -1 azidoEthyl Chemical group 0.000 claims description 34
- 229920002125 Sokalan® Polymers 0.000 claims description 29
- 238000006116 polymerization reaction Methods 0.000 claims description 28
- 239000004584 polyacrylic acid Substances 0.000 claims description 25
- 229920002521 macromolecule Polymers 0.000 claims description 21
- 125000000304 alkynyl group Chemical group 0.000 claims description 18
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 claims description 17
- QZPSOSOOLFHYRR-UHFFFAOYSA-N 3-hydroxypropyl prop-2-enoate Chemical compound OCCCOC(=O)C=C QZPSOSOOLFHYRR-UHFFFAOYSA-N 0.000 claims description 16
- 239000002253 acid Substances 0.000 claims description 16
- 239000005266 side chain polymer Substances 0.000 claims description 14
- 239000002202 Polyethylene glycol Substances 0.000 claims description 10
- 238000007306 functionalization reaction Methods 0.000 claims description 10
- 229920001223 polyethylene glycol Polymers 0.000 claims description 10
- 229920002454 poly(glycidyl methacrylate) polymer Polymers 0.000 claims description 9
- 239000004372 Polyvinyl alcohol Substances 0.000 claims description 8
- 229940114081 cinnamate Drugs 0.000 claims description 8
- UKODFQOELJFMII-UHFFFAOYSA-N pentamethyldiethylenetriamine Chemical compound CN(C)CCN(C)CCN(C)C UKODFQOELJFMII-UHFFFAOYSA-N 0.000 claims description 8
- 229920002451 polyvinyl alcohol Polymers 0.000 claims description 8
- 239000001856 Ethyl cellulose Substances 0.000 claims description 7
- 238000006243 chemical reaction Methods 0.000 claims description 7
- 229920001249 ethyl cellulose Polymers 0.000 claims description 7
- 235000019325 ethyl cellulose Nutrition 0.000 claims description 7
- FQFILJKFZCVHNH-UHFFFAOYSA-N tert-butyl n-[3-[(5-bromo-2-chloropyrimidin-4-yl)amino]propyl]carbamate Chemical compound CC(C)(C)OC(=O)NCCCNC1=NC(Cl)=NC=C1Br FQFILJKFZCVHNH-UHFFFAOYSA-N 0.000 claims description 7
- WBYWAXJHAXSJNI-VOTSOKGWSA-M trans-cinnamate Chemical compound [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 claims description 7
- 229910021589 Copper(I) bromide Inorganic materials 0.000 claims description 6
- 229920002319 Poly(methyl acrylate) Polymers 0.000 claims description 6
- 229920000058 polyacrylate Polymers 0.000 claims description 6
- 229920001610 polycaprolactone Polymers 0.000 claims description 6
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 5
- 150000002148 esters Chemical class 0.000 claims description 5
- 229920000578 graft copolymer Polymers 0.000 claims description 5
- 229920002554 vinyl polymer Polymers 0.000 claims description 5
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims description 4
- ROFVEXUMMXZLPA-UHFFFAOYSA-N Bipyridyl Chemical group N1=CC=CC=C1C1=CC=CC=N1 ROFVEXUMMXZLPA-UHFFFAOYSA-N 0.000 claims description 4
- 241000233803 Nypa Species 0.000 claims description 4
- 235000005305 Nypa fruticans Nutrition 0.000 claims description 4
- 239000003054 catalyst Substances 0.000 claims description 4
- QNILTEGFHQSKFF-UHFFFAOYSA-N n-propan-2-ylprop-2-enamide Chemical compound CC(C)NC(=O)C=C QNILTEGFHQSKFF-UHFFFAOYSA-N 0.000 claims description 4
- 229920000747 poly(lactic acid) Polymers 0.000 claims description 4
- 229920003229 poly(methyl methacrylate) Polymers 0.000 claims description 4
- 239000004632 polycaprolactone Substances 0.000 claims description 4
- 229920002338 polyhydroxyethylmethacrylate Polymers 0.000 claims description 4
- 239000004926 polymethyl methacrylate Substances 0.000 claims description 4
- 238000010189 synthetic method Methods 0.000 claims description 4
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 claims description 3
- 125000000524 functional group Chemical group 0.000 claims description 3
- 229920002239 polyacrylonitrile Polymers 0.000 claims description 3
- NIXOWILDQLNWCW-UHFFFAOYSA-N 2-Propenoic acid Natural products OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims description 2
- 235000010323 ascorbic acid Nutrition 0.000 claims description 2
- 229960005070 ascorbic acid Drugs 0.000 claims description 2
- 239000011668 ascorbic acid Substances 0.000 claims description 2
- NKNDPYCGAZPOFS-UHFFFAOYSA-M copper(i) bromide Chemical compound Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 claims description 2
- NOTIQUSPUUHHEH-UXOVVSIBSA-N dromostanolone propionate Chemical group C([C@@H]1CC2)C(=O)[C@H](C)C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H](OC(=O)CC)[C@@]2(C)CC1 NOTIQUSPUUHHEH-UXOVVSIBSA-N 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 239000004793 Polystyrene Substances 0.000 claims 2
- 150000001875 compounds Chemical class 0.000 claims 2
- 229920002223 polystyrene Polymers 0.000 claims 2
- 229920002689 polyvinyl acetate Polymers 0.000 claims 2
- 239000011118 polyvinyl acetate Substances 0.000 claims 2
- OMIGHNLMNHATMP-UHFFFAOYSA-N 2-hydroxyethyl prop-2-enoate Chemical compound OCCOC(=O)C=C OMIGHNLMNHATMP-UHFFFAOYSA-N 0.000 claims 1
- NLHHRLWOUZZQLW-UHFFFAOYSA-N Acrylonitrile Chemical compound C=CC#N NLHHRLWOUZZQLW-UHFFFAOYSA-N 0.000 claims 1
- IMROMDMJAWUWLK-UHFFFAOYSA-N Ethenol Chemical compound OC=C IMROMDMJAWUWLK-UHFFFAOYSA-N 0.000 claims 1
- 150000001336 alkenes Chemical class 0.000 claims 1
- 150000001408 amides Chemical class 0.000 claims 1
- 229920002678 cellulose Polymers 0.000 claims 1
- 239000001913 cellulose Substances 0.000 claims 1
- 239000003795 chemical substances by application Substances 0.000 claims 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 1
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 claims 1
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical compound CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 15
- 238000001338 self-assembly Methods 0.000 abstract description 8
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 abstract description 5
- 239000000463 material Substances 0.000 abstract description 2
- 239000002243 precursor Substances 0.000 abstract description 2
- 230000002209 hydrophobic effect Effects 0.000 description 15
- 239000000126 substance Substances 0.000 description 15
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 12
- 238000002360 preparation method Methods 0.000 description 12
- 230000002194 synthesizing effect Effects 0.000 description 8
- 239000003814 drug Substances 0.000 description 7
- 239000002994 raw material Substances 0.000 description 7
- 101710141544 Allatotropin-related peptide Proteins 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- BLRPTPMANUNPDV-UHFFFAOYSA-N Silane Chemical compound [SiH4] BLRPTPMANUNPDV-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 238000010560 atom transfer radical polymerization reaction Methods 0.000 description 6
- 239000000523 sample Substances 0.000 description 5
- 229920002818 (Hydroxyethyl)methacrylate Polymers 0.000 description 4
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 4
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 4
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 4
- 229910052794 bromium Inorganic materials 0.000 description 4
- USIUVYZYUHIAEV-UHFFFAOYSA-N diphenyl ether Chemical compound C=1C=CC=CC=1OC1=CC=CC=C1 USIUVYZYUHIAEV-UHFFFAOYSA-N 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 238000005516 engineering process Methods 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- 150000007984 tetrahydrofuranes Chemical class 0.000 description 4
- 239000002775 capsule Substances 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 238000010526 radical polymerization reaction Methods 0.000 description 3
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 description 2
- WOBHKFSMXKNTIM-UHFFFAOYSA-N Hydroxyethyl methacrylate Chemical class CC(=C)C(=O)OCCO WOBHKFSMXKNTIM-UHFFFAOYSA-N 0.000 description 2
- XTXRWKRVRITETP-UHFFFAOYSA-N Vinyl acetate Chemical compound CC(=O)OC=C XTXRWKRVRITETP-UHFFFAOYSA-N 0.000 description 2
- 238000005917 acylation reaction Methods 0.000 description 2
- 238000013019 agitation Methods 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 229920000457 chlorinated polyvinyl chloride Polymers 0.000 description 2
- VOZRXNHHFUQHIL-UHFFFAOYSA-N glycidyl methacrylate Chemical compound CC(=C)C(=O)OCC1CO1 VOZRXNHHFUQHIL-UHFFFAOYSA-N 0.000 description 2
- 125000005395 methacrylic acid group Chemical group 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- NIZKVZYBUGUDTI-UHFFFAOYSA-N pent-3-ynoic acid Chemical compound CC#CCC(O)=O NIZKVZYBUGUDTI-UHFFFAOYSA-N 0.000 description 2
- 230000002572 peristaltic effect Effects 0.000 description 2
- 229920006389 polyphenyl polymer Polymers 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 150000003222 pyridines Chemical class 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 235000019187 sodium-L-ascorbate Nutrition 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 238000012546 transfer Methods 0.000 description 2
- 239000003643 water by type Substances 0.000 description 2
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 229920002845 Poly(methacrylic acid) Polymers 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229920001400 block copolymer Polymers 0.000 description 1
- 238000012661 block copolymerization Methods 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- CQEYYJKEWSMYFG-UHFFFAOYSA-N butyl acrylate Chemical class CCCCOC(=O)C=C CQEYYJKEWSMYFG-UHFFFAOYSA-N 0.000 description 1
- 230000001186 cumulative effect Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 239000000412 dendrimer Substances 0.000 description 1
- 229920000736 dendritic polymer Polymers 0.000 description 1
- 230000005595 deprotonation Effects 0.000 description 1
- 238000010537 deprotonation reaction Methods 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 238000005538 encapsulation Methods 0.000 description 1
- 238000004146 energy storage Methods 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 101150089658 get1 gene Proteins 0.000 description 1
- 239000008384 inner phase Substances 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 230000008863 intramolecular interaction Effects 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000010550 living polymerization reaction Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000002088 nanocapsule Substances 0.000 description 1
- 239000011943 nanocatalyst Substances 0.000 description 1
- 230000005311 nuclear magnetism Effects 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 230000007096 poisonous effect Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000010008 shearing Methods 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 150000005846 sugar alcohols Polymers 0.000 description 1
- ISXSCDLOGDJUNJ-UHFFFAOYSA-N tert-butyl prop-2-enoate Chemical class CC(C)(C)OC(=O)C=C ISXSCDLOGDJUNJ-UHFFFAOYSA-N 0.000 description 1
- 230000010148 water-pollination Effects 0.000 description 1
Classifications
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- C08G81/00—Macromolecular compounds obtained by interreacting polymers in the absence of monomers, e.g. block polymers
- C08G81/02—Macromolecular compounds obtained by interreacting polymers in the absence of monomers, e.g. block polymers at least one of the polymers being obtained by reactions involving only carbon-to-carbon unsaturated bonds
- C08G81/024—Block or graft polymers containing sequences of polymers of C08C or C08F and of polymers of C08G
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- 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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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- 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
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- B01J35/23—Catalysts, in general, characterised by their form or physical properties characterised by their non-solid state in a colloidal state
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- C08F120/00—Homopolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and only one being terminated by only one carboxyl radical or a salt, anhydride, ester, amide, imide or nitrile thereof
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- C08F120/16—Esters of monohydric alcohols or phenols of phenols or of alcohols containing two or more carbon atoms
- C08F120/18—Esters of monohydric alcohols or phenols of phenols or of alcohols containing two or more carbon atoms with acrylic or methacrylic acids
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- C08F120/00—Homopolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and only one being terminated by only one carboxyl radical or a salt, anhydride, ester, amide, imide or nitrile thereof
- C08F120/02—Monocarboxylic acids having less than ten carbon atoms; Derivatives thereof
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- C08F120/26—Esters containing oxygen in addition to the carboxy oxygen
- C08F120/28—Esters containing oxygen in addition to the carboxy oxygen containing no aromatic rings in the alcohol moiety
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- C08F120/00—Homopolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and only one being terminated by only one carboxyl radical or a salt, anhydride, ester, amide, imide or nitrile thereof
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- C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
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- C08G65/329—Polymers modified by chemical after-treatment with organic compounds
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- C08G65/332—Polymers modified by chemical after-treatment with organic compounds containing oxygen containing carboxyl groups, or halides, or esters thereof
- C08G65/3322—Polymers modified by chemical after-treatment with organic compounds containing oxygen containing carboxyl groups, or halides, or esters thereof acyclic
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- 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
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- C08G2650/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
- C08G2650/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule characterized by the type of post-polymerisation functionalisation
- C08G2650/04—End-capping
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- C08G2650/28—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule characterised by the polymer type
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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
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Abstract
The invention belongs to the field of self-assembly high molecular materials, and particularly relates to amphiphilic ternary molecular brush polymer and vermicular mono-molecular micelle constructed by the same. The structural general formula of the polymer is A-g-(B-r-C-r-D), wherein g refers to grafting, r refers to random copolymerization, A refers to polymer main chain, B refers to lipophilic high molecular side chain, C refers to high molecular side chain with photo-crosslinking structure, D refers to hydrophilic high molecular side chain, and the side chains B, C and D are randomly grafted on the main chain A. The vermicular mono-molecular micelle is obtained by slowly adding deionized water into an N, N-dimethyl formamide solution of the amphiphilic polymer dropwise, and removing N, N-dimethyl formanide through dialysis. The vermicular mono-molecular micelle prepared by the method is novel in structure, and shape and size of the micelle can be changed by changing grafting rate and molecular weight of precursor polymer, so that the vermicular mono-molecular micelle is extremely high in controllability.
Description
Technical field
The invention belongs to self assembly polymeric material field, be specifically related to the polymerization of a kind of amphipathic ternary molecular brushThing and the vermiform unimolecular micelle of constructing thereof.
Background technology
Along with the appearance of novel synthetic reaction technology (as active free radical polymerization, click chemistry etc.), pass throughThe technology that polymer is prepared functional nano micella also emerges in multitude. As the modal method of preparing micellaOne of, self-assembly method can pass through composition, the each several part weight ratio of regulation and control block copolymer simply,The length of chain etc. is controlled shape, size and the performance of micella.
At present, the micella that block copolymerization and graft copolymer prepare by self assembly is generally polymolecularMicella. Traditional polymolecular micella really plays very large effect aspect solubilize drugs, and is once being subject to peopleGreat attention. But traditional polymolecular micella is a dynamic balance structure, and its structure can be along with the external worldThe change of environment and changing. When the concentration of polymer is during lower than CMC, micella can de-assembly. In addition,PH in blood circulation system, temperature, ionic strength, the factors such as high shear force also can have influence on the stable of micellaProperty. These factors, all can cause medicine to be released too early, thereby lessen the curative effect.
In order to improve the stability of carrier, people take following two kinds of methods conventionally: 1) polymolecular micella is enteredRow is crosslinked, latch-up structure; 2) replace polymolecular micella with unimolecular micelle.
But, after bag medicine carrying thing, carrying out the structure locking of carrier, chemical crosslink technique can be introduced poisonous conventionallyLittle molecule crosslinked dose, photo-crosslinking rule can make again to be wrapped that to be loaded in inner medicine rotten. Therefore, preparation is manyThe stable unimolecular micelle of sample is better selection.
Except Stability Analysis of Structures, unimolecular micelle has larger specific area, higher medicine carrying amount, moreLittle particle diameter, and can be by the molecular size range of precursor polymer, the micella of the required preparation of structure controlSize and geometric.
At present, most unimolecular micelle is all to prepare by dendritic amphipathic nature polyalcohol. But systemStandby dendritic polymer process is extremely loaded down with trivial details, has had a strong impact on its application. And prepared by amphipathic nature polyalcoholJourney is relatively simple, and can be by the percent grafting of telomerized polymer, close and distant water ratio, and chain lengths etc. are adjustedThe pattern of the micella that joint obtains, size, has good controllability.
But, most of research about graft copolymer at present, to prepare polymolecular micella/capsule as main,As the acid-sensitive type Nano capsule being prepared by graft copolymer of patent CN103289099A report, patentCN103059312A report pass through a kind of multichannel PH response that emulsion self-assembly method preparesNano capsule, the photo-crosslinking type nanometer wax phase change energy storage capsule of patent CN104645908A report, ifCapsule structure is not further locked, they all exist be easily affected by the external environment and occur disintegrate problem.
Summary of the invention
For solving the shortcoming and defect part of prior art, primary and foremost purpose of the present invention is to provide a kind of amphiphilicProperty ternary molecular brush polymer.
Another object of the present invention is to provide the synthetic method of above-mentioned amphipathic ternary molecular brush polymer.
A further object of the present invention is to provide wriggling of being prepared by above-mentioned amphipathic ternary molecular brush polymerWorm shape unimolecular micelle. This vermiform unimolecular micelle has nucleocapsid structure, and kernel is made up of hydrophobic high polymer,Skin is hydrophily high polymer.
The present invention also provides the purposes of above-mentioned vermiform unimolecular micelle.
The object of the invention is achieved through the following technical solutions:
A kind of amphipathic ternary molecular brush polymer has following general formula: A-g-(B-r-C-r-D);
Wherein, g represents grafting, and r represents random copolymerization, and A is main polymer chain, and B is lipophile macromoleculeSide chain, C is the polymer side chain of tool photo-crosslinking structure, D is hydrophilic macromolecule side chain; Lipophile macromoleculeThe polymer side chain C of side chain B, tool photo-crosslinking structure and hydrophilic macromolecule side chain D are randomly grafted on masterOn chain A;
The degree of polymerization of described main polymer chain A is 100～1000, and the degree of polymerization of lipophile polymer side chain B is50～120, the degree of polymerization of the polymer side chain C of tool photo-crosslinking structure is 50～100, hydrophilic macromolecule side chainThe degree of polymerization of D is 100～150; The percent grafting of lipophile polymer side chain B is 1～10%, tool photo-crosslinking knotThe percent grafting of the polymer side chain C of structure is 10～19%, and the percent grafting of hydrophilic macromolecule side chain D is40～70％；
The polymer that forms described main polymer chain A can be azido poly (glycidyl methacrylate) P(GMA-N3), azido ethyl cellulose (EC-N3), alkynyl ethyl cellulose (EC-C ≡ CH), foldedNitrogen base polyvinyl alcohol P (VA-N3), alkynyl polyvinyl alcohol P (VA-C ≡ CH), alkynyl polymethylacrylic acid hydroxylEthyl ester P (HEMA-C ≡ CH), alkynyl PHEMA P (HEA-C ≡ CH), the poly-methyl-prop of alkynylOlefin(e) acid hydroxypropyl acrylate (PHPMA-C ≡ CH), azido polymethylacrylic acid hydroxypropyl acrylate (PHPMA-N3), alkynesBased polyacrylic acid hydroxypropyl acrylate (PHPA-C ≡ CH) and azido polyacrylic acid hydroxypropyl acrylate (PHPA-N3) oneKind;
The polymer that forms described lipophile polymer side chain B is that end is the butyl polyacrylate of alkynyl(PnBA-C ≡ CH), the polyacrylic acid tert-butyl ester (PtBA-C ≡ CH), PMA (PMA-C ≡CH), polymethyl methacrylate (PMMA-C ≡ CH), polycaprolactone (PCL-C ≡ CH), polyphenyl secondAlkene (PS-C ≡ CH), polyacrylonitrile (PAN-C ≡ CH), polylactide (PLA-C ≡ CH) and poly-vinegarOne in vinyl acetate (PVAc-C ≡ CH), or the end butyl polyacrylate (PnBA-that is azidoN3) and the polyacrylic acid tert-butyl ester (PtBA-N3) in one;
The polymer that forms the polymer side chain C of described tool photo-crosslinking structure is that end is the poly-methyl-prop of alkynylOlefin(e) acid cinnamoyl ethyl ester (PCEMA-C ≡ CH), polyacrylic acid cinnamoyl ethyl ester (PCEA-C ≡ CH)And one in polyvinyl cinnamate (PVC-C ≡ CH), or the end poly-methyl-prop that is azidoOlefin(e) acid cinnamoyl ethyl ester (PCEMA-N3), polyacrylic acid cinnamoyl ethyl ester (PCEA-N3) and poly-secondEnol cinnamate (PVC-N3) in one;
The polymer that forms described hydrophilic macromolecule side chain D is that end is the polyethylene glycol (MPEG-C of alkynyl≡ CH), NIPA (PNIPAM-C ≡ CH) and polymine (PEI-C ≡ CH)In one, or the end polyethylene glycol (MPEG-N that is azido3) and poly-(N-isopropyl acrylamideAmine) (PNIPAM-N3) in one;
Above-mentioned amphipathic ternary molecular brush polymer can be synthetic by methods such as living polymerization and some chemistry, and it closesOne-tenth method specifically comprises the following steps:
(1) synthetic main chain, then main chain is carried out to functionalization, obtain functionalization trunk polymer;
(2) synthetic side chain is introduced functional group simultaneously or the side chain after synthetic is carried out to merit in building-up processEnergyization, obtains hydrophilic macromolecule side chain polymer, lipophile polymer side chain polymer and tool photo-crosslinking knotThe polymer side chain polymer of structure;
(3) by functionalization trunk polymer, hydrophilic macromolecule side chain polymer, lipophile polymer side chainThe polymer side chain mixed with polymers of polymer and tool photo-crosslinking structure is carried out a step and " is folded under catalyst existsNitrogen-alkynyl " click chemistry reaction, obtain amphipathic three-component grafted polymer.
The method of the synthetic main chain described in step (1) be radical polymerization, controllable free-radical polymerisation and cloudy fromOne in sub-polymerization;
Functionalization described in step (1) is to introduce alkynyl or azido group on each unit of main chain;
Functionalization trunk polymer described in step (1) can be azido polymethyl acid glycidylEster P (GMA-N3), azido ethyl cellulose (EC-N3), alkynyl ethyl cellulose (EC-C ≡ CH),Azido polyvinyl alcohol P (VA-N3), alkynyl polyvinyl alcohol P (VA-C ≡ CH), alkynyl polymethylacrylic acidHydroxyl ethyl ester P (HEMA-C ≡ CH), alkynyl PHEMA P (HEA-C ≡ CH), the poly-methyl-prop of alkynylOlefin(e) acid hydroxypropyl acrylate (PHPMA-C ≡ CH), azido polymethylacrylic acid hydroxypropyl acrylate (PHPMA-N3), alkynesBased polyacrylic acid hydroxypropyl acrylate (PHPA-C ≡ CH) and azido polyacrylic acid hydroxypropyl acrylate (PHPA-N3) oneKind;
The method of the synthetic side chain described in step (2) be radical polymerization, controllable free-radical polymerisation and cloudy fromOne in sub-polymerization;
Hydrophilic macromolecule side chain polymer described in step (2) is that end is the polyethylene glycol of alkynyl(MPEG-C ≡ CH), NIPA (PNIPAM-C ≡ CH) and polymineOne in (PEI-C ≡ CH), or the end polyethylene glycol (MPEG-N that is azido3) and poly-(N-N-isopropylacrylamide) (PNIPAM-N3) in one;
Lipophile polymer side chain polymer described in step (2) is that end is the butyl polyacrylate of alkynyl(PnBA-C ≡ CH), the polyacrylic acid tert-butyl ester (PtBA-C ≡ CH), PMA (PMA-C ≡CH), polymethyl methacrylate (PMMA-C ≡ CH), polycaprolactone (PCL-C ≡ CH), polyphenyl secondAlkene (PS-C ≡ CH), polyacrylonitrile (PAN-C ≡ CH), polylactide (PLA-C ≡ CH) and poly-vinegarOne in vinyl acetate (PVAc-C ≡ CH), or the end butyl polyacrylate that is azido(PnBA-N3) and the polyacrylic acid tert-butyl ester (PtBA-N3) in one;
The polymer side chain polymer of the tool photo-crosslinking structure described in step (2) is that end is the poly-first of alkynylBase acrylic acid cinnamoyl ethyl ester (PCEMA-C ≡ CH), polyacrylic acid cinnamoyl ethyl ester (PCEA-C≡ CH) and polyvinyl cinnamate (PVC-C ≡ CH) in one, or end to be azido poly-Methacrylic acid cinnamoyl ethyl ester (PCEMA-N3), polyacrylic acid cinnamoyl ethyl ester (PCEA-N3)And polyvinyl cinnamate (PVC-N3) in one;
Introducing functional group described in step (2) and functionalization be on the end of side chain, introduce alkynyl orAzido group;
Catalyst described in step (3) is the one in following combination: copper sulphate and ascorbic acid, brominationCuprous and pentamethyl-diethylenetriamine or cuprous bromide and 2,2'-bipyridyl; Described copper sulphate and ascorbic acidMass ratio be preferably 1:2.
A kind of vermiform unimolecular micelle, length is 20～300nm, width is 15～35nm. By deionizationWater slowly drops in the DMF solution of described amphipathic ternary molecular brush polymer, thenRemove DMF through dialysis and obtain, concrete steps are: by above-mentioned amphipathic 1～10 mass partsThe high grafting density polymer of ternary is dissolved in 1～50 mass parts DMF, then by 50～500 matterAmount part water is slowly added drop-wise in the DMF of above-mentioned amphipathic ternary molecular brush polymer, lastTo water, dialysis is removed DMF and is obtained vermiform unimolecular micelle.
Because percent grafting is high, the mutual eliminating between side chain, the high grafting density polymer of amphipathic ternary cannot look likeThe polymer molecule brush of low percent grafting is the same, shrinks bendingly, forms stable many with other interaction of moleculesMolecule micella, can only be by intramolecular interaction, forms taking hydrophobic side chain B and C as core hydrophilySide chain D is the vermiform unimolecular micelle of hat. The side chain PtBA of this polymer, can through further hydrolysisBecome PAA. PAA has PH response. Self assembly under acid condition, PAA and PCEMA are because dredgingShrinking appears in water, therefore, can in assembling, drug encapsulation be arrived to unimolecular micelle inside, works as surrounding environmentWhile being alkalescence, due to the deprotonation of PAA, bag is loaded in unimolecular micelle inside to Medicine small molecule quilt slowlyDischarge.
Described vermiform unimolecular micelle can be applied to pharmaceutical carrier, nano-reactor or nanocatalyst etc.Field.
Compared with prior art, the present invention has the following advantages and beneficial effect:
(1) the vermiform unimolecular micelle that this technology obtains, novel structure.
(2) pattern of vermiform unimolecule nano-micelle and size can be by regulating backbone length and side chain lengthsControl, improved the controllability of micella appearance and size.
(3) vermiform unimolecule nano-micelle can be because of its concentration, the effect of other factors such as shearing force andDisintegrate. Solve traditional polymolecular micella when lower than critical micelle concentration, or in ionic strength, high shear forceEtc. the problem that occurs under factor effect to disintegrate.
Brief description of the drawings
Fig. 1 is the ternary brush polymer preparing in embodiment 1The nuclear-magnetism figure of PGMA-g-(PtBA-r-PCEMA-r-MPEG), Fig. 1 has illustrated side chainPtBA, PCEMA, MPEG has successfully been grafted on main chain.
Fig. 2 is the ternary brush polymer preparing in embodiment 1The pattern of the polymer chain of PGMA-g-(PtBA-r-PCEMA-r-MPEG) under AFM, Fig. 2Can find out that this polymer molecular chain has vermiform pattern, illustrate that side chain graft density is large, steric hindrance is larger,The main chain that makes polymer cannot be curling and obtains vermiform pattern.
Detailed description of the invention
Below in conjunction with embodiment and accompanying drawing, the present invention is described in further detail, but enforcement side of the present inventionFormula is not limited to this.
Embodiment 1
The high grafting density polymer of a kind of amphipathic ternary, is prepared by following steps:
(1)P(GMA-N3) main chain synthetic
Press amount of substance ratio, get 1 part of 2-isobutyl bromide mono methoxy ethyl ester initator, 700 parts of methacrylic acidsEthylene oxidic ester (GMA), 600 parts of diphenyl ether, 1 part of CuBr and 1 part of N, N, N', N', N " pentamethyl twoEthene triamine (PMDETA), under nitrogen protection, 30 DEG C are carried out ATRP reaction 3 hours, obtain the degree of polymerization(DP) be 260 poly (glycidyl methacrylate) (PGMA).
Press amount of substance ratio, get 1 part of PGMA (DP=260), 1000 parts of NaN3, 130000 parts of diformazansBase formamide (DMF) and 6 parts of AlCl3, at 50 DEG C, react 24 hours, obtain P (GMA-N3), doFor main chain.
Synthesizing of (2) three kinds of side chains
Synthesizing of hydrophilic macromolecule side chain: press amount of substance ratio, get 1 part of mono methoxy polyethylene glycol(Mn=5000), 3 parts of 2-propynyl acetic acid, 4 parts of DMAPs (DMAP), 6 parts of 1-(3-bis-Methylamino propyl group)-3-ethyl-carbodiimide hydrochloride (EDCHCl) and 500 parts of carrene, 30 DEG CReact 24 hours, obtain MPEG-C ≡ CH (DP=114).
Synthesizing of lipophile polymer side chain: press amount of substance ratio, get 1 part of trimethyl silicane propargyl-2-bromine differentButyl ester initator, 80 parts of tert-butyl acrylates (tBA), 120 parts of toluene, 1 part of CuBr and 1 partN, N, N', N', N " pentamethyl-diethylenetriamine (PMDETA), under nitrogen protection 80 DEG C to carry out ATRP anti-Answer 6 hours, obtaining trimethyl silicane alkynyl is the PtBA-C ≡ C-TMS of end. Press amount of substance ratio, get 1Part PtBA-C ≡ C-TMS polymer, is dissolved in 5000 oxolanes, then adds 4 parts of tetrabutyls to fluoridizeAmmonium, is hydrolyzed 24h under room temperature, sloughs after trimethyl silicane group, obtains DP and be 85 PtBA-C ≡ C-TMS.
Synthesizing of the polymer side chain of tool photo-crosslinking structure: press amount of substance ratio, get 1 part of trimethyl silicane alkynes thirdBase-2-bromine isobutyl ester initator, 60 parts of hydroxyethyl methacrylates (HEMA), 100 parts of methyl alcohol, 1 part of CuClAnd 1 part 2,2'-bipyridyl, under nitrogen protection, 50 DEG C are carried out ATRP reaction, obtain the degree of polymerization (DP) to be120 PHEMA-C ≡ CH-TMS. Get 100 parts of PHEMA-C ≡ CH-TMS, 200 parts of cinnamoyl chloridesAnd 300 parts of anhydrous pyridines, under normal temperature, carry out acylation reaction, obtain PCEMA-C ≡ CH-TMS. Get again 1Part PCEMA-C ≡ CH-TMS polymer, is dissolved in 5000 oxolanes, then adds 4 parts of tetrabutylsAmmonium fluoride, is hydrolyzed 24h under room temperature, sloughs after trimethyl silicane group, obtains DP and be 65 PCEMA-C ≡CH。
(3) closing of amphipathic ternary high grafting density polymer P GMA-g-(PtBA-r-PCEMA-r-MPEG)Become
Press amount of substance ratio, get 1 part of P (GMA-N3), part 200 parts of MPEG-C ≡ CH, 46 parts of PtBA-C≡ CH, 5 parts of PCEMA-C ≡ CH are dissolved in 1000 parts of dimethyl formamides (DMF), then add 1 partCuSO4And 2 parts of sodium ascorbates, react 3 days at 30 DEG C, obtain the high grafting density polymerization of amphipathic ternaryThing PGMA-g-(PtBA-r-PCEMA-r-MPEG).
A kind of vermiform unimolecule nano-micelle adopts solution self-assembly method to make, and its preparation method comprises followingStep:
In mass ratio, get 1 part of high grafting density polymer of amphipathic ternary and be dissolved in 10 parts of N, N-dimethyl formylIn amine, under 30 DEG C of magnetic agitation 1000rpm, 30 parts of deionized waters are slowly added drop-wise to polymerization with peristaltic pumpIn thing solution, dropwise and continue to stir 30 minutes, then transfer in bag filter water is dialysed and removed for two daysDMF, obtains with PCEMA, and PtBA is core, and MPEG is the vermiform unimolecular micelle of hat.
Embodiment 2
Preparation method and raw material form all with embodiment 1, only three-component grafted to the amphipathic vermiform of embodiment 1The backbone length of polymer regulates, and can make the nano-micelle of different size. The length of three kinds of main chainsIn table 1.
The impact of table 1 backbone length on unimolecular micelle length
As can be seen from Table 1, by changing the length of main chain, can prepare the vermiform unimolecule of different lengthNano-micelle.
Embodiment 3
Preparation method and raw material, with embodiment 1, are adjusted the close hydrophobic side chain mass ratio of polymer, probe intoThe impact of parent's hydrophobic side chain mass ratio on micella stability, result is as shown in table 2. At this, hydrophobic side chainsFor PCEMA and PtBA.
The impact of the close hydrophobic side chain mass ratio of table 2 on micella stability
As can be seen from Table 2, hydrophobic side chain be greater than total side chain quality 60% time, polymer starts nothingMethod obtains stable unimolecular micelle by the method for embodiment 1, thus Precipitation.
Embodiment 4
Preparation method and raw material, with embodiment 1, are adjusted the volume ratio of PCEMA and PtBA, probe intoThe impact of the volume ratio of PCEMA and PtBA on micella kernel phase structure, result is as shown in table 3.
The impact of the volume ratio of table 3PCEMA and PtBA on micella kernel phase structure
As can be seen from Table 3, when PCEMA volume account for PCEMA and PtBA cumulative volume 12.5% time,Micella kernel has the globular micelle (BCC) that body-centered cubic is arranged; When PCEMA volume fraction reaches 30%,Micella kernel has the shape structure (HEX) of two-dimentional Hexagonal packing; When PCEMA volume fraction reaches 50%, layerShape structure (LAM).
Embodiment 5
The high grafting density polymer of a kind of amphipathic ternary, is prepared by following steps:
(1)P(GMA-N3) main chain synthetic
Press amount of substance ratio, get 1 part of 2-isobutyl bromide mono methoxy ethyl ester initator, 700 parts of methacrylic acidsEthylene oxidic ester (GMA), 600 parts of diphenyl ether, 1 part of CuBr and 1 part of N, N, N', N', N " pentamethyl twoEthene triamine (PMDETA), under nitrogen protection, 30 DEG C are carried out ATRP reaction 3 hours, obtain the degree of polymerization(DP) be 260 poly (glycidyl methacrylate) (PGMA).
Press amount of substance ratio, get 1 part of PGMA (DP=260), 1000 parts of NaN3, 130000 parts of diformazansBase formamide (DMF) and 6 parts of AlCl3, at 50 DEG C, react 24 hours, obtain P (GMA-N3), doFor main chain.
Synthesizing of (2) three kinds of side chains
Synthesizing of hydrophilic macromolecule side chain: press amount of substance ratio, get 1 part of mono methoxy polyethylene glycol(Mn=5000), 3 parts of 2-propynyl acetic acid, 4 parts of DMAPs (DMAP), 6 parts of 1-(3-bis-Methylamino propyl group)-3-ethyl-carbodiimide hydrochloride (EDC.HCl) and 500 parts of carrene, 30 DEG CReact 24 hours, obtain MPEG-C ≡ CH (DP=114).
Synthesizing of lipophile polymer side chain: press amount of substance ratio, get 1 part of trimethyl silicane propargyl-2-bromine differentButyl ester initator, 80 parts of n-butyl acrylates (nBA), 100 parts of toluene, 1 part of CuBr and 1 partN, " pentamethyl-diethylenetriamine (PMDETA), under nitrogen protection, 80 DEG C are carried out ATRP for N, N', N', NReact 6 hours, obtaining trimethyl silicane alkynyl is the PBA-C ≡ C-TMS of end. Press amount of substance ratio, get1 part of PnBA-C ≡ C-TMS polymer, is dissolved in 5000 oxolanes, then adds 4 parts of tetrabutyl fluorineChange ammonium, under room temperature, be hydrolyzed 24h, slough after trimethyl silicane group, obtain DP and be 85 PnBA-C ≡ C-TMS.
Synthesizing of the polymer side chain of tool photo-crosslinking structure: press amount of substance ratio, get 1 part of trimethyl silicane alkynes thirdBase-2-bromine isobutyl ester initator, 60 parts of hydroxyethyl methacrylates (HEMA), 100 parts of methyl alcohol, 1 part of CuClAnd 1 part 2,2'-bipyridyl, under nitrogen protection, 50 DEG C are carried out ATRP reaction, obtain the degree of polymerization (DP) to be120 PHEMA-C ≡ CH-TMS. Get 100 parts of PHEMA-C ≡ CH-TMS, 200 parts of cinnamoyl chloridesAnd 300 parts of anhydrous pyridines, under normal temperature, carry out acylation reaction, obtain PCEMA-C ≡ CH-TMS. Get again 1Part PCEMA-C ≡ CH-TMS polymer, is dissolved in 5000 oxolanes, then adds 4 parts of tetrabutylsAmmonium fluoride, is hydrolyzed 24h under room temperature, sloughs after trimethyl silicane group, obtains DP and be 65 PCEMA-C ≡CH。
(3) the high grafting density polymer P of amphipathic ternary GMA-g-(PnBA-r-PCEMA-r-MPEG)Synthetic
Press amount of substance ratio, get 1 part of P (GMA-N3), part 200 parts of MPEG-C ≡ CH, 46 parts of PnBA-C≡ CH, 5 parts of PCEMA-C ≡ CH are dissolved in 1000 parts of dimethyl formamides (DMF), then add 1 partCuSO4And 2 parts of sodium ascorbates, react 3 days at 30 DEG C, obtain the high grafting density polymerization of amphipathic ternaryThing PGMA-g-(PnBA-r-PCEMA-r-MPEG).
A kind of vermiform unimolecule nano-micelle adopts solution self-assembly method to make, and its preparation method comprises followingStep:
In mass ratio, get 1 part of high grafting density polymer of amphipathic ternary and be dissolved in 10 parts of N, N-dimethyl formylIn amine, under 30 DEG C of magnetic agitation 1000rpm, 30 parts of deionized waters are slowly added drop-wise to polymerization with peristaltic pumpIn thing solution, dropwise and continue to stir 30 minutes, then transfer in bag filter water is dialysed and removed for two daysDMF, obtains with PCEMA, and PnBA is core, and MPEG is the vermiform unimolecular micelle of hat.
Embodiment 6
Preparation method and raw material, with embodiment 5, are only adjusted the degree of polymerization of hydrophilic macromolecule side chain, visitThe impact of the diameter of the degree of polymerization of studying carefully hydrophilic macromolecule side chain on vermiform unimolecular micelle, result is as table 5Shown in.
The impact of the diameter of the degree of polymerization of table 5 hydrophilic side-chains on vermiform unimolecular micelle
From table 5, the degree of polymerization of hydrophilic macromolecule side chain is larger, the diameter of vermiform unimolecular micelleAlso larger.
Embodiment 7
Preparation method and raw material be with embodiment 5, the MPEG of every kind of amphipathic ternary molecular brush polymer,The percent grafting of PCEMA and PnBA side chain is respectively 70%, 8%, 12%, only to lipophile polymer side chainThe degree of polymerization adjust, the degree of polymerization of probing into lipophile polymer side chain is hydrophobic to vermiform unimolecular micelleThe impact of nuclear diameter, result is as shown in table 6.
The impact of the degree of polymerization of table 6 lipophile side chain on vermiform unimolecular micelle hydrophobic core diameter
From table 6, the degree of polymerization of lipophile polymer side chain is larger, vermiform unimolecular micelle hydrophobic coreDiameter is also larger.
Embodiment 8
Preparation method and raw material, with embodiment 5, are adjusted the close hydrophobic side chain mass ratio of polymer, probe intoThe impact of parent's hydrophobic side chain mass ratio on micella stability, result is as shown in table 7. At this, hydrophobic side chainsFor PCEMA and PnBA.
The impact of the close hydrophobic side chain mass ratio of table 7 on micella stability
As shown in Table 7, hydrophobic side chain be greater than total side chain quality 50% time, polymer starts to lead toThe method of crossing embodiment 5 obtains stable unimolecular micelle, thus Precipitation.
Embodiment 9
Preparation method and raw material form all with embodiment 5, only changes the amphipathic ternary molecular brush of embodiment 5The composition of lipophile polymer side chain, PnBA, PCL that the lipophile polymer side chain degree of polymerization is 85, PMA,Prepared by the preparation method of PS and PtBA similar, is to be prepared by conventional ARTP. Every kind amphipathic threeUnit MPEG, the PCEMA of molecular brush polymer and the percent grafting of lipophile polymer side chain be respectively 70%,8%, 12%. Probe into the impact of lipophile polymer side chain structure on phase structure in molecule. Experimental result showsThe unimolecular micelle obtaining as the ternary brush assembling of lipophile polymer side chain taking PnBA, PCL, PMA,Its inner phase structure is roughly the same, and the ternary taking PS as lipophile polymer side chain is brushed the unimolecule preparingMicella, inside is separated not obvious.
Above-described embodiment is preferably embodiment of the present invention, but embodiments of the present invention are not subject to above-mentioned realityExecute routine restriction, other any do not deviate from the change done under Spirit Essence of the present invention and principle, modification,Substitute, combine, simplify, all should be equivalent substitute mode, within being included in protection scope of the present invention.
Claims (8)
1. an amphipathic ternary molecular brush polymer, is characterized in that, described amphipathic ternary molecular brush is poly-Compound has following general formula: A-g-(B-r-C-r-D);
Wherein, g represents grafting, and r represents random copolymerization, and A is main polymer chain, and B is lipophile macromoleculeSide chain, C is the polymer side chain of tool photo-crosslinking structure, D is hydrophilic macromolecule side chain; Lipophile macromoleculeThe polymer side chain C of side chain B, tool photo-crosslinking structure and hydrophilic macromolecule side chain D are randomly grafted on masterOn chain A;
The polymer that forms described main polymer chain A is azido poly (glycidyl methacrylate), azidoEthyl cellulose, alkynyl ethyl cellulose, azido polyvinyl alcohol, alkynyl polyvinyl alcohol, the poly-methyl of alkynylHydroxy-ethyl acrylate, alkynyl PHEMA, alkynyl polymethylacrylic acid hydroxypropyl acrylate, the poly-first of azidoThe one of base hydroxypropyl acrylate, alkynyl polyacrylic acid hydroxypropyl acrylate, azido polyacrylic acid hydroxypropyl acrylate;
The polymer that forms described lipophile polymer side chain B is that end is the butyl polyacrylate, poly-of alkynylTert-butyl acrylate, PMA, polymethyl methacrylate, polycaprolactone, polystyrene, poly-One in acrylonitrile, polylactide and polyvinyl acetate, or the end polyacrylic acid fourth that is azidoOne in ester and the polyacrylic acid tert-butyl ester;
The polymer that forms the polymer side chain C of described tool photo-crosslinking structure is that end is the poly-methyl-prop of alkynylOne in olefin(e) acid cinnamoyl ethyl ester, polyacrylic acid cinnamoyl ethyl ester and polyvinyl cinnamate, orThat end is polymethylacrylic acid cinnamoyl ethyl ester, polyacrylic acid cinnamoyl ethyl ester and the poly-second of azidoOne in enol cinnamate;
The polymer that forms described hydrophilic macromolecule side chain D is that end is the polyethylene glycol of alkynyl, poly-(N-N-isopropylacrylamide) and polymine in one, or the end polyethylene glycol and poly-that is azidoOne in (NIPA).
2. amphipathic ternary molecular brush polymer according to claim 1, is characterized in that, described poly-The degree of polymerization of compound main chain A is 100～1000, and the degree of polymerization of lipophile polymer side chain B is 50～120,The degree of polymerization of the polymer side chain C of tool photo-crosslinking structure is 50～100, the polymerization of hydrophilic macromolecule side chain DDegree is 100～150; The percent grafting of lipophile polymer side chain B is 1～10%, the high score of tool photo-crosslinking structureThe percent grafting of sub-side chain C is 10～19%, and the percent grafting of hydrophilic macromolecule side chain D is 40～70%.
3. the synthetic method of the amphipathic ternary molecular brush polymer described in claim 1 or 2, its feature existsIn, comprise the following steps:
(1) synthetic main chain, then main chain is carried out to functionalization, obtain functionalization trunk polymer;
(2) synthetic side chain is introduced functional group simultaneously or the side chain after synthetic is carried out to merit in building-up processEnergyization, obtains hydrophilic macromolecule side chain polymer, lipophile polymer side chain polymer and tool photo-crosslinking knotThe polymer side chain polymer of structure;
(3) by functionalization trunk polymer, hydrophilic macromolecule side chain polymer, lipophile polymer side chainThe polymer side chain mixed with polymers of polymer and tool photo-crosslinking structure is carried out a step and " is folded under catalyst existsNitrogen-alkynyl " click chemistry reaction, obtain amphipathic three-component grafted polymer.
4. the synthetic method of amphipathic ternary molecular brush polymer according to claim 3, its feature existsIn,
Functionalization trunk polymer described in step (1) be azido poly (glycidyl methacrylate),Azido ethyl cellulose, alkynyl ethyl cellulose, azido polyvinyl alcohol, alkynyl polyvinyl alcohol, alkynylPoly hydroxy ethyl acrylate, alkynyl PHEMA, alkynyl polymethylacrylic acid hydroxypropyl acrylate, nitrineThe one of base polymethylacrylic acid hydroxypropyl acrylate, alkynyl polyacrylic acid hydroxypropyl acrylate, azido polyacrylic acid hydroxypropyl acrylate;
Hydrophilic macromolecule side chain polymer described in step (2) is that end is the polyethylene glycol of alkynyl, poly-(N-N-isopropylacrylamide) and polymine in one, or the end polyethylene glycol and poly-that is azidoOne in (NIPA);
Lipophile polymer side chain polymer described in step (2) be end be alkynyl butyl polyacrylate,The polyacrylic acid tert-butyl ester, PMA, polymethyl methacrylate, polycaprolactone, polystyrene,One in polyacrylonitrile, polylactide and polyvinyl acetate, or the end polyacrylic acid that is azidoOne in butyl ester and the polyacrylic acid tert-butyl ester;
The polymer side chain polymer of the tool photo-crosslinking structure described in step (2) is that end is the poly-first of alkynylOne in base acrylic acid cinnamoyl ethyl ester, polyacrylic acid cinnamoyl ethyl ester and polyvinyl cinnamate,Or the end polymethylacrylic acid cinnamoyl ethyl ester that is azido, polyacrylic acid cinnamoyl ethyl ester and poly-One in vinyl alcohol cinnamate.
5. the synthetic method of amphipathic ternary molecular brush polymer according to claim 3, its feature existsIn, the catalyst described in step (3) is the one in following combination: copper sulphate and ascorbic acid, brominationCuprous and pentamethyl-diethylenetriamine or cuprous bromide and 2,2'-bipyridyl.
6. a vermiform unimolecular micelle, is characterized in that, described vermiform unimolecular micelle length is20～300nm, width is 15～35nm; Described vermiform unimolecular micelle is that deionized water is slowly dropped toIn the DMF solution of the amphipathic ternary molecular brush polymer described in claim 1 or 2,Removing DMF through dialysis again obtains.
7. vermiform unimolecular micelle according to claim 6, is characterized in that, described vermiform listMolecule micella prepares by following steps: by the high grafting density polymer of the amphipathic ternary of 1～10 mass partsBe dissolved in 1～50 mass parts DMF, then 50～500 mass parts water droplets are added to above-mentioned amphiphilicProperty ternary molecular brush polymer DMF in, finally to water, N, N-dimethyl methyl are removed in dialysisAcid amides obtains vermiform unimolecular micelle.
8. vermiform unimolecular micelle claimed in claim 6 is urged in pharmaceutical carrier, nano-reactor or nanometerApplication in agent field.
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