CN102964582B - Segmented copolymer, preparation method thereof and hydrogel - Google Patents
Segmented copolymer, preparation method thereof and hydrogel Download PDFInfo
- Publication number
- CN102964582B CN102964582B CN201210512774.3A CN201210512774A CN102964582B CN 102964582 B CN102964582 B CN 102964582B CN 201210512774 A CN201210512774 A CN 201210512774A CN 102964582 B CN102964582 B CN 102964582B
- Authority
- CN
- China
- Prior art keywords
- formula
- block copolymer
- lactide
- equal
- reaction
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 239000000017 hydrogel Substances 0.000 title claims abstract description 45
- 229920001577 copolymer Polymers 0.000 title abstract description 8
- 238000002360 preparation method Methods 0.000 title description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 44
- 150000001875 compounds Chemical class 0.000 claims abstract description 22
- 229920001400 block copolymer Polymers 0.000 claims description 201
- 238000006243 chemical reaction Methods 0.000 claims description 119
- 239000000243 solution Substances 0.000 claims description 116
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 74
- 239000002202 Polyethylene glycol Substances 0.000 claims description 61
- 229920001223 polyethylene glycol Polymers 0.000 claims description 61
- 229910052757 nitrogen Inorganic materials 0.000 claims description 44
- JJTUDXZGHPGLLC-UHFFFAOYSA-N lactide Chemical compound CC1OC(=O)C(C)OC1=O JJTUDXZGHPGLLC-UHFFFAOYSA-N 0.000 claims description 42
- 238000006116 polymerization reaction Methods 0.000 claims description 29
- 238000002156 mixing Methods 0.000 claims description 22
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 20
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 claims description 19
- 238000000034 method Methods 0.000 claims description 18
- 239000003054 catalyst Substances 0.000 claims description 16
- 230000008878 coupling Effects 0.000 claims description 16
- 238000010168 coupling process Methods 0.000 claims description 16
- 238000005859 coupling reaction Methods 0.000 claims description 16
- 239000003153 chemical reaction reagent Substances 0.000 claims description 14
- 238000007151 ring opening polymerisation reaction Methods 0.000 claims description 13
- 239000012736 aqueous medium Substances 0.000 claims description 12
- 239000002131 composite material Substances 0.000 claims description 12
- 238000006482 condensation reaction Methods 0.000 claims description 12
- KSBAEPSJVUENNK-UHFFFAOYSA-L tin(ii) 2-ethylhexanoate Chemical group [Sn+2].CCCCC(CC)C([O-])=O.CCCCC(CC)C([O-])=O KSBAEPSJVUENNK-UHFFFAOYSA-L 0.000 claims description 10
- 239000010839 body fluid Substances 0.000 claims description 4
- 210000001124 body fluid Anatomy 0.000 claims description 4
- 239000007853 buffer solution Substances 0.000 claims description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 3
- PBMIETCUUSQZCG-UHFFFAOYSA-N n'-cyclohexylmethanediimine Chemical compound N=C=NC1CCCCC1 PBMIETCUUSQZCG-UHFFFAOYSA-N 0.000 claims description 3
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 abstract description 192
- 239000000463 material Substances 0.000 abstract description 19
- 230000004044 response Effects 0.000 abstract description 6
- 239000000693 micelle Substances 0.000 abstract description 4
- 239000007787 solid Substances 0.000 description 69
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 66
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 64
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 64
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 60
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 40
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 40
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 36
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 34
- 239000000047 product Substances 0.000 description 32
- 239000004698 Polyethylene Substances 0.000 description 28
- 229920000573 polyethylene Polymers 0.000 description 28
- ROOXNKNUYICQNP-UHFFFAOYSA-N ammonium persulfate Chemical group [NH4+].[NH4+].[O-]S(=O)(=O)OOS([O-])(=O)=O ROOXNKNUYICQNP-UHFFFAOYSA-N 0.000 description 26
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 26
- 239000003960 organic solvent Substances 0.000 description 25
- 239000002994 raw material Substances 0.000 description 25
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 24
- 238000000967 suction filtration Methods 0.000 description 23
- 239000011259 mixed solution Substances 0.000 description 22
- FALRKNHUBBKYCC-UHFFFAOYSA-N 2-(chloromethyl)pyridine-3-carbonitrile Chemical compound ClCC1=NC=CC=C1C#N FALRKNHUBBKYCC-UHFFFAOYSA-N 0.000 description 21
- 229940014800 succinic anhydride Drugs 0.000 description 21
- 238000001914 filtration Methods 0.000 description 20
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 19
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- 239000012043 crude product Substances 0.000 description 18
- 229920001432 poly(L-lactide) Polymers 0.000 description 18
- 239000007864 aqueous solution Substances 0.000 description 17
- 238000005481 NMR spectroscopy Methods 0.000 description 16
- 239000000203 mixture Substances 0.000 description 16
- 230000000694 effects Effects 0.000 description 15
- 239000007800 oxidant agent Substances 0.000 description 15
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 14
- 229910001870 ammonium persulfate Inorganic materials 0.000 description 13
- 238000004458 analytical method Methods 0.000 description 13
- 238000005227 gel permeation chromatography Methods 0.000 description 13
- 239000011165 3D composite Substances 0.000 description 12
- 238000001035 drying Methods 0.000 description 12
- 238000005406 washing Methods 0.000 description 12
- 229920000642 polymer Polymers 0.000 description 11
- JJTUDXZGHPGLLC-IMJSIDKUSA-N 4511-42-6 Chemical compound C[C@@H]1OC(=O)[C@H](C)OC1=O JJTUDXZGHPGLLC-IMJSIDKUSA-N 0.000 description 10
- 239000000126 substance Substances 0.000 description 10
- 239000003814 drug Substances 0.000 description 9
- 238000010438 heat treatment Methods 0.000 description 9
- 230000001590 oxidative effect Effects 0.000 description 9
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 8
- 238000010521 absorption reaction Methods 0.000 description 8
- 239000002244 precipitate Substances 0.000 description 8
- 238000005086 pumping Methods 0.000 description 8
- 230000008859 change Effects 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- 230000009471 action Effects 0.000 description 6
- 230000018044 dehydration Effects 0.000 description 6
- 238000006297 dehydration reaction Methods 0.000 description 6
- 229910001873 dinitrogen Inorganic materials 0.000 description 6
- 230000035484 reaction time Effects 0.000 description 6
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 5
- 235000011114 ammonium hydroxide Nutrition 0.000 description 5
- 238000013270 controlled release Methods 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 238000009472 formulation Methods 0.000 description 5
- 239000000499 gel Substances 0.000 description 5
- 230000007935 neutral effect Effects 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 238000001291 vacuum drying Methods 0.000 description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- 238000004108 freeze drying Methods 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 4
- 238000007254 oxidation reaction Methods 0.000 description 4
- 238000010926 purge Methods 0.000 description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- 230000015556 catabolic process Effects 0.000 description 3
- 238000006731 degradation reaction Methods 0.000 description 3
- 239000003937 drug carrier Substances 0.000 description 3
- 239000005457 ice water Substances 0.000 description 3
- -1 polyethylene Polymers 0.000 description 3
- 239000002861 polymer material Substances 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 238000005303 weighing Methods 0.000 description 3
- IRPVABHDSJVBNZ-RTHVDDQRSA-N 5-[1-(cyclopropylmethyl)-5-[(1R,5S)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl]pyrazol-3-yl]-3-(trifluoromethyl)pyridin-2-amine Chemical compound C1=C(C(F)(F)F)C(N)=NC=C1C1=NN(CC2CC2)C(C2[C@@H]3CN(C[C@@H]32)C2COC2)=C1 IRPVABHDSJVBNZ-RTHVDDQRSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 2
- AYCPARAPKDAOEN-LJQANCHMSA-N N-[(1S)-2-(dimethylamino)-1-phenylethyl]-6,6-dimethyl-3-[(2-methyl-4-thieno[3,2-d]pyrimidinyl)amino]-1,4-dihydropyrrolo[3,4-c]pyrazole-5-carboxamide Chemical compound C1([C@H](NC(=O)N2C(C=3NN=C(NC=4C=5SC=CC=5N=C(C)N=4)C=3C2)(C)C)CN(C)C)=CC=CC=C1 AYCPARAPKDAOEN-LJQANCHMSA-N 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 229920001940 conductive polymer Polymers 0.000 description 2
- 238000004132 cross linking Methods 0.000 description 2
- 239000011263 electroactive material Substances 0.000 description 2
- 238000007710 freezing Methods 0.000 description 2
- 230000008014 freezing Effects 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 239000003999 initiator Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- MAYZWDRUFKUGGP-VIFPVBQESA-N (3s)-1-[5-tert-butyl-3-[(1-methyltetrazol-5-yl)methyl]triazolo[4,5-d]pyrimidin-7-yl]pyrrolidin-3-ol Chemical compound CN1N=NN=C1CN1C2=NC(C(C)(C)C)=NC(N3C[C@@H](O)CC3)=C2N=N1 MAYZWDRUFKUGGP-VIFPVBQESA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 238000006845 Michael addition reaction Methods 0.000 description 1
- IDRGFNPZDVBSSE-UHFFFAOYSA-N OCCN1CCN(CC1)c1ccc(Nc2ncc3cccc(-c4cccc(NC(=O)C=C)c4)c3n2)c(F)c1F Chemical compound OCCN1CCN(CC1)c1ccc(Nc2ncc3cccc(-c4cccc(NC(=O)C=C)c4)c3n2)c(F)c1F IDRGFNPZDVBSSE-UHFFFAOYSA-N 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 238000013267 controlled drug release Methods 0.000 description 1
- 238000006352 cycloaddition reaction Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000001879 gelation Methods 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 238000011326 mechanical measurement Methods 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000005691 oxidative coupling reaction Methods 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 239000008055 phosphate buffer solution Substances 0.000 description 1
- 108010054442 polyalanine Proteins 0.000 description 1
- 229920001451 polypropylene glycol Polymers 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000001172 regenerating effect Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000027756 respiratory electron transport chain Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 238000007142 ring opening reaction Methods 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 230000001502 supplementing effect Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
Landscapes
- Polyethers (AREA)
Abstract
The invention provides a segmented copolymer which comprises a segment A with a structure shown in a formula (I) or a formula (II) and a segment B with a structure shown in a formula (III) or a formula (IV). A laevo-configuration segmented copolymer and a dextro-configuration segmented copolymer are mixed in a water-based medium, and can be gradually transformed into a three-dimensional compound hydrogel material from a solution. Because the segment with the structure shown in the formula (III) or the formula (IV) contains an aniline oligomer segment, the segment B has a intermolecular pi-pi acting force and conjugated pi electrons have conductivity, the prepared segmented copolymer and the hydrogel have better electrochemical response characteristics; and meanwhile, the segment A is extremely dissolved in water, a packaged micelle formed by the segment A and the segment B under a certain linkage quantity can be dissolved in water. Therefore, the segmented copolymer and hydrogel provided by the invention have better water-solubility.
Description
Technical Field
The invention relates to the field of biomedical high polymer materials, in particular to a block copolymer, a preparation method thereof and hydrogel.
Background
The injectable hydrogel is a polymer with a cross-linked network structure capable of absorbing and retaining a large amount of water, and the material can be cross-linked based on physical acting force, such as hydrophobic effect, electrostatic composite, stereo composite, hydrogen bond effect and the like, and can also be cross-linked based on chemical reaction, such as Michael addition, photo cross-linking, cycloaddition, oxidative coupling, enzyme cross-linking and the like, so that solution-gel conversion is generated, and therefore, the injectable hydrogel has wide application in aspects of regenerative medicine, controlled drug release and the like, and is a new research direction in the field of biomedical materials in recent years. The liquid has the characteristics of good fluidity, convenient use, long detention time, small wound surface, performance similar to human tissues and the like, has better permeability to low-molecular solutes, excellent biocompatibility and better reproducibility, and is easy to synthesize, so the liquid is widely concerned.
The injectable hydrogel can enable the embedded medicine to stably and controllably reach body fluid, and the medicine is mixed with the polymer solution and then injected into the body in situ to form gel so as to achieve the controlled release of the medicine. Electroactive materials, such as conductive polymers, are also well applied in the field of controlled release of drugs due to their advantages of being easier to synthesize, low in cost, and the like. The aniline oligomer with electric activity can be reversibly doped along with the change of pH and electrochemically doped along with the change of redox potential to cause the change of an assembly structure of a polymer material, so that the aniline oligomer has the capacity of embedding and releasing drugs and bioactive molecules, and can be applied to the field of drug controlled release. Meanwhile, based on the fact that the in vivo reaction is related to electron transfer and the sensitivity of cells to electric signals, the adhesion, growth, differentiation and apoptosis of the cells can be regulated and controlled by introducing the electroactive material, so that the conductive polymer with the electroactive has great advantages in the fields of drug controlled release and tissue engineering.
The prior art discloses a variety of injectable hydrogels, such as block copolymer hydrogels of polyethylene glycol and poly (L-lactic acid), that can achieve reversible changes in sol and gel upon temperature changes; block copolymers formed from polyethylene oxide-polypropylene oxide polymers and polyalanine can also form injectable gels at certain concentrations. However, none of the injectable hydrogels prepared by the prior art are electroactive.
Disclosure of Invention
In view of the above, the technical problem to be solved by the present invention is to provide a block copolymer, a preparation method thereof and a hydrogel, wherein the block copolymer and the hydrogel prepared by the preparation method have good water solubility and good electrochemical response characteristics.
The invention provides a block copolymer, which comprises an A block with a structure shown in a formula (I) or a formula (II) and a B block with a structure shown in a formula (III) or a formula (IV):
wherein,
n is polymerization degree, n is more than or equal to 23 and less than or equal to 500;
m is polymerization degree, and m is more than or equal to 3 and less than or equal to 90;
x is polymerization degree, and x is more than or equal to 2 and less than or equal to 5.
Preferably, in the formula (III) or the formula (IV), x is selected from 3 or 4.
Preferably, the B block accounts for 10-50% of the mass percent of the block copolymer.
The invention also provides a preparation method of the block copolymer, which comprises the following steps:
A) mixing polyethylene glycol or polyethylene glycol monomethyl ether with lactide and a catalyst, and carrying out ring-opening polymerization reaction to obtain a block copolymer intermediate, wherein the lactide is levorotatory-lactide or dextrorotatory-lactide;
B) mixing the block copolymer intermediate obtained in the step A) with a coupling reagent and a compound with a structure of a formula (V) to perform condensation reaction to obtain a block copolymer;
wherein,
x is polymerization degree, and x is more than or equal to 2 and less than or equal to 5.
Preferably, the molar ratio of the polyethylene glycol or polyethylene glycol monomethyl ether to the lactide is 1: 1 to 45.
Preferably, the mass ratio of the block copolymer intermediate obtained in step a) to the compound having the structure of formula (v) is 1: 0.01 to 1.
Preferably, the catalyst is stannous octoate, and the coupling reagent is any one or more selected from N, N-cyclohexyl carbodiimide, 1- (3-dimethylaminopropyl) -3-ethyl carbodiimide hydrochloride and 4-dimethylaminopyridine.
Preferably, in the step A), the temperature of the ring-opening polymerization reaction is 100-150 ℃, and the time of the ring-opening polymerization reaction is 12-48 h.
Preferably, in the step B), the temperature of the condensation reaction is 0-60 ℃, and the time of the condensation reaction is 24-72 h.
The invention also provides a hydrogel which comprises an aqueous medium and the stereo composite block copolymer, wherein the aqueous medium is selected from any one or more of water, normal saline, buffer solution, tissue culture solution or body fluid; the stereo composite block copolymer is formed by a first block copolymer formed by a formula (I) and a formula (III) and a second block copolymer formed by a formula (I) and a formula (IV); or a first block copolymer formed from formula (II) and formula (III) and a second block copolymer formed from formula (II) and formula (IV);
wherein,
n is polymerization degree, n is more than or equal to 23 and less than or equal to 500;
m is polymerization degree, and m is more than or equal to 3 and less than or equal to 90;
x is polymerization degree, and x is more than or equal to 2 and less than or equal to 5.
Preferably, the ratio of the number average molecular weight of the first block copolymer formed by the formula (I) and the formula (III) and the number average molecular weight of the second block copolymer formed by the formula (I) and the formula (IV) is 0.5-1.5: 1; the ratio of the number average molecular weight of the first block copolymer formed by the formula (II) and the formula (III) and the number average molecular weight of the second block copolymer formed by the formula (II) and the formula (IV) is 0.5-1.5: 1.
preferably, x is selected from 3 or 4.
The invention provides a block copolymer, which comprises an A block with a structure shown in a formula (I) or a formula (II) and a B block with a structure shown in a formula (III) or a formula (IV). As the B block with the structure of the formula (III) or the formula (IV) contains aniline oligomer segments, the B block has intermolecular pi-pi acting force and conjugated pi electrons have conductivity, the prepared block copolymer has good electrochemical response characteristics; meanwhile, micelles formed by the A block and the B block with a certain chain number ratio are dissolved in water, so that the block copolymer provided by the invention also has good water solubility. The prepared block copolymer with the levorotatory configuration and the block copolymer with the dextrorotatory configuration are mixed in an aqueous medium, a three-dimensional composite hydrogel material can be gradually formed by solution transformation, and the obtained hydrogel has the properties of electric activity, water solubility, degradability, injectability and the like, and can be used as a drug carrier or a bracket material and the like to be applied to the field of biomedical materials.
Drawings
FIG. 1 is a nuclear magnetic resonance hydrogen spectrum of a block copolymer obtained in example 8 of the present invention;
FIG. 2 is a NMR spectrum of a block copolymer prepared in example 70 of the present invention;
FIG. 3 is a graph showing dynamic mechanical measurements of hydrogels formed from block copolymers prepared in examples 58 and 82 of the present invention;
FIG. 4 is a graph of the UV absorption of a block copolymer prepared in example 114 of the present invention;
FIG. 5 is a graph of the UV absorption of a block copolymer prepared in example 144 of the present invention.
Detailed Description
The invention provides a block copolymer, which comprises an A block with a structure shown in a formula (I) or a formula (II) and a B block with a structure shown in a formula (III) or a formula (IV):
wherein,
n is polymerization degree, n is more than or equal to 23 and less than or equal to 500;
m is polymerization degree, and m is more than or equal to 3 and less than or equal to 90;
x is polymerization degree, and x is more than or equal to 2 and less than or equal to 5.
As the B block with the structure of the formula (III) or the formula (IV) contains aniline oligomer segments, the B block has intermolecular pi-pi acting force and conjugated pi electrons have conductivity, the prepared block copolymer and hydrogel have good electrochemical response characteristics; meanwhile, micelles formed by the A block and the B block with a certain chain number proportion are dissolved in water, so that the block copolymer and the hydrogel provided by the invention also have good water solubility.
The invention provides a block copolymer, which comprises an A block with a structure shown in a formula (I) or a formula (II) and a B block with a structure shown in a formula (III) or a formula (IV), preferably, the formula (I) and the formula (III) form a poly (L) lactide-polyethylene glycol-poly (L) lactide block copolymer with a BAB block configuration, the formula (I) and the formula (IV) form a poly (D) lactide-polyethylene glycol-poly (D) lactide block copolymer with a BAB block configuration, the formula (II) and the formula (III) form a polyethylene glycol monomethyl ether-poly (L) lactide block copolymer with an AB block configuration, and the formula (II) and the formula (IV) form a polyethylene glycol monomethyl ether-poly (D) lactide block copolymer with an AB block configuration.
Wherein n is the degree of polymerization, preferably 23. ltoreq. n.ltoreq.500, more preferably 30. ltoreq. n.ltoreq.450; m is the polymerization degree, preferably, m is more than or equal to 3 and less than or equal to 90, more preferably, m is more than or equal to 10 and less than or equal to 80; the x is the polymerization degree, preferably, x is more than or equal to 2 and less than or equal to 5, and more preferably, x is 3 or 4.
The mass percentage of the B block in the block copolymer is preferably 10-50%.
The number average molecular weight of the A block is preferably 1000-22000, and more preferably 1500-20000; the number average molecular weight of the B block is preferably 200-8000, and more preferably 200-6500.
The block copolymer with the levorotatory configuration and the block copolymer with the dextrorotatory configuration are mixed in an aqueous medium, so that the three-dimensional composite hydrogel material with the electric activity can be prepared.
The invention also provides a preparation method of the block copolymer, which comprises the following steps:
A) mixing polyethylene glycol or polyethylene glycol monomethyl ether with lactide and a catalyst, and carrying out ring-opening polymerization reaction to obtain a block copolymer intermediate, wherein the lactide is levorotatory-lactide or dextrorotatory-lactide;
B) mixing the block copolymer intermediate obtained in the step A) with a coupling reagent and a compound with a structure of a formula (V) to perform condensation reaction to obtain a block copolymer;
wherein,
x is polymerization degree, and x is more than or equal to 2 and less than or equal to 5.
Preferably, x is 3 or 4.
Firstly, polyethylene glycol or polyethylene glycol monomethyl ether is mixed with lactide and a catalyst to carry out ring-opening polymerization reaction.
In the invention, the polyethylene glycol or polyethylene glycol monomethyl ether is used as an initiator for lactide ring-opening polymerization, the number average molecular weight is preferably 1000-22000, and the invention has no special requirements on the sources and the purities of the polyethylene glycol and the polyethylene glycol monomethyl ether, and can be generally sold in the market. The source of the L-lactide or D-lactide (hereinafter referred to as (L/D) lactide) is not particularly required, and the L-lactide or D-lactide can be generally sold in the market. The catalyst is preferably stannous octoate, and the source of the stannous octoate is not particularly required, so that the catalyst can be generally sold in the market. In the present invention, the molar ratio of the polyethylene glycol or polyethylene glycol monomethyl ether to the (L/D) lactide is preferably 1: 1-45, more preferably 1: 2-30; the mass ratio of the catalyst to the (L/D) lactide is preferably 0.001-0.05: 1, more preferably 0.005 to 0.03: 1. in the present invention, the ring-opening polymerization reaction is preferably carried out in an organic solvent, and the organic solvent is not particularly limited, and the polyethylene glycol or polyethylene glycol monomethyl ether, the (L/D) lactide, and the catalyst may be dissolved therein, and preferably one or both of toluene and benzene. The invention is preferably carried out under anhydrous and anaerobic conditions, preferably under nitrogen or argon blanket.
Specifically, firstly, toluene or benzene is used for azeotropic dehydration of polyethylene glycol or polyethylene glycol monomethyl ether, and then the toluene or benzene is removed in vacuum, wherein the azeotropic dehydration condition is preferably that the heating and stirring are carried out at 120-160 ℃; meanwhile, recrystallizing and purifying the (L/D) lactide by using ethyl acetate, and then removing the ethyl acetate in vacuum; then mixing a certain amount of dehydrated polyethylene glycol or polyethylene glycol monomethyl ether with recrystallized (L/D) lactide, adding a certain amount of toluene or benzene solution of stannous octoate under anhydrous and anaerobic conditions, wherein the concentration of the toluene or benzene solution of the stannous octoate is preferably 0.02 mmol/mL-0.08 mmol/mL, then supplementing a certain amount of toluene or benzene as a solvent, and carrying out ring-opening polymerization reaction, wherein the reaction condition is preferably stirring reaction, and the temperature of the ring-opening polymerization reaction is preferably 100-150 ℃, more preferably 110-140 ℃; the time of the ring-opening polymerization reaction is preferably 12 to 48 hours, and more preferably 24 to 48 hours. The solvent for the reaction may be benzene or toluene, or a mixed solvent of benzene and toluene, and the present invention is not particularly limited thereto.
After the reaction is finished, purifying the product, preferably, settling the reaction solution by using an ethanol/diethyl ether mixed solution, performing suction filtration to obtain a solid, dissolving the solid by using chloroform, settling by using the ethanol/diethyl ether mixed solution, repeating the process for many times, and performing vacuum drying to obtain a block copolymer intermediate, namely a poly (L/D) lactide-polyethylene glycol-poly (L/D) lactide block copolymer or a polyethylene glycol monomethyl ether-poly (L/D) lactide block copolymer, wherein the specific structure is as follows:
wherein,
n is polymerization degree, n is more than or equal to 23 and less than or equal to 500;
m is polymerization degree, and m is more than or equal to 3 and less than or equal to 90.
After obtaining the intermediate of the block copolymer, mixing the intermediate with a coupling reagent and a compound with a structure of a formula (V) to perform condensation reaction, wherein the coupling reagent is preferably any one or more of N, N-cyclohexyl carbodiimide (DCC), 1- (3-dimethylaminopropyl) -3-ethyl carbodiimide hydrochloride (EDC) and 4-Dimethylaminopyridine (DMAP), and more preferably any one or two of EDC and DMAP. The source of the coupling reagent is not particularly limited in the present invention, and may be generally commercially available.
The present invention does not require any particular source for the compound of formula (v) and can be prepared according to synthetic methods well known to those skilled in the art, and the present invention is preferably prepared according to the following method:
a. reacting N-substituted 1, 4-p-phenylenediamine derivatives under the action of an oxidant to obtain aniline oligomers with amino end groups;
b. and (3) reacting the obtained aniline oligomer with the amino end group with succinic anhydride to obtain the compound with the structure of the formula (V).
Firstly, carrying out condensation reaction on N-substituted 1, 4-p-phenylenediamine derivatives under the action of an oxidant to obtain aniline oligomers with amino end groups. The N-substituted 1, 4-p-phenylenediamine derivative is preferably any one or more of N-phenyl-1, 4-p-phenylenediamine, N- (4-anilino) -1, 4-p-phenylenediamine and N, N-diphenyl-1, 4-p-phenylenediamine, and the N-substituted 1, 4-p-phenylenediamine has no special requirement on the source of the N-substituted 1, 4-p-phenylenediamine and can be generally sold in the market. The oxidant is preferably ammonium persulfate, and may be generally commercially available.
Specifically, the N-substituted 1, 4-p-phenylenediamine derivative is preferably dissolved in a mixed solution of concentrated hydrochloric acid, an organic solvent and water, the organic solvent is an organic solvent miscible with water, and acetone or N, N-dimethylformamide is preferred in the invention; the mass ratio of the N-substituted 1, 4-p-phenylenediamine derivative to concentrated hydrochloric acid, an organic solvent and water is preferably 2-4 g: 10 mL-30 mL: 80 mL-120 mL: 10mL to 120 mL. Then adding an oxidizing agent, wherein the mass ratio of the oxidizing agent to the N-substituted 1, 4-p-phenylenediamine derivative is preferably 1: 0.5 to 2; the oxidizing agent is preferably dissolved in hydrochloric acid aqueous solution with the concentration of 0.8-1.5 mol/L, and then dropwise added into the mixed solution of the N-substituted 1, 4-p-phenylenediamine derivative to perform oxidation reaction, wherein the dropwise addition is preferably performed in an ice-water bath, the reaction time is preferably 1-5 h, and the reaction temperature is not particularly required, and preferably the reaction is performed in the ice bath. And after the reaction is finished, filtering to obtain a solid, preferably washing the solid by sequentially using a hydrochloric acid aqueous solution with the concentration of 0.1-0.8 mol/L and acetone, filtering, performing counter doping treatment by using 0.1-0.6 mol/L ammonia water, washing to be neutral, and drying to obtain the aniline oligomer with the amino end group.
After the aniline oligomer with the amino end group is obtained, mixing the aniline oligomer with succinic anhydride and reacting, preferably, dissolving the aniline oligomer with the amino end group in an organic solvent; then, under the protection of nitrogen, succinic anhydride is dissolved in an organic solvent; then the two are mixed and stirred for reaction. The organic solvent is not specially required, and the aniline oligomer with the amino end group and succinic anhydride can be dissolved, wherein dichloromethane is preferred; the molar ratio of the amino-terminated aniline oligomer to succinic anhydride is preferably 1: 5-15, more preferably 1: 8-12; the reaction time is preferably 2 to 10 hours, and more preferably 3 to 8 hours; the invention has no special requirement on the reaction temperature, and can be a room temperature reaction; the reaction is preferably carried out under the protection of nitrogen in the invention. After the reaction is finished, preferably, the obtained solid is extracted by dichloromethane in a Soxhlet extractor, and then washed by water and dried to obtain the compound with the structure of the formula (V).
In the present invention, the compound having the structure of formula (v) is preferably the following structure:
the compound represented by the formula (V-a) is preferably prepared by the following method:
reacting N-phenyl-1, 4-p-phenylenediamine under the action of an oxidant to obtain an aniline tetramer with an amino end group;
and (3) reacting the obtained aniline tetramer with the amino end group with succinic anhydride to obtain the compound with the structure of the formula (V-a).
Firstly, N-phenyl-1, 4-p-phenylenediamine is reacted under the action of an oxidant, wherein the oxidant is preferably ammonium persulfate and can be generally commercially available. The N-phenyl-1, 4-p-phenylenediamine may be generally commercially available. Specifically, the N-phenyl-1, 4-p-phenylenediamine is preferably dissolved in a mixed solution of concentrated hydrochloric acid, an organic solvent and water, the organic solvent is an organic solvent miscible with water, and the invention is preferably acetone or N, N-dimethylformamide; the volume ratio of the mass of the N-phenyl-1, 4-p-phenylenediamine to the volume of concentrated hydrochloric acid, an organic solvent and water is preferably 2-4 g: 10 mL-30 mL: 80 mL-120 mL: 10mL to 120 mL. Then adding an oxidant, wherein the mass ratio of the oxidant to the N-phenyl-1, 4-p-phenylenediamine is preferably 1: 0.5 to 2; the oxidizing agent is preferably dissolved in hydrochloric acid aqueous solution with the concentration of 0.8-1.5 mol/L, and then dropwise added into the mixed solution of the N-phenyl-1, 4-p-phenylenediamine for oxidation reaction, wherein the dropwise addition is preferably carried out in an ice-water bath, the reaction time is preferably 1-5 h, and the reaction temperature is not particularly required, and preferably the reaction is carried out in the ice bath. And after the reaction is finished, filtering to obtain a solid, preferably washing the solid by sequentially using a hydrochloric acid aqueous solution with the concentration of 0.1-0.8 mol/L and acetone, filtering, performing counter doping treatment by using 0.1-0.6 mol/L ammonia water, washing to be neutral, and drying to obtain the aniline tetramer with the end group of amino.
After the aniline tetramer with the end group of amino is obtained, mixing the aniline tetramer with the end group of amino with succinic anhydride and reacting, preferably, dissolving the aniline tetramer with the end group of amino in an organic solvent; then, under the protection of nitrogen, succinic anhydride is dissolved in an organic solvent; then the two are mixed and stirred for reaction. The organic solvent is not specially required, and the aniline tetramer with the amino end group and succinic anhydride can be dissolved, wherein dichloromethane is preferred; the molar ratio of the aniline tetramer with the amino end group to the succinic anhydride is preferably 1: 5-15, more preferably 1: 8-12; the reaction time is preferably 2 to 10 hours, and more preferably 3 to 8 hours; the invention has no special requirement on the reaction temperature, and can be a room temperature reaction; the reaction is preferably carried out under the protection of nitrogen in the invention. After the reaction is finished, preferably, the obtained solid is extracted by dichloromethane in a Soxhlet extractor, and then washed by water and dried to obtain the compound with the structure of the formula (V-a).
The compound represented by the formula (V-b) is preferably prepared by the following method:
reacting N- (4-anilino) -1, 4-p-phenylenediamine and N, N-diphenyl-1, 4-p-phenylenediamine under the action of a catalyst to obtain an aniline pentamer with an amino end group;
and (3) reacting the obtained aniline pentamer with the amino end group with succinic anhydride to obtain the compound with the structure of the formula (V-b).
Firstly, N- (4-anilino) -1, 4-p-phenylenediamine and N, N-diphenyl-1, 4-p-phenylenediamine are reacted under the action of an oxidant, preferably ammonium persulfate, which can be generally commercially available. The N- (4-anilino) -1, 4-p-phenylenediamine and N, N-diphenyl-1, 4-p-phenylenediamine may be generally commercially available. Specifically, the N- (4-anilino) -1, 4-p-phenylenediamine and the N, N-diphenyl-1, 4-p-phenylenediamine are preferably dissolved in a mixed solution of concentrated hydrochloric acid, an organic solvent and water, the organic solvent is an organic solvent which can be mixed with water, and the N- (4-anilino) -1, 4-p-phenylenediamine and the N, N-diphenyl-1, 4-p-phenylenediamine are preferably dissolved in acetone or N, N-dimethylformamide; the volume ratio of the mass of the N- (4-anilino) -1, 4-p-phenylenediamine to the mass of the N, N-diphenyl-1, 4-p-phenylenediamine to the volume of concentrated hydrochloric acid, an organic solvent and water is preferably 2 g-4 g: 2 g-4 g: 10 mL-30 mL: 80 mL-120 mL: 10mL to 120 mL. Then adding an oxidizing agent, wherein the mass ratio of the oxidizing agent to the N- (4-anilino) -1, 4-p-phenylenediamine and the N, N-diphenyl-1, 4-p-phenylenediamine is preferably 1: 0.5-2: 0.5 to 2; the catalyst is preferably dissolved in hydrochloric acid aqueous solution with the concentration of 0.8-1.5 mol/L, then dropwise added into the mixed solution of the N- (4-anilino) -1, 4-p-phenylenediamine and the N, N-diphenyl-1, 4-p-phenylenediamine for oxidation reaction, the dropwise addition is preferably carried out in an ice water bath, the reaction time is preferably 1-5 h, the temperature of the reaction is not particularly required, and the reaction is preferably carried out in the ice bath. And after the reaction is finished, filtering to obtain a solid, preferably washing the solid with hydrochloric acid with the concentration of 0.1-0.8 mol/L and water in sequence, filtering, performing counter doping treatment with ammonia water with the concentration of 0.1-0.6 mol/L, washing with water to be neutral, and drying to obtain the aniline pentamer with the amino end group.
After the aniline pentamer with the amino end group is obtained, mixing the aniline pentamer with the amino end group with succinic anhydride and reacting, preferably, dissolving the aniline pentamer with the amino end group in an organic solvent; then, under the protection of nitrogen, succinic anhydride is dissolved in an organic solvent; then the two are mixed and stirred for reaction. The organic solvent is not specially required, and the aniline pentamer with the amino end group and succinic anhydride can be dissolved, wherein dichloromethane is preferred; the molar ratio of the aniline pentamer with the amino end group to succinic anhydride is preferably 1: 5-15, more preferably 1: 8-12; the reaction time is preferably 2 to 10 hours, and more preferably 3 to 8 hours; the invention has no special requirement on the reaction temperature, and can be a room temperature reaction; the reaction is preferably carried out under the protection of nitrogen in the invention. After the reaction is finished, preferably, the obtained solid is extracted by dichloromethane in a Soxhlet extractor, and then washed by water and dried to obtain the compound with the structure of the formula (V-b).
Mixing a block copolymer intermediate with a coupling reagent and a compound with a structure of formula (V) to perform condensation reaction, wherein the mass ratio of the block copolymer intermediate to the compound with the structure of formula (V) is preferably 1: 0.01 to 1, more preferably 1: 0.02 to 0.6; the mass ratio of the coupling reagent to the block copolymer intermediate is preferably 0.001-1: 1, more preferably 0.003 to 0.8: 1. the condensation reaction is preferably carried out in an organic solvent, the organic solvent is not particularly limited in the present invention, and the block copolymer intermediate, the coupling reagent and the compound having the structure of formula (v) can be dissolved, and any one or more of N, N-dimethylformamide, dimethyl sulfoxide and N-methylpyrrolidone are preferably used in the present invention. The invention is preferably carried out under nitrogen protection.
Specifically, the block copolymer intermediate, the coupling reagent and the compound with the structure of the formula (V) are respectively treated by organic reagents, and then are mixed and reacted. The organic reagent is preferably any one or more of N, N-dimethylformamide, dimethyl sulfoxide and N-methylpyrrolidone, and the raw materials are preferably treated and mixed to react under the protection of nitrogen in the invention. The reaction temperature is preferably 0-60 ℃, and more preferably 20-50 ℃; the time of the condensation reaction is preferably 24-72 h, and more preferably 24-48 h.
After the reaction is finished, preferably, the reaction solution is settled by using ether, a crude product is obtained by suction filtration, then the crude product is dissolved by using chloroform, insoluble substances are removed by filtration, the chloroform solution is settled by using ethanol, a solid is obtained by suction filtration, the steps of chloroform dissolution and ethanol settlement are repeated for many times, the product is further purified, and the block copolymer is obtained by drying.
The nuclear magnetic resonance analysis of the block copolymer shows that the obtained block copolymer comprises an A block with a structure shown in a formula (I) or a formula (II) and a B block with a structure shown in a formula (III) and a formula (IV):
wherein,
n is polymerization degree, n is more than or equal to 23 and less than or equal to 500;
m is polymerization degree, and m is more than or equal to 3 and less than or equal to 90;
x is polymerization degree, and x is more than or equal to 2 and less than or equal to 5.
The ultraviolet absorption detection is carried out on the prepared block copolymer, and the result shows that the block copolymer provided by the invention has good electric activity.
In the invention, polyethylene glycol monomethyl ether or polyethylene glycol with different molecular weights is used as an initiator to carry out ring-opening reaction with (L/D) lactide with different feeding amounts, so that polyethylene glycol monomethyl ether-poly (L/D) lactide or poly (L/D) lactide-polyethylene glycol-poly (L/D) lactide copolymers with different chain lengths can be obtained, and then the polyethylene glycol monomethyl ether-poly (L/D) lactide or poly (L/D) lactide-polyethylene glycol-poly (L/D) lactide copolymers are reacted with aniline oligomers, the proportion of the (L/D) lactide and the type of the aniline oligomers are controlled, so that polymer materials with different concentrations, compound rates, electroactive response properties and optical rotation properties can be.
The invention also discloses a hydrogel which comprises an aqueous medium and the stereo composite block copolymer, wherein the aqueous medium is selected from any one or more of water, normal saline, buffer solution, tissue culture solution or body fluid; the stereo composite block copolymer is formed by a first block copolymer formed by a formula (I) and a formula (III) and a second block copolymer formed by a formula (I) and a formula (IV); or a first block copolymer formed from formula (II) and formula (III) and a second block copolymer formed from formula (II) and formula (IV);
wherein,
n is polymerization degree, n is more than or equal to 23 and less than or equal to 500;
m is polymerization degree, and m is more than or equal to 3 and less than or equal to 90;
x is polymerization degree, and x is more than or equal to 2 and less than or equal to 5.
Preferably, x is 3 or 4.
The block copolymer provided by the invention is formed by condensing polyethylene glycol monomethyl ether or polyethylene glycol and lactide, and the lactide has a levorotatory or dextrorotatory spatial configuration, so that the prepared block copolymer also has the levorotatory or dextrorotatory spatial configuration. The block copolymer with the levorotatory configuration and the block copolymer with the dextrorotatory configuration which have similar structures and number average molecular weights are mixed, for example, the polyethylene glycol monomethyl ether-poly (L) lactide coupling aniline tetramer is mixed with the polyethylene glycol monomethyl ether-poly (D) lactide coupling aniline tetramer, or the poly (L) lactide-polyethylene glycol-poly (L) lactide coupling aniline pentamer is mixed with the poly (D) lactide-polyethylene glycol-poly (D) lactide coupling aniline pentamer, so that the three-dimensional composite block copolymer can be obtained. The stereo composite block copolymer is mixed with water medium and can be gradually converted from solution to form stereo composite hydrogel with electric activity.
The ratio of the number average molecular weight of the first block copolymer formed by the formula (I) and the formula (III) and the number average molecular weight of the second block copolymer formed by the formula (I) and the formula (IV) is preferably 0.5 to 1.5: 1, more preferably 0.8 to 1.2: 1; the ratio of the number average molecular weight of the first block copolymer formed of the formula (II) and the formula (III) to the number average molecular weight of the second block copolymer formed of the formula (II) and the formula (IV) is preferably 0.5 to 1.5: 1, more preferably 0.8 to 1.2: 1.
most preferably, x has the same value in the first block copolymer of formula (I) and formula (III) and the second block copolymer of formula (I) and formula (IV); in the first block copolymer formed by the formula (II) and the formula (III) and the second block copolymer formed by the formula (II) and the formula (IV), x has the same value.
The mass fraction of the stereo composite block copolymer in the aqueous medium is preferably 5-30%, and more preferably 10-25%.
The block copolymer with the left-handed configuration and the block copolymer with the right-handed configuration are mixed in a solvent, so that the three-dimensional composite hydrogel material with the electric activity can be prepared, the gel forming time, the strength and the solubility of the three-dimensional composite hydrogel can be adjusted by adjusting the chain segment length of the block copolymer and the concentration of a polymer solution, and the prepared hydrogel has good electric activity due to the introduction of the aniline oligomer. Because the prepared block copolymers have good water solubility, the prepared hydrogel also has good water solubility. And testing the degradation period of the hydrogel, wherein the result shows that the degradation period of the hydrogel is 4-8 weeks. Therefore, the hydrogel provided by the invention has the characteristics of injectability, degradability, good biocompatibility and good electrical activity, can be used in the field of biomedical materials, and particularly has a wide application range in the aspects of controlled release of drugs, tissue engineering and the like.
The invention provides a block copolymer, which comprises an A block with a structure shown in a formula (I) or a formula (II) and a B block with a structure shown in a formula (III) or a formula (IV). As the B block with the structure of the formula (III) or the formula (IV) contains aniline oligomer segments, the B block has intermolecular pi-pi acting force and conjugated pi electrons have conductivity, the prepared block copolymer has good electrochemical response characteristics; meanwhile, micelles formed by the A block and the B block with a certain chain number proportion are dissolved in water, so that the block copolymer provided by the invention also has good water solubility. The block copolymer with the levorotatory configuration and the block copolymer with the dextrorotatory configuration prepared by the invention are mixed in an aqueous medium, and after a period of time, a three-dimensional composite hydrogel material can be formed, and the obtained hydrogel has the properties of electric activity, water solubility, degradability, injectability and the like, and can be used as a drug carrier or a bracket material and the like to be applied to the field of biomedical materials.
In order to further illustrate the present invention, the block copolymer, the preparation method thereof and the hydrogel provided by the present invention will be described in detail below with reference to examples.
Example 1
Dissolving 3.68g (0.02 mol) of N-phenyl-1, 4-p-phenylenediamine in a mixed solution of 100mL of acetone, 100mL of water and 25mL of concentrated hydrochloric acid to obtain an N-phenyl-1, 4-p-phenylenediamine mixed solution, and freezing to 0 ℃; weighing 4.56g (0.02 mol) of Ammonium Persulfate (APS) and dissolving the Ammonium Persulfate (APS) in 50mL of 1mol/L HCl aqueous solution to obtain an APS solution, slowly dripping the APS solution into the N-phenyl-1, 4-p-phenylenediamine mixed solution in ice bath (about half an hour of dripping off), reacting for 3 hours after dripping off, filtering to obtain a solid, washing the solid with 0.6mol/L HCl aqueous solution and acetone in sequence, filtering, back-doping the solid with 0.5mol/L ammonia water, washing the solid with water for three times to be neutral, and drying in vacuum after freeze-drying to obtain the aniline tetramer with amino end groups as the end groups. The yield was 80%.
Example 2
Dissolving 3.5g of N- (4-anilino) -1, 4-p-phenylenediamine and 2.6g of N, N-diphenyl-1, 4-p-phenylenediamine in a mixed solution of 100mL of N, N-dimethylformamide, 15mL of water and 15mL of concentrated hydrochloric acid to obtain a mixed solution of the N- (4-anilino) -1, 4-p-phenylenediamine and the N, N-diphenyl-1, 4-p-phenylenediamine, and freezing to 0 ℃; and then weighing ammonium persulfate APS2.28g (0.01 mol) and dissolving in 50mL of 1mol/L HCl aqueous solution to obtain an APS solution, slowly dripping the APS solution into the mixed solution of N- (4-anilino) -1, 4-p-phenylenediamine and N, N-diphenyl-1, 4-p-phenylenediamine (dripping off about half an hour) in ice bath, reacting for 1 hour after dripping, then pouring the product into 700mL of water for precipitation, filtering to obtain a solid, sequentially washing the solid with 0.1mol/L HCl aqueous solution and water for three times, then back doping the solid with 0.1mol/L ammonia water, finally washing the solid with water for three times until the solid is neutral, and performing vacuum drying after freeze-drying to obtain the aniline pentamer with the end group of which is amino. The yield was 80%.
Example 3
3g of the aniline tetramer having an amino group as a terminal group obtained in example 1 was dissolved in methylene chloride to obtain an aniline tetramer solution; and then dissolving 4.1g of succinic anhydride in 400mL of dichloromethane under the protection of nitrogen to obtain a succinic anhydride solution, mixing the aniline tetramer solution with the succinic anhydride solution, quickly stirring for reaction, gradually separating out black precipitates, filtering a reaction product after 5 hours of reaction to obtain black precipitates, extracting the black precipitates in a Soxhlet extractor by using dichloromethane, finally washing the black precipitates for three times by using water once, freeze-drying and drying in vacuum to obtain the product aniline tetramer with the end group of carboxyl. The yield was 80%.
Example 4
Dissolving 3g of the aniline pentamer with the amino end group obtained in example 2 in dichloromethane to obtain an aniline pentamer solution; and then dissolving 5.6g of succinic anhydride in 400mL of dichloromethane under the protection of nitrogen to obtain a succinic anhydride solution, mixing the aniline pentamer solution with the succinic anhydride solution, carrying out rapid stirring reaction, gradually separating out black precipitates, filtering a reaction product after 5 hours of reaction to obtain black precipitates, extracting the black precipitates in a Soxhlet extractor with dichloromethane, finally washing the black precipitates with water for three times, freeze-drying and carrying out vacuum drying to obtain the aniline pentamer with the end group of carboxyl. The yield was 70%.
Examples 5 to 16
Placing the methoxypolyethylene glycol into a dry reaction bottle, carrying out azeotropic dehydration in an oil bath at 140 ℃ by using toluene, and carrying out vacuum pumping to obtain the dehydrated methoxypolyethylene glycol. Placing the L-lactide in a dry reaction bottle, recrystallizing for three times by using ethyl acetate, and performing vacuum pumping to obtain the recrystallized L-lactide. According to the proportion in the table 1, 5g of dehydrated polyethylene glycol monomethyl ether and recrystallized L-lactide are added into a dry reaction bottle together, under the anhydrous and anaerobic conditions, a stannous octoate catalyst toluene solution with the concentration of 0.05mmol/mL is added, then toluene is added, the mixture is placed in a 120 ℃ oil bath, and the mixture is stirred and reacts for 24 hours. After the reaction is finished, the reaction solution is settled by using 500mL of ethanol/ether mixed solution, solid is obtained by suction filtration, the solid is dissolved by using 50mL of chloroform, then the solid is settled by using 500mL of ethanol/ether mixed solution, the above steps are repeated for three times, and finally the obtained solid is dried for 48 hours in vacuum, thus obtaining the product. The yield is more than 80%.
The nuclear magnetic resonance analysis of the obtained block copolymers was performed, and as shown in fig. 1, fig. 1 is a nuclear magnetic resonance hydrogen spectrum of the block copolymer obtained in example 8 of the present invention, and as can be seen from the chemical shifts in fig. 1, 3.5ppm is a characteristic peak of polyethylene glycol monomethyl ether, and lactide is 5.1ppm, which indicates that the reaction of polyethylene glycol monomethyl ether and L-lactide occurs, and the block copolymer is generated. The number average molecular weight of the block copolymer obtained was measured by Gel Permeation Chromatography (GPC), and the results are shown in Table 1, where Table 1 summarizes the amounts of the raw materials and the number average molecular weight of the product in examples 5 to 16 of the present invention.
Table 1 in examples 5 to 16 of the present invention, the amounts of the respective raw materials and the number average molecular weights of the products are summarized
Examples 17 to 28
Placing the methoxypolyethylene glycol into a dry reaction bottle, carrying out azeotropic dehydration in an oil bath at 140 ℃ by using toluene, and carrying out vacuum pumping to obtain the dehydrated methoxypolyethylene glycol. Placing the dextro (D) -lactide into a dry reaction bottle, recrystallizing for three times by using ethyl acetate, and performing vacuum pumping to obtain the recrystallized D-lactide. According to the proportion shown in the table 2, 5g of dehydrated polyethylene glycol monomethyl ether and recrystallized D-lactide are added into a dry reaction bottle together, under the anhydrous and anaerobic conditions, a stannous octoate catalyst toluene solution with the concentration of 0.05mmol/mL is added, then toluene is added, the mixture is placed in a 120 ℃ oil bath, and the mixture is stirred and reacts for 24 hours. After the reaction is finished, the reaction solution is settled by using 500mL of ethanol/ether mixed solution, solid is obtained by suction filtration, the solid is dissolved by using 50mL of chloroform, then the solid is settled by using 500mL of ethanol/ether mixed solution, the above steps are repeated for three times, and finally the obtained solid is dried for 48 hours in vacuum, thus obtaining the product. The yield is more than 80%.
The nuclear magnetic resonance analysis is respectively carried out on the obtained block copolymers, and the results show that the polyethylene glycol monomethyl ether reacts with the D-lactide to generate the block copolymers. The number average molecular weight of the block copolymer obtained was measured by GPC, and the results are shown in Table 2, where Table 2 summarizes the amounts of the raw materials and the number average molecular weights of the products in examples 17 to 28 of the present invention.
Table 2 summarizes the amounts of the raw materials and the number average molecular weights of the products in examples 17 to 28 of the present invention
Examples 29 to 40
Placing polyethylene glycol in a dry reaction bottle, carrying out azeotropic dehydration in oil bath at 140 ℃ by using toluene, and carrying out vacuum pumping to obtain the dehydrated polyethylene glycol. And (3) putting the L-lactide into a dry reaction bottle, recrystallizing for three times by using ethyl acetate, and performing vacuum pumping to obtain the recrystallized L-lactide. According to the proportion in the table 3, 5g of dehydrated polyethylene glycol and recrystallized L-lactide are added into a dry reaction bottle together, under the anhydrous and anaerobic conditions, a stannous octoate catalyst toluene solution with the concentration of 0.05mmol/mL is added, then toluene is added, the mixture is placed in a 120 ℃ oil bath, and the mixture is stirred and reacts for 24 hours. After the reaction is finished, the reaction solution is settled by using 500mL of ethanol/ether mixed solution, solid is obtained by suction filtration, the solid is dissolved by using 50mL of chloroform, then the solid is settled by using 500mL of ethanol/ether mixed solution, the above steps are repeated for three times, and finally the obtained solid is dried for 48 hours in vacuum, thus obtaining the product. The yield is more than 80%.
The nuclear magnetic resonance analysis is respectively carried out on the obtained block copolymers, and the results show that the polyethylene glycol reacts with the L-lactide to generate the block copolymers. The number average molecular weight of the block copolymer obtained was measured by GPC, and the results are shown in Table 3, where Table 3 summarizes the amounts of the respective raw materials and the number average molecular weights of the products in examples 29 to 40 of the present invention.
TABLE 3 summary of the amounts of the raw materials and the number average molecular weights of the products in examples 29 to 40 of the present invention
Examples 41 to 52
Placing polyethylene glycol in a dry reaction bottle, carrying out azeotropic dehydration in oil bath at 140 ℃ by using toluene, and carrying out vacuum pumping to obtain the dehydrated polyethylene glycol. And (3) placing the D-lactide into a dry reaction bottle, recrystallizing for three times by using ethyl acetate, and performing vacuum pumping to obtain the recrystallized D-lactide. According to the proportion in the table 4, 5g of polyethylene glycol after water removal and D-lactide after recrystallization are respectively added into a dry reaction bottle, a stannous octoate catalyst toluene solution with the concentration of 0.05mmol/mL is added under the anhydrous and oxygen-free conditions, then toluene is added, the mixture is placed in an oil bath at the temperature of 120 ℃, and the mixture is stirred for reaction for 24 hours. After the reaction is finished, the reaction solution is settled by using 500mL of ethanol/ether mixed solution, solid is obtained by suction filtration, the solid is dissolved by using 50mL of chloroform, then the solid is settled by using 500mL of ethanol/ether mixed solution, the above steps are repeated for three times, and finally the obtained solid is dried for 48 hours in vacuum, thus obtaining the product. The yield is more than 80%.
The nuclear magnetic resonance analysis is respectively carried out on the obtained block copolymers, and the results show that the polyethylene glycol reacts with the D-lactide to generate the block copolymers. The number average molecular weight of the block copolymer obtained was measured by GPC, and the results are shown in Table 4, where Table 4 summarizes the amounts of the raw materials and the number average molecular weights of the products in examples 41 to 52 of the present invention.
Table 4 summarizes the amounts of the raw materials and the number average molecular weights of the products in examples 41 to 52 of the present invention
Examples 53 to 64
According to the formulation shown in Table 5, 1g of the intermediate polyethylene glycol monomethyl ether-poly (L) lactide block copolymer prepared in example 5, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC) and 4-Dimethylaminopyridine (DMAP) were charged into three reaction bottles with stirring members, and after nitrogen was exchanged three times for each reaction bottle, 20mL of N, N-dimethylformamide was injected as a solvent, and the reaction was carried out at room temperature for 2 days to obtain a block copolymer solution, an EDC solution and a DMAP solution, respectively. The carboxyl-terminated aniline tetramer prepared in example 3 is filled into a reaction bottle, nitrogen is exchanged for three times, and 10mL of N, N-dimethylformamide is injected to be completely dissolved, so that an aniline tetramer solution is obtained; and mixing the block copolymer solution, the EDC solution, the DMAP solution and the aniline tetramer solution under the protection of nitrogen, and heating to 50 ℃ for reacting for 24 hours. After the reaction is finished, the reaction solution is settled by using ether, and a crude product is obtained by suction filtration. And (3) purifying the crude product, firstly dissolving the solid by using chloroform, filtering to remove insoluble substances, then settling the chloroform solution by using ethanol, performing suction filtration to obtain a solid, continuously dissolving the solid by using chloroform, repeating the steps for three times, and drying the solid for 24 hours in vacuum at room temperature to obtain the methoxy polyethylene glycol-poly (L) lactide coupled aniline tetramer block copolymer, wherein the yield is higher than 80%.
The nuclear magnetic resonance analysis of the obtained block copolymer shows that a characteristic peak of the aniline tetramer appears at 6.5-7.5ppm, which indicates that the aniline tetramer reacts with the polyethylene glycol monomethyl ether-poly (L) lactide to generate the block copolymer. The molecular weight of the block copolymer obtained was measured by GPC, and the results are shown in Table 5, where Table 5 summarizes the amounts of the raw materials and the number average molecular weights of the products in examples 53 to 64 of the present invention.
TABLE 5 summary of the amounts of the raw materials and the number average molecular weights of the products in inventive examples 53 to 64
Examples 65 to 76
In accordance with the formulation shown in Table 6, 1g of the poly (L) lactide-polyethylene glycol-poly (L) lactide block copolymer intermediate prepared in example 29, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC) and 4-Dimethylaminopyridine (DMAP) were charged into three stirred reaction vials, and after purging nitrogen three times, 20mL of N, N-dimethylformamide was injected into each reaction vial, and the reaction was carried out at room temperature for 2 days to obtain a block copolymer solution, an EDC solution and a DMAP solution, respectively. The carboxyl-terminated aniline tetramer prepared in example 3 is filled into a reaction bottle, nitrogen is exchanged for three times, and 10mL of N, N-dimethylformamide is injected to be completely dissolved, so that an aniline tetramer solution is obtained; and mixing the block copolymer solution, the EDC solution, the DMAP solution and the aniline tetramer solution under the protection of nitrogen, and heating to 50 ℃ for reacting for 24 hours. After the reaction is finished, the reaction solution is settled by using ether, and a crude product is obtained by suction filtration. And (3) purifying the crude product, firstly dissolving the solid with chloroform, filtering to remove insoluble substances, then settling the chloroform solution with ethanol, performing suction filtration to obtain a solid, continuously dissolving the solid with chloroform, repeating the steps for three times, and drying the solid at room temperature in vacuum for 24 hours to obtain the poly (L) lactide-polyethylene glycol-poly (L) lactide coupled aniline tetramer block copolymer, wherein the yield is higher than 80%.
The nuclear magnetic resonance analysis of the obtained block copolymer showed that the result is shown in FIG. 2, FIG. 2 is a nuclear magnetic resonance hydrogen spectrum of the block copolymer prepared in example 70 of the present invention, and it can be seen from FIG. 2 that a characteristic peak of aniline tetramer appeared at 6.5 to 7.5ppm, which indicates that aniline tetramer reacted with poly (L) lactide-polyethylene glycol-poly (L) lactide to produce the block copolymer. The molecular weight of the block copolymer obtained was measured by GPC, and the results are shown in Table 6, where Table 6 summarizes the amounts of the raw materials and the number average molecular weights of the products in examples 65 to 76 of the present invention.
TABLE 6 summary of the amounts of the raw materials and the number average molecular weights of the products in inventive examples 65 to 76
Examples 77 to 88
1g of the intermediate of the polyethylene glycol monomethyl ether-poly (D) lactide block copolymer prepared in example 17, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC) and 4-Dimethylaminopyridine (DMAP) were charged into three reaction bottles with a stirrer, and after three nitrogen changes for each reaction bottle, 20mL of N, N-dimethylformamide was added as a solvent, and the mixture was reacted at room temperature for 2 days to obtain a block copolymer solution, an EDC solution and a DMAP solution, respectively. The carboxyl-terminated aniline tetramer prepared in example 3 was charged into a reaction flask, nitrogen gas was purged three times, and 10mL of N, N-dimethylformamide was injected to completely dissolve the polymer, thereby obtaining an aniline tetramer solution. And mixing the block copolymer solution, the EDC solution, the DMAP solution and the aniline tetramer solution under the protection of nitrogen, and heating to 50 ℃ for reacting for 24 hours. After the reaction is finished, the reaction solution is settled by using ether, and a crude product is obtained by suction filtration. And (3) purifying the crude product, firstly dissolving the solid by using chloroform, filtering to remove insoluble substances, then settling the chloroform solution by using ethanol, performing suction filtration to obtain a solid, continuously dissolving the solid by using chloroform, repeating the steps for three times, and drying the solid for 24 hours in vacuum at room temperature to obtain the methoxy polyethylene glycol-poly (D) lactide coupled aniline tetramer block copolymer, wherein the yield is higher than 80%.
The nuclear magnetic resonance analysis of the obtained block copolymer shows that a characteristic peak of the aniline tetramer appears at 6.5-7.5ppm, which indicates that the aniline tetramer reacts with the polyethylene glycol monomethyl ether-poly (D) lactide to generate the block copolymer. The molecular weight of the block copolymer obtained was measured by GPC, and the results are shown in Table 7, where Table 7 summarizes the amounts of the raw materials and the number average molecular weights of the products in examples 77 to 88 of the present invention.
TABLE 7 summary of the amounts of the raw materials and the number average molecular weights of the products in inventive examples 77 to 88
Examples 89 to 100
In accordance with the formulation shown in Table 8, 1g of the poly (D) lactide-polyethylene glycol-poly (D) lactide block copolymer intermediate prepared in example 41, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC) and 4-Dimethylaminopyridine (DMAP) were charged into three stirred reaction vials, and after purging nitrogen three times, 20mL of N, N-dimethylformamide was injected into each reaction vial, and the reaction was carried out at room temperature for 2 days to obtain a block copolymer solution, an EDC solution and a DMAP solution, respectively. The carboxyl-terminated aniline tetramer prepared in example 3 was charged into a reaction flask, nitrogen gas was purged three times, and 10mL of N, N-dimethylformamide was injected to completely dissolve the polymer, thereby obtaining an aniline tetramer solution. And mixing the block copolymer solution, the EDC solution, the DMAP solution and the aniline tetramer solution under the protection of nitrogen, and heating to 50 ℃ for reacting for 24 hours. After the reaction is finished, the reaction solution is settled by using ether, and a crude product is obtained by suction filtration. And (3) purifying the crude product, firstly dissolving the solid with chloroform, filtering to remove insoluble substances, then settling the chloroform solution with ethanol, performing suction filtration to obtain a solid, continuously dissolving the solid with chloroform, repeating the steps for three times, and performing vacuum drying on the solid at room temperature for 24 hours to obtain the poly (D) lactide-polyethylene glycol-poly (D) lactide coupled aniline tetramer block copolymer, wherein the yield is higher than 80%.
The nuclear magnetic resonance analysis of the obtained block copolymer shows that a characteristic peak of the aniline tetramer appears at 6.5-7.5ppm, which indicates that the aniline tetramer reacts with the poly (D) lactide-polyethylene glycol-poly (D) lactide to generate the block copolymer. The molecular weight of the block copolymer obtained was measured by GPC, and the results are shown in Table 8, where Table 8 summarizes the amounts of the raw materials and the number average molecular weights of the products in examples 89 to 100 of the present invention.
TABLE 8 summary of the amounts of the raw materials and the number average molecular weights of the products in inventive examples 89 to 100
Examples 101 to 112
1g of the intermediate of the polyethylene glycol monomethyl ether-poly (L) lactide block copolymer prepared in example 5, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC) and 4-Dimethylaminopyridine (DMAP) were charged into three reaction bottles with a stirrer, and after three nitrogen changes for each reaction bottle, 20mL of N, N-dimethylformamide was added as a solvent, and the reaction was carried out at room temperature for 2 days to obtain a block copolymer solution, an EDC solution and a DMAP solution, respectively. The carboxyl-terminated aniline pentamer prepared in example 4 was charged into a reaction flask, nitrogen gas was purged three times, and 10mL of N, N-dimethylformamide was injected to completely dissolve the polymer, thereby obtaining an aniline pentamer solution. And mixing the block copolymer solution, the EDC solution, the DMAP solution and the aniline pentamer solution under the protection of nitrogen, and heating to 50 ℃ for reacting for 24 hours. After the reaction is finished, the reaction solution is settled by using ether, and a crude product is obtained by suction filtration. And (3) purifying the crude product, firstly dissolving the solid by using chloroform, filtering to remove insoluble substances, then settling the chloroform solution by using ethanol, performing suction filtration to obtain a solid, continuously dissolving the solid by using chloroform, repeating the steps for three times, and drying the solid for 24 hours in vacuum at room temperature to obtain the methoxypolyethylene glycol-poly (L) lactide coupled aniline pentamer block copolymer, wherein the yield is higher than 80%.
The nuclear magnetic resonance analysis of the obtained block copolymer shows that the aniline pentamer reacts with the polyethylene glycol monomethyl ether-poly (L) lactide to generate the block copolymer. The molecular weight of the block copolymer obtained was measured by GPC, and the results are shown in Table 9, where Table 9 summarizes the amounts of the raw materials and the number average molecular weights of the products in examples 101 to 112 of the present invention.
TABLE 9 summary of the amounts of the raw materials and the number average molecular weights of the products in inventive examples 101 to 112
Examples 113 to 124
In accordance with the formulation shown in Table 10, 1g of the poly (L) lactide-polyethylene glycol-poly (L) lactide block copolymer intermediate prepared in example 29, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC) and 4-Dimethylaminopyridine (DMAP) were charged into three stirred reaction vials, and after purging nitrogen three times, 20mL of N, N-dimethylformamide was injected into each reaction vial, and the reaction was carried out at room temperature for 2 days to obtain a block copolymer solution, an EDC solution and a DMAP solution, respectively. The carboxyl-terminated aniline pentamer prepared in example 4 was charged into a reaction flask, nitrogen gas was purged three times, and 10mL of N, N-dimethylformamide was injected to completely dissolve the polymer, thereby obtaining an aniline pentamer solution. And mixing the block copolymer solution, the EDC solution, the DMAP solution and the aniline pentamer solution under the protection of nitrogen, and heating to 50 ℃ for reacting for 24 hours. After the reaction is finished, the reaction solution is settled by using ether, and a crude product is obtained by suction filtration. And (3) purifying the crude product, firstly dissolving the solid with chloroform, filtering to remove insoluble substances, then settling the chloroform solution with ethanol, performing suction filtration to obtain a solid, continuously dissolving the solid with chloroform, repeating the steps for three times, and drying the solid at room temperature in vacuum for 24 hours to obtain the poly (L) lactide-polyethylene glycol-poly (L) lactide coupled aniline pentamer block copolymer, wherein the yield is higher than 80%.
Nuclear magnetic resonance analysis of the obtained block copolymer shows that aniline pentamer reacts with poly (L) lactide-polyethylene glycol-poly (L) lactide to form the block copolymer. The molecular weight of the block copolymer obtained was measured by GPC, and the results are shown in Table 10, where Table 10 summarizes the amounts of the raw materials and the number average molecular weights of the products in examples 113 to 124 of the present invention.
TABLE 10 in examples 113 to 124 of the present invention, the amounts of the respective raw materials and the number average molecular weights of the products are summarized
Examples 125 to 136
1g of the intermediate polyethylene glycol monomethyl ether-poly (D) lactide block copolymer prepared in example 17, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC) and 4-Dimethylaminopyridine (DMAP) were charged into three reaction bottles with a stirrer, and after three nitrogen changes for each reaction bottle, 20mL of N, N-dimethylformamide was added as a solvent, and the mixture was reacted at room temperature for 2 days to obtain a block copolymer solution, an EDC solution and a DMAP solution, respectively. The carboxyl-terminated aniline pentamer prepared in example 4 was charged into a reaction flask, nitrogen gas was purged three times, and 10mL of N, N-dimethylformamide was injected to completely dissolve the polymer, thereby obtaining an aniline pentamer solution. And mixing the block copolymer solution, the EDC solution, the DMAP solution and the aniline pentamer solution under the protection of nitrogen, and heating to 50 ℃ for reacting for 24 hours. After the reaction is finished, the reaction solution is settled by using ether, and a crude product is obtained by suction filtration. And (3) purifying the crude product, firstly dissolving the solid by using chloroform, filtering to remove insoluble substances, then settling the chloroform solution by using ethanol, performing suction filtration to obtain a solid, continuously dissolving the solid by using chloroform, repeating the steps for three times, and drying the solid for 24 hours in vacuum at room temperature to obtain the methoxypolyethylene glycol-poly (D) lactide coupled aniline pentamer block copolymer, wherein the yield is higher than 80%.
The nuclear magnetic resonance analysis of the obtained block copolymer shows that the aniline pentamer reacts with the polyethylene glycol monomethyl ether-poly (D) lactide to generate the block copolymer. The molecular weight of the block copolymer obtained was measured by GPC, and the results are shown in Table 11, where Table 11 summarizes the amounts of the raw materials and the number average molecular weights of the products in inventive examples 125 to 136.
TABLE 11 summary of the amounts of raw materials and the number average molecular weights of the products in inventive examples 125-136
Examples 137 to 148
In accordance with the formulation shown in Table 12, 1g of the poly (D) lactide-polyethylene glycol-poly (D) lactide block copolymer intermediate prepared in example 41, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC) and 4-Dimethylaminopyridine (DMAP) were charged into three stirred reaction vials, and after purging nitrogen three times, 20mL of N, N-dimethylformamide was injected into each reaction vial, and the reaction was carried out at room temperature for 2 days to obtain a block copolymer solution, an EDC solution and a DMAP solution, respectively. The carboxyl-terminated aniline pentamer prepared in example 4 was charged into a reaction flask, nitrogen gas was purged three times, and 10mL of N, N-dimethylformamide was injected to completely dissolve the polymer, thereby obtaining an aniline pentamer solution. And mixing the block copolymer solution, the EDC solution, the DMAP solution and the aniline pentamer solution under the protection of nitrogen, and heating to 50 ℃ for reacting for 24 hours. After the reaction is finished, the reaction solution is settled by using ether, and a crude product is obtained by suction filtration. And (3) purifying the crude product, firstly dissolving the solid with chloroform, filtering to remove insoluble substances, then settling the chloroform solution with ethanol, performing suction filtration to obtain a solid, continuously dissolving the solid with chloroform, repeating the steps for three times, and performing vacuum drying on the solid at room temperature for 24 hours to obtain the poly (D) lactide-polyethylene glycol-poly (D) lactide coupled aniline pentamer block copolymer, wherein the yield is higher than 80%.
The nuclear magnetic resonance analysis of the obtained block copolymer shows that the aniline pentamer reacts with poly (D) lactide-polyethylene glycol-poly (D) lactide to generate the block copolymer. The molecular weight of the block copolymer obtained was measured by GPC, and the results are shown in Table 12, where Table 12 summarizes the amounts of the raw materials and the number average molecular weights of the products in examples 137 to 148 of the present invention.
TABLE 12 summary of the amounts of the raw materials and the number average molecular weights of the products in inventive examples 137 to 148
Example 149
Respectively preparing the block copolymers prepared in the embodiments 53 to 148 into aqueous solutions with mass concentration of 20%, according to the pairing mode of polyethylene glycol monomethyl ether-poly (L) lactide-aniline tetramer and polyethylene glycol monomethyl ether-poly (D) lactide-aniline tetramer, poly (L) lactide-polyethylene glycol-poly (L) lactide-aniline tetramer and poly (D) lactide-polyethylene glycol-poly (D) lactide-aniline tetramer, polyethylene glycol monomethyl ether-poly (L) lactide-aniline pentamer and polyethylene glycol monomethyl ether-poly (D) lactide-aniline pentamer, poly (L) lactide-polyethylene glycol-poly (L) lactide-aniline pentamer and poly (D) lactide-polyethylene glycol-poly (D) lactide-aniline pentamer, block copolymers with correspondingly similar molecular weights and different chiralities, such as those prepared in example 58 and example 82, or example 67 and example 91, respectively, are prepared into 10wt% solutions, 0.5mL of each is uniformly mixed, the mixture is left for a period of time, the viscosity change is observed by a small tube inversion method, and the flow does not occur to be a gelation point within 30s of the small tube inversion.
Experimental results show that the levorotatory block copolymer and the dextrorotatory block copolymer provided by the invention are mixed in an aqueous medium and can be gradually converted from a solution to form a three-dimensional composite hydrogel material.
Example 150
The block copolymer prepared in the embodiment 53-148 of the invention is prepared into the three-dimensional composite hydrogel according to the method in the embodiment 149, then 3mL of phosphate buffer solution is added into the hydrogel, every other day, the solution is taken out, a sample is analyzed by adopting a weighing method, and then 3mL of new buffer solution is added. The result shows that the degradation period of the block copolymer prepared by the invention is 4-8 weeks.
Example 151
The block copolymer prepared in the embodiment 53-148 is prepared into the three-dimensional composite hydrogel according to the method in the embodiment 149, and the change condition of the three-dimensional composite modulus of the polymer aqueous solution along with time is measured by a rheometer. The experimental results are shown in fig. 3, and fig. 3 is a dynamic mechanical test chart of hydrogels formed by the block copolymers prepared in examples 58 and 82, and it can be seen from fig. 3 that the elastic modulus of the stereo-composite hydrogel prepared by the present invention is higher than the loss modulus thereof.
Example 152
The block copolymer prepared in the embodiment 53-148 is prepared into 0.05mg/mL aqueous solution, 0.1mol/L hydrochloric acid aqueous solution is gradually added into the aqueous solution, and the ultraviolet absorption change process of gradual doping of aniline oligomer in the material is observed. The experimental results are shown in fig. 4, fig. 4 is a graph of the ultraviolet absorption of the block copolymer of poly (L) lactide-polyethylene glycol-poly (L) lactide-coupled aniline pentamer prepared in example 114 of the present invention, and it can be seen from fig. 4 that the block copolymer provided by the present invention has good electrical activity.
Example 153
The block copolymer prepared in the embodiment 53-148 is prepared into 0.05mg/mL aqueous solution, 0.01mmol/L ammonium persulfate solution is gradually added into the aqueous solution, and the ultraviolet absorption change process of gradual oxidation of aniline oligomer in the material is observed. The experimental results are shown in fig. 5, fig. 5 is a graph of the ultraviolet absorption of the block copolymer of poly (D) lactide-polyethylene glycol-poly (D) lactide-coupled aniline pentamer prepared in example 144 of the present invention, and it can be seen from fig. 5 that the block copolymer provided by the present invention has good electrical activity.
Comparative example 1
The block copolymers prepared in examples 5 to 52 of the present invention were prepared into a 0.05mg/mL aqueous solution, and subjected to an ultraviolet absorption test according to the method of example 152. Experimental results show that the block copolymers prepared in examples 5-52 have no electric activity.
The above examples and comparative examples show that the block copolymer provided by the present invention has good water solubility and electrical activity, and the block copolymer with the levorotatory configuration and the block copolymer with the dextrorotatory configuration are mixed in an aqueous medium, and after a period of time, a three-dimensional composite hydrogel material can be formed, and the three-dimensional composite hydrogel material has properties of electrical activity, water solubility, degradability, injectability, etc., and can be used as a drug carrier or a stent material, etc., and applied to the field of biomedical materials.
The above description of the embodiments is only intended to facilitate the understanding of the method of the invention and its core idea. It should be noted that, for those skilled in the art, it is possible to make various improvements and modifications to the present invention without departing from the principle of the present invention, and those improvements and modifications also fall within the scope of the claims of the present invention.
Claims (12)
1. A block copolymer for preparing a hydrogel, comprising an A block having a structure of formula (I) or formula (II) and a B block having a structure of formula (III) or formula (IV):
wherein,
n is polymerization degree, n is more than or equal to 23 and less than or equal to 500;
m is polymerization degree, and m is more than or equal to 3 and less than or equal to 90;
x is polymerization degree, and x is more than or equal to 2 and less than or equal to 5.
2. The block copolymer of claim 1, wherein in formula (III) or formula (IV), x is selected from 3 or 4.
3. The block copolymer according to claim 1 or 2, wherein the B block accounts for 10 to 50% by mass of the block copolymer.
4. A method for preparing a block copolymer, comprising:
A) mixing polyethylene glycol or polyethylene glycol monomethyl ether with lactide and a catalyst, and carrying out ring-opening polymerization reaction to obtain a block copolymer intermediate, wherein the lactide is levorotatory-lactide or dextrorotatory-lactide;
B) mixing the block copolymer intermediate obtained in the step A) with a coupling reagent and a compound with a structure of a formula (V) to perform condensation reaction to obtain a block copolymer;
wherein,
x is polymerization degree, and x is more than or equal to 2 and less than or equal to 5.
5. The method according to claim 4, wherein the molar ratio of polyethylene glycol or polyethylene glycol monomethyl ether to lactide is 1: 1 to 45.
6. The method according to claim 4, wherein the mass ratio of the block copolymer intermediate obtained in step A) to the compound having the structure of formula (V) is 1: 0.01 to 1.
7. The method of claim 4, wherein the catalyst is stannous octoate, and the coupling reagent is selected from any one or more of N, N-cyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and 4-dimethylaminopyridine.
8. The method according to claim 4, wherein the temperature of the ring-opening polymerization reaction in the step A) is 100 ℃ to 150 ℃, and the time of the ring-opening polymerization reaction is 12h to 48 h.
9. The method according to claim 4, wherein in the step B), the temperature of the condensation reaction is 0-60 ℃, and the time of the condensation reaction is 24-72 h.
10. A hydrogel comprises an aqueous medium and a stereo composite block copolymer, wherein the aqueous medium is selected from any one or more of water, normal saline, buffer solution, tissue culture solution or body fluid; the stereo composite block copolymer is formed by a first block copolymer formed by a formula (I) and a formula (III) and a second block copolymer formed by a formula (I) and a formula (IV); or a first block copolymer formed from formula (II) and formula (III) and a second block copolymer formed from formula (II) and formula (IV);
wherein,
n is polymerization degree, n is more than or equal to 23 and less than or equal to 500;
m is polymerization degree, and m is more than or equal to 3 and less than or equal to 90;
x is polymerization degree, and x is more than or equal to 2 and less than or equal to 5.
11. The hydrogel according to claim 10, wherein the ratio of the number average molecular weight of the first block copolymer of formula (I) and formula (III) to the number average molecular weight of the second block copolymer of formula (I) and formula (IV) is 0.5 to 1.5: 1; the ratio of the number average molecular weight of the first block copolymer formed by the formula (II) and the formula (III) and the number average molecular weight of the second block copolymer formed by the formula (II) and the formula (IV) is 0.5-1.5: 1.
12. the hydrogel of claim 10, wherein x is selected from 3 or 4.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210512774.3A CN102964582B (en) | 2012-12-04 | 2012-12-04 | Segmented copolymer, preparation method thereof and hydrogel |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210512774.3A CN102964582B (en) | 2012-12-04 | 2012-12-04 | Segmented copolymer, preparation method thereof and hydrogel |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102964582A CN102964582A (en) | 2013-03-13 |
| CN102964582B true CN102964582B (en) | 2014-10-22 |
Family
ID=47795035
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201210512774.3A Active CN102964582B (en) | 2012-12-04 | 2012-12-04 | Segmented copolymer, preparation method thereof and hydrogel |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102964582B (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103936981B (en) * | 2014-04-10 | 2016-03-30 | 中国科学院长春应用化学研究所 | One kind glycopeptide and preparation method thereof, syringeability hydrogel |
| CN105642184B (en) * | 2014-12-02 | 2018-05-04 | 中国科学院宁波材料技术与工程研究所 | Graphene dispersion agent and its application |
| CN105788874B (en) * | 2014-12-24 | 2018-10-26 | 中国科学院宁波材料技术与工程研究所 | A kind of composite graphite alkene paper and preparation method thereof |
| CN106785029B (en) * | 2016-12-27 | 2020-01-14 | 中国科学院青岛生物能源与过程研究所 | Pluronic block copolymer-based hydrogel electrolyte and application thereof |
| CN108925396A (en) * | 2018-06-26 | 2018-12-04 | 常州市蒽盗钟情生物科技有限公司 | A kind of road flower nursery special environment protection contains soil material |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1887854A (en) * | 2006-06-16 | 2007-01-03 | 中国科学院长春应用化学研究所 | Aniline oligomer, its aliphatic polyester copolymer and their prepn |
| CN101555316A (en) * | 2009-05-11 | 2009-10-14 | 山东大学 | Synthetic method of amino-terminated polyethylene glycol-polylactide block copolymer |
| CN102659978A (en) * | 2012-05-09 | 2012-09-12 | 中国科学院长春应用化学研究所 | Segmented copolymer, preparation method thereof and hydrogel |
-
2012
- 2012-12-04 CN CN201210512774.3A patent/CN102964582B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1887854A (en) * | 2006-06-16 | 2007-01-03 | 中国科学院长春应用化学研究所 | Aniline oligomer, its aliphatic polyester copolymer and their prepn |
| CN101555316A (en) * | 2009-05-11 | 2009-10-14 | 山东大学 | Synthetic method of amino-terminated polyethylene glycol-polylactide block copolymer |
| CN102659978A (en) * | 2012-05-09 | 2012-09-12 | 中国科学院长春应用化学研究所 | Segmented copolymer, preparation method thereof and hydrogel |
Also Published As
| Publication number | Publication date |
|---|---|
| CN102964582A (en) | 2013-03-13 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102964593B (en) | Block polymer, preparation method thereof and electrically active hydrogel | |
| CN102964582B (en) | Segmented copolymer, preparation method thereof and hydrogel | |
| EP2678326B1 (en) | Monomers and polymers for functional polycarbonates and poly (ester-carbonates) and peg-co-polycarbonate hydrogels | |
| Wei et al. | Gel formation and photopolymerization during supramolecular self-assemblies of α-CDs with LA–PEG–LA copolymer end-capped with methacryloyl groups | |
| Zhao et al. | Single component thermo-gelling electroactive hydrogels from poly (caprolactone)–poly (ethylene glycol)–poly (caprolactone)-graft-aniline tetramer amphiphilic copolymers | |
| KR20050012533A (en) | Thermosensitive poly(organophosphazenes), preparation method thereof and injectable thermosensitive polyphosphazene hydrogels using the same | |
| CN101328251B (en) | Biodegradable temperature/pH dual responsiveness aquagel | |
| Wu et al. | Lipase-catalyzed synthesis of acid-degradable poly (β-thioether ester) and poly (β-thioether ester-co-lactone) copolymers | |
| CN105694030B (en) | A kind of oligomeric amino acid and the compound hydridization anti-bacterial hydrogel of sodium alginate | |
| He et al. | Synthesis and physicochemical characterization of biodegradable and pH‐responsive hydrogels based on polyphosphoester for protein delivery | |
| US20050020719A1 (en) | Environment responsive gelling copolymer | |
| CN110423337B (en) | Temperature-sensitive supramolecular polymer regulated and controlled by multiple hydrogen bonds and preparation method thereof | |
| Cui et al. | Novel amphiphilic diblock copolymers bearing acid-labile oxazolidine moieties: Synthesis, self-assembly and responsive behavior in aqueous solution | |
| Li et al. | Synthesis, Characterization, and Morphology Studies of Biodegradable Amphiphilic Poly [(R)-3-hydroxybutyrate]-a lt-Poly (ethylene glycol) Multiblock Copolymers | |
| CN105732990A (en) | Method for preparing selenium-containing degradable polymer through ring-opening polymerization and application thereof to hydrogel | |
| CN103113579A (en) | Polyglutamic acid derivative as well as hydrogel and preparation method of polyglutamic acid derivative | |
| Audebeau et al. | One-pot synthesis and gelation by borax of glycopolymers in water | |
| Zeng-guo et al. | Synthesis and characterization of biodegradable hydrogels based on photopolymerizable acrylate-terminated CL-PEG-CL macromers with supramolecular assemblies of α-cyclodextrins | |
| KR101293618B1 (en) | Cell injectable hydrogel copolymerized with biodegradable synthetic polymers and the preparation method thereof | |
| US20090076223A1 (en) | Shape memory polymer with polyester and polyacrylate segments and process for its production and programming | |
| Mancera et al. | New derivatives of d-mannaric and galactaric acids.: Synthesis of a new stereoregular Nylon 66 analog from carbohydrate-based monomers having the d-manno configuration | |
| CN110204703B (en) | Diatomite-based composite material and preparation method thereof | |
| Jia et al. | DNA hydrogels formed of bended DNA scaffolds and properties study | |
| CN113024781B (en) | Preparation method of cyclic polylactone | |
| CN109679071B (en) | PCLT-g-PEDOT conductive compound and preparation method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| C41 | Transfer of patent application or patent right or utility model | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20161202 Address after: 213000 Jiangsu City, Changzhou Province, East Sea Road, No. 9 Patentee after: Changzhou Institute of Energy Storage Materials & Devices Address before: 130022 Changchun people's street, Jilin, No. 5625 Patentee before: Changchun Institue of Applied Chemistry, Chinese Academy of Sciences |
|
| C56 | Change in the name or address of the patentee | ||
| CP02 | Change in the address of a patent holder |
Address after: Changzhou City, Jiangsu province Hehai road 213000 No. 9 Patentee after: Changzhou Institute of Energy Storage Materials & Devices Address before: 213000 Jiangsu City, Changzhou Province, East Sea Road, No. 9 Patentee before: Changzhou Institute of Energy Storage Materials & Devices |