CN103113579A - Polyglutamic acid derivative as well as hydrogel and preparation method of polyglutamic acid derivative - Google Patents
Polyglutamic acid derivative as well as hydrogel and preparation method of polyglutamic acid derivative Download PDFInfo
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- CN103113579A CN103113579A CN2013100550492A CN201310055049A CN103113579A CN 103113579 A CN103113579 A CN 103113579A CN 2013100550492 A CN2013100550492 A CN 2013100550492A CN 201310055049 A CN201310055049 A CN 201310055049A CN 103113579 A CN103113579 A CN 103113579A
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Abstract
The invention discloses a polyglutamic acid derivative as well as a hydrogel and a preparation method of the polyglutamic acid derivative. The structure formula of the polyglutamic acid derivative is shown in a formula (I), wherein n is any integer of 20-60. During the preparation, isopropamide is successfully introduced into a methoxy polyethylene glycol-b-polyglutamic acid block copolymer through a simple chemical modification method and a biodegradable hydrogel material with a certain mechanical strength is successfully prepared. The mechanical property of the hydrogel material can be changed by controllably changing the length of the polymer chain segment, so that the polyglutamic acid derivative and the hydrogel disclosed by the invention can be widely applied to the fields of medicine carriers, tissue engineering scaffolds and the like.
Description
Technical field
The present invention relates to field of biomedical polymer materials, be specifically related to a kind of polyglutamic acid derivative and hydrogel and preparation method.
Background technology
Bio-medical material (biomedical material) is for organism being diagnosed, treat, repairs or replace its disease damage tissue, organ or promoting the novel high polymer material of its function.It is the basis of research artificial organs and medicine equipment and pharmaceutical preparation, has become the important branch of material subject.Biological medical polymer material is as a subdiscipline of macromolecular material subject, and within nearly 40 years, the fast development that is accompanied by biotechnology has just really begun research and the understanding of people to it especially.Except natural medical polymer materials, the synthesising biological medical macromolecular materials are accompanied by the continuous progress of macromolecule synthesising technology and arise at the historic moment.
The macromolecular material that poly-fret peptide is connected by peptide bond as a kind of main chain polyamino acid material that is otherwise known as, usually obtain homopolymer or multipolymer by one or several amino acid or derivatives thereofs by polyreaction, it has unique secondary structure, good biodegradability and biocompatibility, is widely used in the fields such as drug release and organizational project.
The synthetic polyamino acid of the amino acid of different structure has different side chains, controls the hydrophilic and hydrophobic of side chain group, charged lotus property or acid-basicity, physical and chemical performance and degradation speed that can telomerized polymer.The structure of polyamino acid uniqueness makes it be different from traditional polymkeric substance, and having a not available advantage of a lot of traditional polymers, biocompatibility, degradability, self-assembly behavior, liquid crystal phenomenon and mechanical property provide desirable material for biomedicine and organizational engineering field well for they.Wherein the self-assembly behavior of polyamino acid and multipolymer thereof is that the pharmaceutical carrier of development of new has been created condition, this pharmaceutical carrier has the plurality of advantages such as capable of realizing controlled-release, targeted, the insoluble drug absorption rate of raising and degradable, has become the important research direction in biopolymer field at present.
Most poly-peptides is owing to reaching the intermolecular hydrogen bonding effect, to such an extent as to its solvability in the aqueous solution and bad in serious molecule.And polyoxyethylene glycol is as a kind of biological medical polymer material commonly used, has good water-soluble and biocompatibility, be used for improving hydrophobic polymer water-soluble by increasing investigator nearly decades, perhaps deep research carried out in the self-assembly behavior of multipolymer.In recent years, gather multipolymer, especially the polyoxyethylene glycol Polypeptide copolymer of peptidyl, become the hot fields of present research; And due to its unique biological nature, more and more be applied on new biological active materials.
In addition, hydrogel is a kind ofly typically the material of major application prospect to be arranged aspect soft tissue and bone engineering.The water-absorbent that hydrogel is good and infiltration structure can simulating nature circle the extracellular model, these key characteristics make it in these areas good application can be arranged.In order to substitute the nature model, need to build many structure and function characteristics in the synthetic water gel.Gratifying characteristic comprises biocompatibility, the degradability that can allow the growth of cell, syringeability and forms fast in the wound, can adapt to mechanical property of different purposes etc.But in many concrete instances, the synthetic and formation of hydrogel is very complicated, and this has limited the practical application of material.The more important thing is, the complicacy of these systems combines the limited means of adjusting molecular parameter, has caused independently regulating most characteristic; Such as it is very useful also keeping a constant hydrogel grid size when regulating support intensity, and such individual system should allow the impact of direct test bracket intensity on cell proliferation.Yet normally because adopted degradable crosslinked, so this is difficult to regulate degradation rate and thereby the mechanical property of the initial water gel that increases by changing cross-linking density due to the degradability of hydrogel.It is all simultaneous regulating due to the characteristic of a lot of hydrogels, therefore is difficult at present determine most important gellifying property.The hydrogel of synthesize polypeptide class but can be regulated a lot of performance perameters well, for its application in organizational project provides a good platform.
At present, also comparatively rare by the hydrogel material of polyglutamic acid derivative preparation.(the Soft Matter of Deming seminar, 2005,1:28 – 35) once synthetic (1B-hydrogen bromide), poly-(the Pidolidone sodium salt) of being gathered forms the amphiphilic block peptide with hydrophobic alpha-helix polylalanine respectively, and prepare its hydrogel material, combination by chemosynthesis and structural characterization, detailed material structure and property relationship are set up, make gel-strength, the gel space, the performance height such as dielectric stability are controlled, and many parameters can be carried out independent adjusting.Also cause the field of its application to be greatly limited but the mechanical strength of this copolymerization peptide gel is low, can't be applied to the field of tissue engineering technology higher to mechanics of materials requirement of strength; And the preparation of the poly-peptide hydrogel material that present side chain is amido linkage is also there are no crossing report.
Summary of the invention
The object of the present invention is to provide a kind of polyglutamic acid derivative and hydrogel and preparation method.The present invention successfully introduces Isopropylamine on poly glycol monomethyl ether-b-polyglutamic acid block copolymer by simple chemical modification method and successfully it is prepared into the biodegradable hydrogel material of certain mechanical strength, can change the mechanical property of hydrogel material and have certain mechanical strength by the controlled change polymkeric substance even length of section; Polyglutamic acid derivative of the present invention and hydrogel thereof can be widely used in the fields such as pharmaceutical carrier, tissue engineering bracket.
The objective of the invention is to be achieved through the following technical solutions:
First aspect the present invention relates to a kind of polyglutamic acid derivative, and its structural formula is as shown in formula I:
Second aspect the present invention relates to a kind of preparation method of aforesaid polyglutamic acid derivative, and described method comprises the steps:
A, with anhydrous N, dinethylformamide is solvent, under nitrogen protection, obtain poly glycol monomethyl ether-b-poly benzyl glutamate segmented copolymer to hold amino poly glycol monomethyl ether to cause Pidolidone benzyl ester-N-carboxylic acid inner-acid anhydride polymerization as macromole evocating agent;
B, described poly glycol monomethyl ether-b-poly benzyl glutamate segmented copolymer is dissolved in dichloro acetic acid, adds the CH that contains HBr33wt%
3COOH solution, the benzyl ester blocking group is removed at room temperature hydrolysis, gets poly glycol monomethyl ether-b-polyglutamic acid block copolymer;
C, described poly glycol monomethyl ether-b-polyglutamic acid block copolymer is dissolved in anhydrous N, in dinethylformamide, add EDC(1-ethyl-(3-dimethylaminopropyl) carbodiimide under stirring), the NHS(N-N-Hydroxysuccinimide) activation after, add the Isopropylamine stirring reaction, reaction product namely gets described polyglutamic acid derivative with the deionized water postlyophilization of dialysing.
Preferably, the poly glycol monomethyl ether by regulating the end amino in described steps A and the molar feed ratio of Pidolidone benzyl ester-N-carboxylic acid inner-acid anhydride (BLG-NCA) monomer obtain the polyglutamic acid derivative of different molecular weight and composition.
Further preferably, the number-average molecular weight of the poly glycol monomethyl ether of described end amino is 2000.
Further preferably, the molar feed ratio of the poly glycol monomethyl ether of described end amino and Pidolidone benzyl ester-N-carboxylic acid inner-acid anhydride (BLG-NCA) monomer is 1:(20～60).
Preferably, in step C, the mol ratio of described poly glycol monomethyl ether-b-polyglutamic acid block copolymer and EDC, NHS is 1:5:5.
The third aspect the present invention relates to the purposes of a kind of aforesaid polyglutamic acid derivative in preparation hydrogel carrier.
Preferably, described polyglutamic acid derivative is added in the phosphate buffer solution of pH=7.4 to be made into thick solution, 37 ℃ of isothermal vibrations namely get described hydrogel carrier.
Further preferably, in described hydrogel carrier, the mass percentage content that described polyglutamic acid derivative accounts for gross weight is 7.5～12.5%.
Compared with prior art, the beneficial effect that has of the present invention is:
1, the present invention is incorporated into the polyglutamic acid side chain by simple reaction with isopropylamine base, had the amido linkage group on the polyglutamic acid side chain thereby make, and the reactant that adopts is simple and easy to, and technique is simple, and is easy to operate, and synthetic method is comparatively ripe.
2, the modification of side chain has changed the essential property of corresponding polyglutamic acid material and has been prepared into biodegradable and has the hydrogel material of certain mechanical strength, has greatly expanded the polyglutamic acid material in the application in biological medicine, organizational engineering field.
Description of drawings
By reading the detailed description of non-limiting example being done with reference to the following drawings, it is more obvious that other features, objects and advantages of the present invention will become:
Fig. 1 is the hydrogen nuclear magnetic resonance spectrogram of embodiment 1, and wherein, A is the hydrogen nuclear magnetic resonance spectrogram of mPEG-b-PBLG, and B is the hydrogen nuclear magnetic resonance spectrogram of mPEG-b-PGA, and C is the hydrogen nuclear magnetic resonance spectrogram of mPEG-b-PIGA;
Fig. 2 is that poly-(N-sec.-propyl-L-glutaminate) the hydrogel storage modulus of the poly glycol monomethyl ether-b-of different molecular weight and massfraction in embodiment 2 is with the spectrogram of strain change of frequency.
Embodiment
The present invention is described in detail below in conjunction with the drawings and specific embodiments.Following examples will help those skilled in the art further to understand the present invention, but not limit in any form the present invention.Should be pointed out that to those skilled in the art, without departing from the inventive concept of the premise, can also make some distortion and improvement.These all belong to protection scope of the present invention.
The polyglutamic acid derivative of the present embodiment is the poly glycol monomethyl ether modified of Isopropylamine-b-polyglutamic acid derivative, is specially poly glycol monomethyl ether-b-poly-(N-sec.-propyl-L-glutaminate), and it is prepared as follows:
(1) preparation of poly glycol monomethyl ether-b-poly-L-glutamic acid acid benzyl ester (mPEG-b-PBLG) segmented copolymer
Under nitrogen protection, the poly glycol monomethyl ether that end is amino is dissolved in anhydrous N, in dinethylformamide, cause Pidolidone benzyl ester-N-carboxylic acid inner-acid anhydride (BLG-NCA) in nitrogen environment after the airtight ring-opening polymerization 72h of room temperature (15～25 ℃), with reaction solution sedimentation in excessive anhydrous diethyl ether, suction filtration gets the white solid final vacuum and is dried to constant weight; Get poly glycol monomethyl ether-b-poly benzyl glutamate segmented copolymer.
Wherein, Pidolidone benzyl ester-N-carboxylic acid inner-acid anhydride (BLG-NCA) is prepared as: take anhydrous ethyl acetate as solvent; with Pidolidone benzyl ester (BLG) and triphosgene at 70 ℃; under nitrogen protection, reaction generates Pidolidone benzyl ester-N-carboxylic acid inner-acid anhydride (BLG-NCA) monomer; product is recrystallization in ethyl acetate and normal hexane mixed solvent; filter and drying, obtain the higher Pidolidone benzyl ester of purity-N-carboxylic acid inner-acid anhydride (BLG-NCA).
(2) preparation of poly glycol monomethyl ether-b-L-glutamic acid (mPEG-b-PGA) segmented copolymer
Poly glycol monomethyl ether-b-L-glutamic acid benzyl ester block copolymer is dissolved in dichloro acetic acid, adds 33wt%HBr/CH
3COOH solution, under room temperature, reaction is 2 hours, the benzyl ester blocking group is removed in hydrolysis, with reaction solution sedimentation in excessive anhydrous diethyl ether, remove wash with a large amount of ether after supernatant liquid after with solid vacuum-drying to constant weight; Get poly glycol monomethyl ether-b-L-glutamic acid segmented copolymer.
(3) poly-(N-sec.-propyl-L-glutaminate) (mPEG-b-PIGA) preparation of segmented copolymer of poly glycol monomethyl ether-b-
Poly glycol monomethyl ether-b-L-glutamic acid segmented copolymer is dissolved in anhydrous N, in dinethylformamide, rapid weighing also adds EDC and NHS in solution, after 2 hours to be activated (purpose of this activation is to activate the side chain carboxyl group of polyglutamic acid), Isopropylamine is added in solution reacted 24 hours; React complete, postlyophilization that solution is dialysed under the deionized water environment gets white cotton-shaped solid and is product; Wherein, the mol ratio of poly glycol monomethyl ether-b-L-glutamic acid segmented copolymer and EDC, NHS is 1:5:5.
Poly-(N-sec.-propyl-L-glutaminate) segmented copolymer of described poly glycol monomethyl ether-b-L-glutamic acid benzyl ester block copolymer, poly glycol monomethyl ether-b-L-glutamic acid segmented copolymer and poly glycol monomethyl ether-b-is carried out hydrogen nuclear magnetic resonance spectrum detect, result such as Fig. 1.
In the present invention, by holding amino poly glycol monomethyl ether and the molar feed ratio of BLG-NCA monomer, can obtain the segmented copolymer of different molecular weight and composition.In the present embodiment, be 1:20,1:40,1:60 by the poly glycol monomethyl ether of adjustable side amino and the molar feed ratio of BLG-NCA monomer, the synthetic poly glycol monomethyl ether-b-poly-(N-sec.-propyl-L-glutaminate) that obtains different molecular weight the results are shown in Table 1.
The experimental result of table 1 poly glycol monomethyl ether-b-poly-(N-sec.-propyl-L-glutaminate)
The mol ratio of the poly glycol monomethyl ether of A/I finger tip amino and monomers B LG-NCA in upper table, DP (PIGA) is the polymerization degree of poly-(L-glutamy Isopropylamine), Mn is the number-average molecular weight of segmented copolymer; Wherein DP (PIGA) and Mn all by
1H NMR measures and obtains.
Poly glycol monomethyl ether-b-gathers (N-sec.-propyl-L-glutaminate) preparation of gels:
(1) configuration of pH=7.4 phosphate buffer solution
Accurately take in the distilled water that 9.078g potassium primary phosphate and 23.876g Sodium phosphate dibasic be dissolved in respectively 1000mL and stir, potassium dihydrogen phosphate constant volume in the volumetric flask of 1000mL of then getting the disodium phosphate soln of 800mL and 200mL obtains the phosphate buffer solution of pH=7.4.
(2) poly-(N-sec.-propyl-L-glutaminate) preparation of gels of poly glycol monomethyl ether-b-
Poly glycol monomethyl ether-b-poly-(N-sec.-propyl-L-glutaminate) is dissolved in the phosphate buffer solution of pH=7.4, is made into thick solution and put in 37 ℃ of isothermal vibration casees 2 hours, the hydrogel of polymkeric substance forms; Adopt " bottle inverted type " macroscopic view to characterize the formation of hydrogel, bottle is taken out and is inverted, do not observed liquid and flow down within 1 minute, think gel formation at this moment.
By changing respectively polymericular weight and quality, prepared the test that different hydrogel materials carries out mechanical property, as shown in Figure 2, and wherein, with 7.5wt%mPEG-PIGA
21Be example, expression be hydrogel material with poly-(N-sec.-propyl-L-glutaminate) the multipolymer preparation quality mark 7.5% of poly glycol monomethyl ether-b-, the polymerization degree of 21 poly-(N-sec.-propyl-L-glutaminate) segments of expression wherein; As can see from Figure 2, along with the variation of answering Frequency, the storage modulus of hydrogel material is in same numerical value substantially; Along with the growth of poly-peptide segment (n is the polymerization degree of poly-peptide segment), the Young's modulus of the hydrogel material of massfraction 7.5wt% also constantly increases; In hydrogel material, the massfraction of polymkeric substance is increased to 12.5wt% by 7.5wt%, and the Young's modulus of polyalcohol hydrogel material has also had significantly to be increased, more than having reached 20000Pa.
Above specific embodiments of the invention are described.It will be appreciated that, the present invention is not limited to above-mentioned specific implementations, and those skilled in the art can make various distortion or modification within the scope of the claims, and this does not affect flesh and blood of the present invention.
Claims (8)
1. polyglutamic acid derivative, its structural formula is as shown in formula I:
2. the preparation method of a polyglutamic acid derivative according to claim 1, is characterized in that, described method comprises the steps:
A, with anhydrous N, dinethylformamide is solvent, under nitrogen protection, obtain poly glycol monomethyl ether-b-poly benzyl glutamate segmented copolymer to hold amino poly glycol monomethyl ether to cause Pidolidone benzyl ester-N-carboxylic acid inner-acid anhydride polymerization as macromole evocating agent;
B, described poly glycol monomethyl ether-b-poly benzyl glutamate segmented copolymer is dissolved in dichloro acetic acid, adds the CH that contains HBr33wt%
3COOH solution, the benzyl ester blocking group is removed at room temperature hydrolysis, gets poly glycol monomethyl ether-b-polyglutamic acid block copolymer;
C, described poly glycol monomethyl ether-b-polyglutamic acid block copolymer is dissolved in anhydrous N, in dinethylformamide, after adding EDC, NHS activation under stirring, add the Isopropylamine stirring reaction, reaction product namely gets described polyglutamic acid derivative with the deionized water postlyophilization of dialysing.
3. the preparation method of polyglutamic acid derivative according to claim 2, it is characterized in that, poly glycol monomethyl ether by regulating the end amino in described steps A and the molar feed ratio of Pidolidone benzyl ester-N-carboxylic acid inner-acid anhydride monomer obtain the polyglutamic acid derivative of different molecular weight and composition.
4. the preparation method of polyglutamic acid derivative according to claim 3, is characterized in that, the number-average molecular weight of the poly glycol monomethyl ether of described end amino is 2000.
5. the preparation method of polyglutamic acid derivative according to claim 3, is characterized in that, the molar feed ratio of the poly glycol monomethyl ether of described end amino and Pidolidone benzyl ester-N-carboxylic acid inner-acid anhydride monomer is 1:(20～60).
6. the preparation method of polyglutamic acid derivative according to claim 2, is characterized in that, in step C, the mol ratio of described poly glycol monomethyl ether-b-polyglutamic acid block copolymer and EDC, NHS is 1:5:5.
A polyglutamic acid derivative according to claim 1 preparation and hydrogel, it is characterized in that, described hydrogel be prepare by the following method and: it is characterized in that, described polyglutamic acid derivative is added in the phosphate buffer solution of pH=7.4 and be made into thick solution, 37 ℃ of isothermal vibrations namely get described hydrogel.
8. hydrogel according to claim 7, is characterized in that, in described hydrogel, the mass percentage content that described polyglutamic acid derivative accounts for gross weight is 7.5～12.5%.
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| CN103600435A (en) * | 2013-08-05 | 2014-02-26 | 怡维怡橡胶研究院有限公司 | Rubber master batch continuous manufacturing method and rubber master batch prepared thereby |
| CN103980487A (en) * | 2014-05-06 | 2014-08-13 | 成都市绿科华通科技有限公司 | Preparation method for degradable porous polyethylene glycol |
| CN104761721A (en) * | 2015-03-31 | 2015-07-08 | 青岛科技大学 | Amphipathic molecule injectable and non-ionic super water gel based on oligomeric amino acid |
| CN105949458A (en) * | 2016-06-08 | 2016-09-21 | 长春理工大学 | Poly(L-glutamate)-grafted cinnamyl alcohol, preparation method and drug-loaded nano-material |
| CN109734911A (en) * | 2019-03-13 | 2019-05-10 | 南京苏睿医药科技有限公司 | A kind of quasi- preparation method for carrying scutelloside |
| CN113582770A (en) * | 2021-08-12 | 2021-11-02 | 吉林隆源农业服务有限公司 | Slow-release long-acting compound fertilizer for corn planting and preparation method thereof |
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| CN103600435A (en) * | 2013-08-05 | 2014-02-26 | 怡维怡橡胶研究院有限公司 | Rubber master batch continuous manufacturing method and rubber master batch prepared thereby |
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| CN113582770A (en) * | 2021-08-12 | 2021-11-02 | 吉林隆源农业服务有限公司 | Slow-release long-acting compound fertilizer for corn planting and preparation method thereof |
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