CN100365043C - Synthesis of ABA polypeptide -b- polytetrahydrofuran-b-polypeptide triblock copolymer - Google Patents
Synthesis of ABA polypeptide -b- polytetrahydrofuran-b-polypeptide triblock copolymer Download PDFInfo
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Abstract
The present invention relates to a synthetic method of ABA type polypeptide-b-polytetrahydrofuran-b-polypeptide triblock copolymers. The triblock copolymers are obtained by the ring-opening polymerization of alpha-amino acid-N-carboxy inner acid anhydride(NCA) generated by amino acid and triphosgene, and the ring-opening polymerization is initiated by terminal amino polyoxytetramethylene used as initiators. The ABA type triblock copolymers with different block lengths can be prepared according to the mixing molar rate of NCA to the initiators and the difference of the molecular weight of the initiators, wherein the section B is polytetrahydrofuran, and the section A is polypeptide homopolymers or copolymers (the structural formula of which is disclosed in the first figure). The copolymers can be prepared by changing the molecular weight of each block and the chemical constitution of the blocks of the homopolymers or the copolymers. The synthetic polymers can be applied to the fields of cells of regeneration medicine, support materials cultured by tissue engineering, the controlled release of drugs, carriers used for gene transfection treatment, macromolecule prodrugs, the surface decoration of biological materials, etc.
Description
Technical field
The invention belongs to field of biomedical polymer materials, relating generally to a class is the poly-peptide triblock copolymer of polyethers and the synthetic method thereof of central block with the polytetrahydrofuran.The poly-peptide triblock copolymer of this polyethers has excellent biological compatibility, mechanical property and degradability, and its mechanical property and degradation property can be regulated by the molecular weight and the composition variation thereof of polyethers and poly-polypeptide block.This segmented copolymer mainly is applicable to the carrier of cell and organizational project are cultivated in the regenerative medicine support, medicine controlled releasing and gene transfection, macromolecule precursor medicament, fields such as biomaterial surface modification.
Background technology
Chemosynthesis polyamino acid or poly-peptide compounds have the structure and properties similar to natural protein or polypeptide (Hayashi T.Polymer Journal, 1993,25:481), demonstrate and cell and highly organized biocompatibility; Owing to have a large amount of peptide bonds on the poly-peptide main chain, in body, very easily be subjected to the effect of enzyme simultaneously, generate nontoxic little peptide or amino acid product, can be absorbed and metabolism by body, thereby have excellent biodegradability and security thereby can degrade.They are cell and the support of organizational project cultivation and desirable biomaterials of medicine controlled release carrier in the current regenerative medicine, also can be widely used in the gene transfection carrier, macromolecule precursor medicament, fields such as biomaterial surface modification after the deprotection base is handled.
The poly-peptide of chemosynthesis contains a large amount of hydrogen bonds equally makes it have stable secondary structure, and interactions such as their hydrophobic, static and dipole-dipole make it to have had the self-assembly characteristic in addition.If can accomplish to make synthesize polypeptide to have narrow molecular weight and disperse, it just might form the nanostructure that is similar to natural protein by self-assembly.The synthesize polypeptide distinctive molecular structure makes it be different from traditional synthesized polymer material, and has a not available performance of a lot of traditional macromolecular materials, as excellent biological compatibility, degradability, self-assembly behavior, liquid crystal phenomenon and mechanical property etc., be the selection of bio-medical material ideal.No matter be directly to obtain after the ring-opening polymerization; or the synthesize polypeptide that after the deprotection base is handled, is generated; all can be used as the timbering material that cell and organizational project are cultivated; formed support not only has controlled biological degradability and suitable mechanical property, also has the avtive spot that can supply the cell adhesion growth to discern in a large number simultaneously.In addition, the self-assembly behavior of poly-peptide provides condition for exploitation controlled release drug novel form, but makes that medicine has had controlled release, targeted, the insoluble drugs specific absorption improves greatly and plurality of advantages such as degradable.Polylysine and multipolymer etc. thereof are being played the part of the effect of polymer carrier in gene transfection, it is sent into bring into play therapeutic action in the nucleus by being compounded to form nano particle, aspect hereditary relevant difficult and complicated illness, will play a significant role in treatment with foreign gene.The synthesize polypeptide material has become important directions (Yoda R.J Biomater Sci Polym Ed, 1998,9 (6): 561 of present synthesising biological medical polymer research field as medicine controlled releasing and gene transfection solid support material; Pack D.W.NatureReview Drug Discovery, 2005,4:581).Poly-peptide after the deprotection base is handled has more provided in a large number can be for the reactive group that further carries out chemically modified; as amino; carboxyl, hydroxyl etc., picture taxol in grafting on these groups; cancer therapy drugs such as Zorubicin can be made into macromole prerequisite medicine; not only can reduce the toxicity of cancer therapy drug greatly, but also can improve the accumulate concentration of medicine, obviously improve result of treatment (the Haag R and Kratz F.Angew Chem Int Ed of medicine at tumor locus; 2006,45:1198).
The natural protein hydrogel has been widely used in fields such as food, makeup, pharmaceutical carrier and tissue engineering bracket material.Because this material causes its character homogeneity poor because of the difference in the place of production, source etc., and the diseases such as cross infection that may occur between potential people and animal, causes it to be not suitable for being applied to field of biomedical materials.So people turn to the research of the poly-peptide hydrogel of chemosynthesis one after another in recent years.For example, people such as Deming (Nature 2002,417:424) synthesized the poly-peptide hydrogel of a series of amphiphilic diblocks, find that the character of this hydrogel can be regulated by the molecular structure and the chain length that change two blocks.(Angew Chem Int Ed 2005 44:7964) finds that the di-block copolymer that contains poly-γ-benzyl-L-glutamate can self-assembly form organic gelinite in toluene solution to people such as while Taek.People such as Anderson (Biomed MaterSymp, 1970,5:197) prepared γ-benzyl-L-glutamate and leucic multipolymer have very good tissue affinity, in implanting the experiment mice body after 200 days, fairly obvious growth of new tissue is arranged around the implant, this multipolymer also has the favorable biological degradability energy, and degradation speed changes with the change of copolymerization component.Chen Xuesis etc. are at first made initiator with poly glycol monomethyl ether, and stannous octoate is a catalyzer, cause the ring-opening polymerization of aliphatics cyclic ester monomer and have obtained poly glycol monomethyl ether-aliphatic polyester Synthetic rubber, isoprene-styrene, hydrogenated, block, diblock.And then change the terminal hydroxy group of this multipolymer into the phenylpropyl alcohol amino acid ester, and be macromole evocating agent with it, re-initiation γ-benzyl-L-L-glutamic acid-ring-opening polymerizations such as N-carboxyl inner-acid anhydride obtain polyoxyethylene glycol-aliphatic polyester-polyamino acid triblock copolymer (2003, CN 1440995A).
Also can reach the purpose that changes degradation speed by the hydrophilic, hydrophobic property of regulating poly-polypeptide block side-chain radical in addition, also can change the mechanical property of material simultaneously, other performances such as self-assembly behavior.Woods is praised equality (MacromoRapid Commun, 2004,25:1241-6) cause γ-benzyl-L-L-glutamic acid-N-carboxyl inner-acid anhydride and prepared homopolymerization γ-benzyl-L-glutamate with triethylamine, by transesterification reaction polyoxyethylene glycol is grafted on the homopolymerization peptide chain then, and has studied its self-assembly behavior.Jeong etc. (Polymer, 2003,44:583-91) prepare the poly aspartic acid-g-polycaprolactone multipolymer of amphiphilic biologically degradable, and prepared the corresponding polymer micella.These materials have determined them will have a wide range of applications in biomedical materials field because of the excellent properties that existence presented of poly-polypeptide block.
A large amount of synthesising biological degradable materials that adopt are mainly poly-glycollide (PGA), polylactide (PLA), poly-epsilon-caprolactone polyester compounds such as (PCL) in the organizational project at present.Though they all have good physical and mechanical properties and biocompatibility, can participate in the absorption and the metabolism of body, do not produce cytotoxicity, but all lack the avtive spot of discerning for the cell adhesion growth in its molecular structure, when it is used, all will not carry out the material surface modifying processing exceptionally and just can make the cell well-grown.In addition, have more and more evidences to show, these materials the non-specific aseptic inflammation reaction of the caused surrounding tissue of acidic substance that is produced by degraded also can occur in clinical application; Simultaneously accumulate the self-catalysis that is caused and to accelerate material degradation and disintegration, finally cause support integral body to subside by acid product; And descend and cause the phenomenon of a large amount of cytotoxics even death by the too high pH of the causing value of the formed hydroxycarboxylic acid partial concn of degraded.In contrast to this, the poly-peptide homopolymerization of chemosynthesis and the molecular structure of multipolymer are made up of the amino acid unit, and has an alpha-helix that extensively exists in chirality and the organism, secondary structures such as beta sheet, thereby demonstrate excellent biological compatibility with cell, tissue and other organism, its degraded product mainly is each seed amino acid that is easily absorbed by organism, can not cause body to poison and cause inflammation.In addition, they also have good mechanical performance, film-forming properties and spinning property, make its cell and field of tissue engineering technology in regenerative medicine become New-support material and the face finish material that substitutes degradable aliphatic polyester.
Usually introduce polyoxyethylene glycol improves material as hydrophilic segment wetting ability in the at present poly-polypeptide block polymkeric substance.Although polyoxyethylene glycol has excellent biological compatibility, anticoagulant property, nontoxic and hypoimmunity because polyoxyethylene glycol very easily absorbs water, can cause the mechanical property of material to reduce significantly, and use occasion is restricted.Therefore, the present invention replaces polyoxyethylene glycol as mid-block with polytetrahydrofuran, to improve the moisture-resistant intensity of material.Polytetrahydrofuran often as polyester soft segment, is used widely in embedded materials such as artificial blood vessel, artificial heart, all kinds of conduit, weighting material in medical polyurethane material.The present invention adopts polytetrahydrofuran can not have influence on the biocompatibility and the security of material as mid-block.
Summary of the invention (general introduction)
The object of the invention aims to provide the synthetic method of the poly-peptide of a kind of new A BA type-poly-peptide triblock copolymer of b-polytetrahydrofuran-b-.Preparation process is as follows:
A) with the anhydrous tetrahydro furan be solvent, each seed amino acid and derivative thereof and triphosgene reaction are generated corresponding N CA, product filters with dry oil ether precipitation then, drying, product.
B) with anhydrous N, dinethylformamide is a solvent, under anhydrous, oxygen free condition, be that macromole evocating agent causes corresponding amino acid whose NCA ring-opening polymerization and forms the poly-peptide of ABA type-poly-peptide triblock copolymer of b-polytetrahydrofuran-b-to hold amino polytetrahydrofuran, be settled out the product of wanting with anhydrous methanol again, vacuum-drying gets the finished product then.By the amino polytetrahydrofuran macromole evocating agent molecular weight in adjustable side and with the molar feed ratio of different aminoacids NCA, can obtain different molecular weight, different form segmented copolymer.
Among the above-mentioned preparation method, different aminoacids and derivative thereof at first obtain the raw material that purity meets the polymerization requirement by recrystallization.
Among the above-mentioned preparation method, the preparation of different aminoacids NCA, temperature generally can be controlled in 25 ℃～65 ℃ reactions, and the time is 0.5～6 hour.
Among the above-mentioned preparation method, different aminoacids NCA uses anhydrous ethyl acetate/dry oil ether recrystallization respectively repeatedly, and fusing point conforms to literature value, and ultimate analysis measured value and theoretical value differ less than 3 ‰.Vacuum condition is preserved stand-by down.
Among the above-mentioned preparation method, hold amino polytetrahydrofuran macromole evocating agent, reduce to room temperature then 60 ℃～140 ℃ following vacuum-dryings 2～12 hours.
Among the above-mentioned preparation method, holding amino polytetrahydrofuran to cause the NCA ring-opening polymerization time is 48～96 hours, 20 ℃～60 ℃ of range of reaction temperature.
Among the above-mentioned preparation method, be settled out the poly-peptide of ABA type-poly-polypeptide block multipolymer of b-polytetrahydrofuran-b-as precipitation agent,, get final product then 20 ℃～60 ℃ following vacuum-dryings 24 hours with anhydrous methanol.
γ-phenmethyl-the L-glutamate is an example to the product that the present invention makes for the structure of the poly-peptide of ABA type-poly-polypeptide block multipolymer of b-polytetrahydrofuran-b-is gathered with poly-γ-phenmethyl-L-glutamate-b-polytetrahydrofuran-b-.
Embodiment
Embodiment 1
Poly-(γ-benzyl-L-glutamate)-b-polytetrahydrofuran-b-poly-(γ-benzyl-L-glutamate) is synthetic
Hold amino polytetrahydrofuran to be added in the flask 5g,, naturally cool to room temperature 120 ℃ of vacuum-dryings 2 hours.Under anhydrous, protection of inert gas, will contain the N of 25g γ-benzyl-L-L-glutamic acid-N-carboxyl inner-acid anhydride (BLG-NCA), dinethylformamide solution adds in the flask.Under room temperature, stirring, successive reaction 72 hours.Then reaction solution slowly is added drop-wise in the excessive absolute methanol solution, the adularescent precipitation generates, filter, and washing, 40 ℃ of following vacuum-drying 24b weigh, and get final product.Gained the results are shown in Table 1.
The experimental result of poly-(γ-benzyl-L-the glutamate)-b-polytetrahydrofuran-b-of table 1 poly-(γ-benzyl-L-glutamate)
| Numbering | ?A/I | ?Yield(％) | ?DP(PBLG) | ? |
| ?1 | ?10 | ?73 | ?12 | ?3500 |
| ?2 | ?20 | ?75 | ?16 | ?4700 |
| ?3 | ?30 | ?76 | ?28 | ?7500 |
| ?4 | ?50 | ?80 | ?45 | ?10911 |
| ?5 | ?80 | ?82 | ?60 | ?14042 |
The molar feed ratio of amino polytetrahydrofuran of A/I finger tip and monomers B LG-NCA in the last table; Productive rate is polymer weight and the ratio of holding amino polytetrahydrofuran and BLG-NCA total monomer weight; DP (PBLG) is
1The polymerization degree of poly-(γ-benzyl-L-glutamate) that H NMR records; Mn serves as reasons
1H NMR measures the number-average molecular weight of the ABA triblock polymer that obtains.
Embodiment 2
Poly-(γ-methyl-L-glutamate)-b-polytetrahydrofuran-b-poly-(γ-methyl-L-glutamate) is synthetic
Hold amino polytetrahydrofuran to be added in the flask 2.3g,, naturally cool to room temperature 120 ℃ of vacuum-dryings 2 hours.Under anhydrous, protection of inert gas, will contain the N of 12g γ-methyl-L-L-glutamic acid-N-carboxyl inner-acid anhydride (MLG-NCA), dinethylformamide solution adds in the flask.Under room temperature, stirring, successive reaction 72 hours.Then reaction solution slowly is added drop-wise in the excessive absolute methanol solution, the adularescent precipitation generates, filter, and washing, 40 ℃ of following vacuum-drying 24h weigh, and get final product.Gained the results are shown in Table 2.
Table 2 gathers the experimental result of (γ-methyl-L-glutamate)-b-polytetrahydrofuran-b-(poly-γ-methyl-L-glutamate)
| Numbering | ?A/I | ?Yield(％) | ?DP(PMLG) | ? |
| ?1 | ?10 | ?73 | ?9 | ?2387 |
| ?2 | ?20 | ?75 | ?17 | ?3531 |
The mol ratio of amino polytetrahydrofuran of A/I finger tip and monomer M LG-NCA in the last table; Productive rate is polymer weight and the ratio of holding amino polytetrahydrofuran and MLG-NCA total monomer weight; DP (PMLG) by
1H NMR measures the polymerization degree of poly-(γ-methyl-L-glutamate) that obtain; serves as reasons
1H NMR measures the number-average molecular weight of the ABA triblock polymer that obtains.
Embodiment 3
Poly-(ε-carbobenzoxy-(Cbz)-L-Methionin)-b-polytetrahydrofuran-b-poly-(ε-carbobenzoxy-(Cbz)-L-Methionin) is synthetic
Press the feed ratio in the table 3, at first will hold amino polytetrahydrofuran to be added in the flask,, naturally cool to room temperature 120 ℃ of vacuum-dryings 2 hours.Under anhydrous, protection of inert gas, will contain the N of γ-carbobenzoxy-(Cbz)-L-Methionin-N-carboxyl inner-acid anhydride (BZL-Lys NCA) then, dinethylformamide solution adds in the flask.At room temperature stir successive reaction 72 hours.After the reaction end reaction solution slowly is added drop-wise in the excessive absolute methanol solution, the adularescent precipitation generates, filter, and washing, 40 ℃ of following vacuum-drying 24h get final product.Gained the results are shown in Table 3.
The experimental result of poly-(ε-carbobenzoxy-(Cbz)-L-the Methionin)-b-polytetrahydrofuran-b-of table 3 poly-(ε-carbobenzoxy-(Cbz)-L-Methionin)
| Numbering | ?A/I | ?Yield(％) | ?DP(PZLL) | ? |
| ?1 | ?20 | ?65 | ?18 | ?5821 |
| ?2 | ?40 | ?77 | ?34 | ?10018 |
| ?3 | ?60 | ?81 | ?60 | ?16820 |
The mol ratio of amino polytetrahydrofuran of A/I finger tip and monomers B ZL-NCA in the last table; Productive rate is polymer weight and the ratio of holding amino polytetrahydrofuran and BZL-NCA total monomer weight; DP (PZLL) by
1H NMR measures the polymerization degree of poly-(ε-carbobenzoxy-(Cbz)-L-Methionin) that obtain; serves as reasons
1H NMR measures the number-average molecular weight of the ABA triblock polymer that obtains.
Embodiment 4
Poly-(ε-trifluoroacetyl group-L-the Methionin)-b-polytetrahydrofuran-b-'s of ABA type poly-(ε-trifluoroacetyl group-L-Methionin) is synthetic
Press the feed ratio in the table 4, at first will hold amino polytetrahydrofuran to be added in the flask,, naturally cool to room temperature 120 ℃ of vacuum-dryings 2 hours.Under anhydrous, protection of inert gas, will contain the N of ε-trifluoroacetyl group-L-Methionin-N-carboxyl inner-acid anhydride (TFA-Lys NCA) then, dinethylformamide solution adds in the flask.Under stirring at room, successive reaction 72 hours.After the reaction end reaction solution slowly is added drop-wise in the excessive distilled water, the adularescent precipitation generates, filter, and washing, 40 ℃ of following vacuum-drying 24h get final product.Gained the results are shown in Table 4
The experimental result of poly-(ε-trifluoroacetyl group-L-the Methionin)-b-polytetrahydrofuran-b-of table 4 poly-(ε-trifluoroacetyl-L-Methionin)
| Numbering | ?A/I | ?Yield(％) | ?DP(PTLL) | ? |
| ?1 | ?40 | ?36 | ?28 | ?7377 |
| ?2 | ?60 | ?50 | ?34 | ?8722 |
| ?3 | ?80 | ?48 | ?45 | ?11189 |
The mol ratio of amino polytetrahydrofuran of A/I finger tip and monomer TFA-Lys NCA in the last table; Productive rate is polymer weight and the ratio of holding amino polytetrahydrofuran and BZL-NCA total monomer weight; DP (PTLL) is by the polymerization degree of determination of elemental analysis poly-(ε-trifluoroacetyl group-L-Methionin); is the number-average molecular weight of ABA triblock polymer, is obtained by determination of elemental analysis.
Claims (8)
1. the poly-peptide of ABA type-b-polytetrahydrofuran-b-gathers the peptide triblock copolymer, and this multipolymer comprises:
(a) molecular weight ranges of polytetrahydrofuran block is 800 to 10,000 in the multipolymer;
(b) poly-polypeptide block causes various protections by the amino polytetrahydrofuran of end as initiator and unprotected amino acid-N-carboxyl inner-acid anhydride (NCA) ring-opening polymerization obtains in the multipolymer, can change molecular weight and the composition of controlling this block by NCA and initiator molar feed ratio;
This triblock copolymer can be directly be used for that regenerative medicine cell and organizational project are cultivated the preparation of support and as the solid support material of medicine controlled releasing as Biodegradable material; Also can make the poly-peptide triblock copolymer of the poly-peptide-b-polytetrahydrofuran-b-that contains pendant carboxylic group or amino reactive group, be used for the gene transfection treatment by deprotection reaction, macromolecule precursor medicament, biomaterial surface is modified the field.
2. according to the poly-peptide triblock copolymer of the poly-peptide-b-polytetrahydrofuran-b-of claim 1, the molecular weight ranges from 800 to 10,000 of the amino polytetrahydrofuran polyethers of wherein said end is variable.
3. according to the poly-peptide triblock copolymer of the poly-peptide-b-polytetrahydrofuran-b-of claim 1, wherein poly-polypeptide block can be prepared by ring-opening polymerization by amino acid-N-carboxyl inner-acid anhydride; And amino acid-N-carboxyl inner-acid anhydride can prepare by each seed amino acid and derivative thereof and (three) phosgene reaction, and involved amino acid and derivative thereof include γ-benzyl-L-glutamate, γ-methyl-L-glutamate, γ-ethyl-L-glutamate; ε-carbobenzoxy-(Cbz)-Methionin, ε-tertbutyloxycarbonyl-Methionin, ε-trifluoroacetyl group-Methionin; Leucine (Leu), L-Ala (Ala), tryptophane (Trp), phenylalanine (Phe), Isoleucine (Ile), glycine (Gly), proline(Pro) (Pro), aspartic acid (Asp), Serine (Ser), halfcystine (Cys), tyrosine (Tyr), arginine (Arg), asparagine (Asn), glutamine (Gln), Histidine (His).
4. according to the poly-peptide triblock copolymer of the poly-peptide-b-polytetrahydrofuran-b-of claim 1, the molar feed ratio example of amino polytetrahydrofuran of its middle-end and NCA is 1: 10 to 1: 200, polyreaction is controlled in this scope, and the molecular weight of multipolymer can be regulated and control by changing feed ratio.
5. according to the poly-peptide triblock copolymer of the poly-peptide-b-polytetrahydrofuran-b-of claim 1, wherein the molecular weight ranges of this multipolymer from 1,800 to 50,000 changes.
6. according to the poly-peptide triblock copolymer of the poly-peptide-b-polytetrahydrofuran-b-of claim 1, poly-polypeptide block wherein can be the polyamino acid homopolymer by same seed amino acid-N-carboxyl inner-acid anhydride prepares through ring-opening polymerization.
7. according to the poly-peptide triblock copolymer of the poly-peptide-b-polytetrahydrofuran-b-of claim 1, wherein the composition of poly-polypeptide block also can be the amino acid-N-carboxyl inner-acid anhydride monomer by two or more, by priority order of addition(of ingredients), the polyamino acid segmented copolymer for preparing through ring-opening polymerization.
8. according to the poly-peptide triblock copolymer of the poly-peptide-b-polytetrahydrofuran-b-of claim 1, wherein the composition of poly-polypeptide block can adopt one pot of feeding method, by two or more amino acid-N-carboxyl inner-acid anhydride monomer, the polyamino acid random copolymers for preparing through ring-opening polymerization.
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| CN101775134B (en) * | 2010-02-01 | 2011-12-14 | 浙江大学 | Method for synthesizing high-molecular-weight polypeptide through catalysis by using hydroborated rare earth as catalyst |
| CN103772712B (en) * | 2012-10-23 | 2016-03-02 | 北京化工大学 | The preparation method of a kind of poly-peptide and polytetrahydrofuran multipolymer |
| CN109206612B (en) * | 2017-07-06 | 2021-06-04 | 香港理工大学深圳研究院 | Bionic spider silk polyamino acid biological elastomer material and preparation method thereof |
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| CN1146726A (en) * | 1994-02-28 | 1997-04-02 | 耐克麦德英梅金公司 | Block copolymers |
| CN1315997A (en) * | 1998-07-17 | 2001-10-03 | 诺沃奇梅兹有限公司 | Polypeptide-polymer conjugate with improved wash performance |
| CN1503664A (en) * | 2001-04-02 | 2004-06-09 | ÷ | Colloidal suspension of nanoparticles based on am amphiphilic copolymer |
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| CN1146726A (en) * | 1994-02-28 | 1997-04-02 | 耐克麦德英梅金公司 | Block copolymers |
| CN1315997A (en) * | 1998-07-17 | 2001-10-03 | 诺沃奇梅兹有限公司 | Polypeptide-polymer conjugate with improved wash performance |
| CN1503664A (en) * | 2001-04-02 | 2004-06-09 | ÷ | Colloidal suspension of nanoparticles based on am amphiphilic copolymer |
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