CN103159947A - Preparation method of phosphatidylcholine-biomimetic-modified polylactic acid material - Google Patents
Preparation method of phosphatidylcholine-biomimetic-modified polylactic acid material Download PDFInfo
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- CN103159947A CN103159947A CN2011104126594A CN201110412659A CN103159947A CN 103159947 A CN103159947 A CN 103159947A CN 2011104126594 A CN2011104126594 A CN 2011104126594A CN 201110412659 A CN201110412659 A CN 201110412659A CN 103159947 A CN103159947 A CN 103159947A
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Abstract
The invention relates to a preparation method of a phosphatidylcholine-biomimetic-modified polylactic acid material. Currently, when polylactic acid is adopted as a biomedical material, an acid-induced autocatalytic degradation acceleration effect still exists in a degradation process; polylactic acid hydrophobicity is high, no site is provided for cell to identify, such that cell biocompatibility is poor; and polylactic acid hemocompatibility is poor when contacting blood. The method is provided aiming at the above problems. The method mainly comprises the steps that: with a free radial polymerization reaction, maleic anhydride is grafted on a side chain of the polylactic acid; diaminobutane is subjected to a reaction with maleic anhydride; with introduced active reaction group and double-bond of 2-acryloyloxyethyl phosphatidylcholine, a Micheal addition reaction is carried out, and phosphatidylcholine biomimetic modification upon polylactic acid is realized. Compared with polylactic acid, the phosphatidylcholine-biomimetic-modified polylactic acid material provided by the invention has a substantial inhibition effect against acid-induced degradation, better cell compatibility, and good hemocompatibility.
Description
Technical field
The present invention relates to the biomaterial preparation method of the good cell intermiscibility of a kind of tool and blood compatibility, particularly a kind of preparation method of phosphatidyl choline biomimetic modification poly-lactic acid material.
Background technology
Poly(lactic acid) (Polylactic acid, PLA) has good biocompatibility and biodegradability, and the metabolism final product is CO in vivo
2And H
2O, intermediate product lactic acid are also the products of eubolism in body, thereby obtain in fields such as organizational project and medicine controlled releasings as bio-medical material paying much attention to and broad research.But PLA still comes with some shortcomings, and occurs the effect (bio-medical material .2000.54-55.) that acid causes the autocatalysis accelerated degradation in degradation process as (1); (2) hydrophobicity is strong, does not have for the site of cell recognition, to cause not strong (the J Biomater Sci:Polymer Edn.2001.12 (1): 107-124.) of cell biological consistency; When (3) contacting with blood, the blood compatibility of PLA is not enough waits (Journalof Electroanalytical Chemistry, 2008,621 (1): 69-74.; European Journal of Pharmaceutics and Biopharmaceutics, 2005,59 (3): 375-388.).
The defective that exists in order to overcome poly(lactic acid), people have launched research widely, particularly PLA being carried out modification can significantly improve its biocompatibility also and then give its biological activity, wherein focus (J Mater Sci Technol.2005,21 (4): 571-576 of research both at home and abroad it is carried out the imitation biochemistry modification especially; Trends Biotechnol.2002,20 (1): 16-21.).Because phospholipid molecule (the most important thing is the phosphatidyl choline molecule) is one of chief component of cytolemma; cytolemma is not only the material integral part of cell; play a part protection and sustenticular cell; and cytolemma also participates in playing a part very important such as processes such as the growth of energy transformation, matter transportation, signal transmission and identification and cell and differentiation.So the polymer that contains at present phosphatide has become the study hotspot of high-molecular biologic field of medical materials.Nineteen ninety, Ishihara professor (the PolymJ.1990 of Japan, 22:355-360.25) first has manually synthesized the phosphatidyl choline molecule (MPC) that contains two keys, recycle two keys and other high molecular pair of key copolymerization of phosphatidyl choline molecule, obtained containing the polymeric biomaterial of phosphatide choline molecule.Studies show that, this phosphatidyl choline type macromolecular material can reduce the absorption of material surface protein, stop thrombocyte in adhesion and the gathering of material surface, extend the clotting time of material, strengthened material blood compatibility (J Biomed Mater Res, 2003,65A:164-169.7), can also give material the anti-inflammatory performance (J BiomedMater Res 2005,73A:359-366.) etc.The research report of phosphatidyl choline molecular modification PLA is for counting seldom.(the biomedical engineering magazine .2008.25 (6): 1344-1348.) with natural glycerin phosphatidyl choline and rac-Lactide ring-opening polymerization, obtain phosphatidyl choline modification PLA (PLLA-PC-PLLA) such as Luo Juan; Result shows, due to the introducing of phosphatidyl choline molecule, and the trend of the phosphatidyl choline functional group oriented surface transport in water surrounding in polymer molecular structure, the wetting ability of PLA has had very large improvement; Inoculation culture endotheliocyte (ECV304) on material, proving that the PLA that contains biological function group phospholipid choline is the same with PLA does not have a cytotoxicity, and endotheliocyte can stick in the above, breed.Iwasaki teaches (Biomaterials.2002,23:3897-3903.27) by rac-Lactide and Yelkin TTS copolymerization, success is introduced the phosphatidyl choline molecule in the PLA body construction, result shows: the protein of modification PLA material surface is relevant with the amount of the phosphatidyl choline molecule of connection with the thrombocyte absorption property, increase along with phosphatidyl choline molecule in the PLA matrix, protein adsorption amount and the platelet adhesion reaction amount of material surface all greatly reduce, and the introducing of phosphatidyl choline molecule has also suppressed leukocytic adhesive capacity.(the Biomaterials.2002 such as Yasuhiko, 23:3897-3903.) with phosphatidyl choline molecule and 2-ethylhexyl methacrylic acid (2-ethylhexyl methacrylate, EHMA) carry out copolymerization, and then carry out blend with the PLGA material, find that this material can obviously reduce the inflammatory response that the PLGA material causes.(Materials Science and Engineering C.2006 for Junji etc., 2:227-231Science and Technology of Advanced Materials.2004,4:539-544.) double bond containing MPC and the PLA that n-butyl methyl methyl acrylate and end contain two keys are carried out terpolymer, in its product, phosphatidyl choline reduces the protein adherence amount at material surface, and the modifier segment has strengthened the ability of material for cell adhesion; The ratio of Reasonable Regulation And Control MPC and PLA can well be controlled the adhesion growth behavior of cell.Therefore, using the phosphatidyl choline molecule comes the biomimetic modification poly-lactic acid material will effectively improve the biocompatibility of poly-lactic acid material, give the poly-lactic acid material new biological activity, prepare body and be implanted into medicine equipment widening the poly(lactic acid) bio-medical material, particularly the good built-in apparatus of blood compatibility, have very important scientific meaning and use value.
Summary of the invention
For the technical problem of above-mentioned existence, the object of the present invention is to provide a kind of preparation method of phosphatidyl choline biomimetic modification poly-lactic acid material.Utilize two keys of 2-acryloxy ethyl phosphatidyl choline and the amino of maleic anhydride/butanediamine modified polylactic acid to carry out the Micheal addition reaction, realize the phosphatidyl choline biomimetic modification to poly(lactic acid).Its synthetic route is as follows:
The synthetic route of phosphatidyl choline biomimetic modification poly(lactic acid)
Studies show that phosphatidyl choline biomimetic modification poly(lactic acid) has obvious inhibition acid and causes Degradation.The cell in vitro morphology observation confirms that the poly(lactic acid) that phosphorylcholine is modified has good biocompatibility.Simultaneously, the platelet adhesion reaction experiment shows that this polymkeric substance has good blood compatibility.
Embodiment
1. maleic anhydride modified poly(lactic acid) (MPLA) is synthetic
PDLLA is dissolved in methylene dichloride, adds MA and BPO (MA quality 5%) in 10% ratio, after fully stirring, in room temperature vacuum-drying to constant weight; Reacted 10 hours under 100 ℃ under nitrogen protection, obtain MPLA.With product with chloroform-methanol separation and purification 3 times, vacuum-drying, standby.The product weight-average molecular weight is Mw=5.18 * 10
5
2. diamine modified poly-latic acid (DPLA) is synthetic
The tetrahydrofuran (THF) (THF) that adds 5mL BDA in there-necked flask; After a certain amount of MPLA is dissolved in 50mL THF, splash into flask at whipped state, control temperature of reaction lower than 20 ℃.After dropwising, rising temperature to 37 ℃ reaction 30min.BDA stoichiometric 200% adds by it.React complete after, product is splashed in excessive distilled water, collect surface film, obtain white cotton-shaped DPLA.And then, with THF and aqueous systems precipitate and separate purifying 3 times, vacuum-drying, standby.
3.2-acryloxy ethyl phosphonic acid choline (APC) is synthetic
Vinylformic acid 2-hydroxyl ethyl ester (HEA, 2.811g, 24.2mmol) and triethylamine (TEA, 2.45g, 24.2mmol) mix and add in 20mLTHF, argon shield, and be cooled to-15 ℃, standby.2-chloro-2-oxygen-1,3,2-dioxaphospholane (COP, 3.46g, 24.2mmol) be dissolved in 10-20mL THF, be added drop-wise in 30min in HEA solution, stirring reaction 4h filters and desolventizing, obtain 2-(2-oxygen-1,3,2-dioxy phosphorus heterocycle ethyl propenoate (OPEA).OPEA intermediate (3.94g, 17.7mmol) is dissolved in the 30mL acetonitrile, under agitation adds the 2mL Trimethylamine, react 7h under 60 ℃.Reaction mixture solution is cooled to-15 ℃ and keeps 72h.The precipitated product that obtains is 2-acryloxy ethyl phosphonic acid choline.
4.APC biomimetic modification poly(lactic acid) (PLA-PC) is synthetic
Add in the 100mL there-necked flask in the THF solution of APC (4g, 0.014mol) (20mL), logical nitrogen protection at 0 ℃ of THF solution that dropwise adds DPLA, continues after dropwising to stir 30min under 0 ℃, then at room temperature reacts 72h.React complete and remove last reaction monomers by methanol extraction, obtain product B PLA.
Studies show that: APC biomimetic modification poly-lactic acid material biological degradation experiment shows that this Polylatides has obvious inhibition acid and causes Degradation, the cell in vitro morphology observation confirms to have good biocompatibility, and the platelet adhesion reaction experiment shows that this material has good blood compatibility.
Explanation is at last, above embodiment is only unrestricted in order to technical scheme of the present invention to be described, although by invention has been described with reference to the preferred embodiments of the present invention, but those of ordinary skill in the art is to be understood that, can make various changes to it in the form and details, and not depart from the spirit and scope of the present invention that appended claims limits.
Claims (1)
1. the preparation method of a phosphatidyl choline biomimetic modification poly-lactic acid material, its feature comprises following process:
Utilize two keys of 2-acryloxy ethyl phosphonic acid choline and the amino of maleic anhydride/butanediamine modified polylactic acid to carry out the Micheal addition reaction, realize the phosphatidyl choline biomimetic modification to poly(lactic acid).Its synthetic route is as follows:
The synthetic route of phosphatidyl choline biomimetic modification poly(lactic acid)
1.MPLA synthetic
PDLLA is dissolved in methylene dichloride, adds MA and BPO (3-6% of MA quality) in the 5-15% ratio, after fully stirring, in room temperature vacuum-drying to constant weight; In 100 ℃-130 ℃ reactions 8-12 hour, obtain MPLA under nitrogen protection.With product with chloroform-methanol separation and purification 3 times, vacuum-drying, standby.
2.DPLA synthetic
The tetrahydrofuran (THF) (THF) that adds 5mL BDA in there-necked flask; After a certain amount of MPLA is dissolved in 50mL THF, splash into flask at whipped state, control temperature of reaction lower than 20 ℃.After dropwising, rising temperature to 37 ℃ reaction 30min.BDA stoichiometric 200% adds by it.React complete after, product is splashed in excessive distilled water, collect surface film, obtain white cotton-shaped DPLA.And then, with THF and aqueous systems precipitate and separate purifying 3 times, vacuum-drying, standby.
3.2-acryloxy ethyl phosphonic acid choline (APC) is synthetic
Vinylformic acid 2-hydroxyl ethyl ester (HEA, 2.811g, 24.2mmol) and triethylamine (TEA, 2.45g, 24.2mmol) mix and add in 20mLTHF, argon shield, and be cooled to-15 ℃, standby.2-chloro-2-oxygen-1,3,2-dioxaphospholane (COP, 3.46g, 24.2mmol) be dissolved in 1020mL THF, be added drop-wise in 30min in HEA solution, stirring reaction 4h filters and desolventizing, obtain 2-(2-oxygen-1,3,2-dioxy phosphorus heterocycle ethyl propenoate (OPEA).OPEA intermediate (3.94g, 17.7mmol) is dissolved in the 30mL acetonitrile, under agitation adds the 2mL Trimethylamine, react 7h under 60 ℃.Reaction mixture solution is cooled to-15 ℃ and keeps 72h.The precipitated product that obtains is 2-acryloxy ethyl phosphonic acid choline.
4. phosphorylcholine biomimetic modification poly(lactic acid) (PLA-PC) is synthetic
Add in the 100mL there-necked flask in the THF solution of APC (4g, 0.014mol) (20mL), logical nitrogen protection at 0 ℃ of THF solution that dropwise adds DPLA, continues after dropwising to stir 30min under 0 ℃, then at room temperature reacts 72h.React complete and remove unreacted monomer by methanol extraction, obtain product P LA-PC.
Claim is protected the global design of whole modification reaction process, also comprises reaction designing and the condition in each step in concrete process.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104292444A (en) * | 2014-10-15 | 2015-01-21 | 四川大学 | Synthesis method of bola-like polylactic acid with precise controlled molecular structure |
| WO2022252413A1 (en) * | 2021-06-03 | 2022-12-08 | 中国科学技术大学 | Method for preparing polylactic acid zwitterionic compound, and polymer vesicle |
| CN117017852A (en) * | 2023-08-03 | 2023-11-10 | 佛山市思怡诺生物科技有限公司 | Slowly-released antibacterial breath freshener and preparation method thereof |
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| CN1435438A (en) * | 2002-09-24 | 2003-08-13 | 重庆大学 | Diamine modified poly-latic acid, method for preparing same and use thereof |
| CN1775313A (en) * | 2005-10-14 | 2006-05-24 | 浙江大学 | Polymer brush for improving biomedical material compatibility and its preparing method |
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2011
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| CN1435438A (en) * | 2002-09-24 | 2003-08-13 | 重庆大学 | Diamine modified poly-latic acid, method for preparing same and use thereof |
| CN1775313A (en) * | 2005-10-14 | 2006-05-24 | 浙江大学 | Polymer brush for improving biomedical material compatibility and its preparing method |
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| 张玉: "甲基丙烯酰氧基乙基磷酸胆碱及其共聚合物的合成", 《中国优秀硕士学位论文全文数据库工程科技Ⅰ辑》, no. 8, 15 August 2009 (2009-08-15), pages 21 - 23 * |
| 罗彦凤等: "RGDS和胶原改性聚(DL-乳酸)的合成与表征", 《高分子材料科学与工程》, vol. 24, no. 5, 15 May 2008 (2008-05-15) * |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104292444A (en) * | 2014-10-15 | 2015-01-21 | 四川大学 | Synthesis method of bola-like polylactic acid with precise controlled molecular structure |
| CN104292444B (en) * | 2014-10-15 | 2016-06-29 | 四川大学 | There is the synthetic method of the class meteor plektron polylactic acid of controllable precise molecular structure |
| WO2022252413A1 (en) * | 2021-06-03 | 2022-12-08 | 中国科学技术大学 | Method for preparing polylactic acid zwitterionic compound, and polymer vesicle |
| CN117017852A (en) * | 2023-08-03 | 2023-11-10 | 佛山市思怡诺生物科技有限公司 | Slowly-released antibacterial breath freshener and preparation method thereof |
| CN117017852B (en) * | 2023-08-03 | 2024-04-26 | 佛山市思怡诺生物科技有限公司 | Slowly-released antibacterial breath freshener and preparation method thereof |
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Application publication date: 20130619 |