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通过光引发聚合制备的聚(谷氨酸)-聚(乙二醇)水凝胶:蛋白质药物的合成、表征及初步释放研究

Poly(glutamic acid) poly(ethylene glycol) hydrogels prepared by photoinduced polymerization: Synthesis, characterization, and preliminary release studies of protein drugs.

作者信息

Yang Zhiqiang, Zhang Yuehua, Markland Peter, Yang Victor C

机构信息

College of Pharmacy, The University of Michigan, Ann Arbor, Michigan 48109-1065, USA.

出版信息

J Biomed Mater Res. 2002 Oct;62(1):14-21. doi: 10.1002/jbm.10219.

Abstract

A class of new biodegradable hydrogels based on poly(ethylene glycol) methacrylate-graft-poly(glutamic acid) and poly(ethylene glycol) dimethacrylate was synthesized by photoinduced polymerization. Because all the polymeric constituents were highly hydrophilic, crosslinking could be performed in aqueous solutions. This type of crosslinked hydrogel was prepared by modifying a select number of acidic side-groups on poly(glutamic acid) with poly(ethylene glycol) methacrylate. These modified chains were then crosslinked in the presence of poly(ethylene glycol) dimethacrylate under a photoinduced polymerization at a wavelength of 365 nm. Swelling experiments were conducted to study the crosslinking density, pH-responsive behavior, and degradation of the hydrogel. Results showed that the degree of swelling of this type of hydrogels increased as the crosslinker concentration (or density) was reduced. Because of the presence of acidic side chains on poly(glutamic acid), swelling behavior was found to be pH-responsive, increasing at high pH in response to the increase in the amount of ionized acidic side chains. The degradation rate of these hydrogels also varied with pH. More rapid degradation was observed under stronger alkaline conditions because of the hydrolysis of the ester bonds between the crosslinker and the polymer backbone. Practically useful degradation rates could be achieved for such hydrogels under physiological conditions. Drug release rates from these hydrogels were found to be proportional to the protein molecular weight and the crosslinker density; increasing at lower protein molecular weight or crosslinker density. The preliminary findings presented in this article suggest that this class of biodegradable hydrogels could be an attractive avenue for drug delivery applications. The specific photoinduced crosslinking chemistry used would permit hydrogels to be synthesized in existence of the entrapped macromolecular drugs including peptides, proteins, and cells. In addition, the rapid feature of this polymerization procedure along with the ability to perform hydrogel synthesis and drug loading in an aqueous environment would offer great advantages in retaining drug activity during hydrogel synthesis.

摘要

通过光引发聚合反应合成了一类基于聚甲基丙烯酸乙二醇酯接枝聚谷氨酸和聚乙二醇二甲基丙烯酸酯的新型可生物降解水凝胶。由于所有聚合物成分都具有高度亲水性,因此交联反应可以在水溶液中进行。这种交联水凝胶是通过用聚甲基丙烯酸乙二醇酯修饰聚谷氨酸上选定数量的酸性侧基而制备的。然后,这些修饰的链在聚乙二醇二甲基丙烯酸酯存在下,于365nm波长的光引发聚合反应中进行交联。进行了溶胀实验以研究水凝胶的交联密度、pH响应行为和降解情况。结果表明,这类水凝胶的溶胀度随着交联剂浓度(或密度)的降低而增加。由于聚谷氨酸上存在酸性侧链,发现溶胀行为具有pH响应性,在高pH下,随着离子化酸性侧链数量的增加而增加。这些水凝胶的降解速率也随pH而变化。在较强碱性条件下观察到更快的降解,这是由于交联剂与聚合物主链之间的酯键水解。在生理条件下,这种水凝胶可以实现实际有用的降解速率。发现这些水凝胶的药物释放速率与蛋白质分子量和交联剂密度成正比;在较低的蛋白质分子量或交联剂密度下增加。本文提出的初步研究结果表明,这类可生物降解水凝胶可能是药物递送应用的一个有吸引力的途径。所使用的特定光引发交联化学方法将允许在包含肽、蛋白质和细胞等包封大分子药物的存在下合成水凝胶。此外,这种聚合过程的快速特性以及在水性环境中进行水凝胶合成和药物负载的能力,将在水凝胶合成过程中保持药物活性方面提供巨大优势。

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