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Synthesis of Malic Acid Polymer and Its Hydrolysis Behavior

苹果酸聚合物的合成及其水解行为

基本信息

批准号：
61550685
负责人：
OUCHI Tatsuro
金额：
$ 1.15万
依托单位：
Kansai University
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (C)
财政年份：
1986
资助国家：
日本
起止时间：
1986 至 1988
项目状态：
已结题

项目摘要

Since malic acid polymer is a bioadsortable lactic acid type's polyester having pendent modifiable carboxylic acid groups, it is worthy of remark as the polymeric drug carrier which is able to attach covalently both parent monomeric drug and targeting agent unit. Poly(beta-malic acid) and poly(alpha,beta-mailc acid) have be synthesized by organic chemical techniques.The present report deals with the synthesis of poly(alpha-malic acid) by means of ring-opening homopolymerization of malide dibenzyl ester, which is a cyclic dimer of beta-benzyl malate. It was found from the results of hydrolysis of poly(alpha-malic acid) that the main chain ester bonds were cleaved randomly and slowly in vitro. In order to provide the macromolecular pro-drug of 5-fluoro-uracil (5FU) reducing the side-effects of 5FU, the covalent attachent of 5FUs poly(alpha-malic acid) was carried out. The anti-tumor activity of malic acid polymer-5FU conjugate obtained was tested against p-388 lymphocytic leukemia in mice in vivo (i.p./i.p.). When the unreacted pendent carboxylic acid groups in malic acid polymer-5FU conjugate wrer masked by methyl groups, that sample showed the high level of prolongation of life and did not display an acute toxicity even in the high dose. Therefore, that sample was suggested to act as a macromolecular pro-drug of 5FU.Thus we concluded that malic acid polymer is intersted in the application as a bioresorbable carrier of polymeric drug, which can be modified chemically.

苹果酸聚合物是一种生物可吸附的乳酸型聚酯，具有侧基可修饰的羧酸基，是一种既能共价结合母体单体药物，又能与靶向基团共价结合的聚合物药物载体。用有机化学方法合成了聚(β-苹果酸)和聚(α，β-苹果酸)，报道了用开环均聚法合成聚α-苹果酸的方法。结果表明，聚α-苹果酸的主链酯键在体外以随机方式缓慢断裂。为了给5-氟尿嘧啶(5FU)提供减轻其副作用的大分子前体药，进行了5FU聚α-苹果酸的共价键合。用小鼠p-388淋巴细胞白血病模型(I.P./I.P.)测定了苹果酸聚合物-5FU结合物的抗肿瘤活性。当苹果酸聚合物-5FU偶联物中未反应的侧链羧酸基被甲基掩盖时，该样品表现出较高的延长寿命的水平，即使在高剂量下也没有表现出急性毒性。因此，该样品可作为5-氟尿嘧啶的大分子前体药物。因此，苹果酸聚合物作为一种可生物吸收的高分子药物载体具有重要的应用价值，可以进行化学修饰。