Synthesis of Malic Acid Polymer and Its Hydrolysis Behavior

由于苹果酸聚合物是一种可生物吸附的乳酸型聚酯，具有侧链可修饰的羧酸基团，因此它作为能够共价连接母体单体药物和靶向剂单元的聚合物药物载体是值得注意的。用有机化学方法合成了聚β-苹果酸和聚α，β-苹果酸，本文报道了由β-苹果酸苄酯的环状二聚体马来酰二苄酯开环均聚合成聚α-苹果酸。从聚α-苹果酸的水解结果发现，在体外，主链酯键被随机缓慢地断裂。为了提供能减少5-氟尿嘧啶（5-fluoro-uracil，5 FU）毒副作用的大分子前药，对5 FU聚α-苹果酸进行了共价连接。在小鼠体内（i. p./lymphocytic leukemia）测试所获得的苹果酸聚合物-5FU缀合物针对p-388淋巴细胞白血病的抗肿瘤活性。i.p.）。当苹果酸聚合物-5FU缀合物中未反应的侧链羧酸基团被甲基掩蔽时，该样品显示出高水平的寿命延长，并且即使在高剂量下也没有显示出急性毒性。因此，苹果酸聚合物作为高分子药物的生物可吸收载体，具有很好的应用前景。

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.