Synthesis of Malic Acid Polymer and Its Hydrolysis Behavior

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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.