DESIGN OF POLY(ALPHA-MALIC ACID) - 5FU CONJUGATE EXHIBITING ANTITUMOR-ACTIVITY

Since poly(α-malic acid) is a biodegradable and bioabsorbable lactic acid type polyester having pendent carboxylic acid groups, it is of interest for application as the polymer carrier to covalently attach both a parent drug and a targeting agent. In order to provide a macromolecular prodrug of 5-fluorouracil (5FU) with reduced side-effects and exhibiting high antitumor activity, the covalent attachment of 5FU to poly(α-malic acid) through hydrophobic spacer groups, ester or amide and carbamoyl groups was carried out. In order to estimate the release behavior of 5FU from poly(α-malic acid)-5FU conjugates, the hydrolysis of the pendent ester or amide and carbamoyl groups in the conjugates obtained was investigated in vitro using various kinds of aqueous solution at 37°C. The effect on prolongation of life was tested in vivo against p-388 lymphocytic leukemia in female CDF1 mice by intraperitoneal (i.p.) i.p. injection. These poly(α-malic acid) 5FU conjugates gave a high survival rate and did not display acute toxicity in the high dose range of 200-800 mg/kg.