SYNTHESIS AND ANTITUMOR-ACTIVITY OF CONJUGATES OF POLY(ALPHA-MALIC ACID) AND 5-FLUOROURACILS BOUND VIA ESTER, AMIDE OR CARBAMOYL BONDS

Since poly(malic acid) is a biodegradable and bioabsorbable lactic acid-type polyester having pendent modifiable carboxylic acid groups, it is of interest as a polymeric carrier of drugs. In order to provide macromolecular pro-drugs of 5-fluorouracil (5FU), and so reduce the side-effects of 5FU, the covalent attachment of 5FUs to poly(α-malic acid) and poly(α-malic acid-co-lactic acid) through amide, ester or carbamoyl bonds was carried out. The antitumor activity of the resulting 5FU conjugates with poly(α-malic acid) was tested against P-388 lymphocytic leukemia in mice in vivo (i.p./i.p.). When the unreacted pendent carboxylic acid groups in the polyα-malic acid)-5FU conjugates were masked by methyl groups, conjugates were obtained which prolonged life and did not display acute toxicity at a dose of 200-800 mg/kg. These samples were therefore considered to be macromolecular pro-drugs of 5FU. Furthermore, for the purpose of elucidating the nature of 5FU release and main-chain cleavage in vivo, the hydrolyses of the pendent amide, ester or carbamoyl bonds and the main-chain ester bonds in poly(α-malic acid)-5FU conjugates and poly(α-malic acid-co-lactic acid)-5FU conjugates were studied in vitro at 37° C in aqueous solutions of various kinds. © 1990.