Design of poly(α‐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 CDF 1 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.