Physicochemical properties and antitumor activities of polymeric prodrugs of mitomycin C with different regeneration rates

Abstract

Three types of conjugates of mitomycin C (MMC) with dextran ( M w: 70,000) (MMCD) were synthesized employing γ-aminobutyric acid (MMC(C4)D), ε-aminocaproic acid (MMC(C6)D), and ω-aminocaprylic acid (MMC(C8)D) and their physicochemical properties and antitumor activities were studied. MMC was released from MMCDs by chemical hydrolysis with different rates depending on the length of the spacer; i.e., half-lives (pH 7.4, 37°C) were 11.0, 24.2, and 42.2 h for MMC(C4)D, MMC(C6)D, and MMC(C8)D, respectively. MMCDs have a polycationic nature and were adsorbed on tumor cell surfaces. In a continuous exposure experiment, MMCD showed growth inhibitory activities against cultured L1210 mouse leukemia cells in proportion to the release rates of MMC. Activity of MMC(C4)D was the highest and comparable to free MMC. In a 1 h exposure experiment, the cytotoxicities of MMC(C6)D and MMC(C8)D, which showed strong interaction with tumor cells, were superior to free MMC while MMC(C4)D had only slight growth inhibitory effect. MMCDs prolonged the survival of mice bearing P388 leukemia in an i.p.-i.p. system. Especially, MMC(C6)D showed a superior effect and an excellent therapeutic index as compared with free MMC and other conjugates. Thus, the spacer length of MMCD was proved to be the determinant of the regeneration rate of MMC and subsequent antitumor activity.