Development of a novel polymeric prodrug of mitomycin C, mitomycin C-dextran conjugate with anionic charge. I. Physicochemical characteristics and in vivo and in vitro antitumor activities

Abstract

A novel polymeric prodrug of mitomycin C (MMC), mitomycin C-dextran conjugate with anionic charge (MMC-Dan.) was developed employing 6-bromohexanoic acid as a spacer. Three types of MMC-Dan., conjugates with dextran with molecular weights of 10,000, 70,000 and 500,000 were synthesized, and physicochemical characteristics, such as molecular size, electrical charge and drug release rate, and in vitro and in vivo antitumor activities were investigated. All types of MMC-Dan. were estimated to contain about 8% MMC (w/w) and MMC was released from the conjugate by a chemical hydrolysis. In vitro antitumor activity was evaluated by L1210 cell culture system. All types of MMC-Dan. showed less cytotoxicity than MMC in continuous or one-hour drug exposure experiments, regardless of molecular size. In vivo antitumor activity was tested in mice bearing P388 leukemia. Intravenous and intraperitoneal injection of MMC-Dan. prolonged the survival of mice inoculated tumor cells by the same route. Especially, large MMC-Dan. exhibited a superior effect and a larger therapeutic index as compared with MMC. The usefulness of mitomycin C-dextran conjugates with anionic charge as a potent reservoir which supplies active MMC in the body was thus suggested.