Preclinical evaluation of Promitil®, a radiation-responsive liposomal formulation of mitomycin C prodrug, in chemoradiotherapy

Abstract Purpose Mitomycin C (MMC) is a potent chemotherapeutic and radiosensitizer, but its use has been limited by toxicity. Promitil is a pegylated liposomal formulation of a MMC lipid-based prodrug, which has shown a significantly lower toxicity profile in preclinical and phase I clinical investigations. In this study, we examined the effect of radiation on in vitro drug release and examined the efficacy and toxicity of Promitil with concurrent radiation in colorectal cancer models. Methods and Materials Promitil was obtained from LipoMedix under a research agreement. We tested the effects of radiation on release of active MMC from Promitil in vitro . We next examined the radiosensitization effect of Promitil in vitro . We further evaluated the toxicity of a single injection of free MMC or Promitil when combined with radiation by assessing the effects on blood counts and in-field skin and hair toxicity. Finally, we compared the efficacy of MMC and Promitil in chemoradiotherapy using mouse xenograft models. Results MMC was released from Promitil in a controlled release profile, and the rate of release was significantly increased in medium from previously irradiated cells. Both Promitil and MMC potently radiosensitized HT-29 cells in vitro . Toxicity of MMC (8.4 mg/kg) was substantially greater than equivalent doses of Promitil (30 mg/kg). Mice treated with human equivalent doses of MMC (3.3 mg/kg) experienced comparable levels of toxicity as Promitil-treated mice. Promitil improved the antitumor efficacy of 5-Fluorouracil-based chemoradiotherapy in mouse xenograft models of colorectal cancer; equitoxic doses of MMC did not. Conclusions We demonstrated that Promitil is an attractive agent for chemoradiotherapy because it demonstrates a radiation-triggered release of active drug. We further demonstrated that Promitil is a well-tolerated and potent radiosensitizer at doses not achievable with free MMC. These results support clinical investigations utilizing Promitil in chemoradiotherapy.