Improved therapeutic index of a mitomycin-C (MMC) prodrug formulated in pegylated liposomes: Studies in human xenograft tumor models of gastrointestinal (GI) origin.

Abstract

e13628 Background: A MMC lipid-based prodrug (MLP) formulated in pegylated liposomes (PL-MLP) was previously reported to have significant antitumor activity and reduced toxicity in mouse tumor models (Clin Cancer Res 12:1913-20, 2006). MLP is activated by thiolysis releasing MMC which rapidly dissociates from liposomes. The purpose of this study was to examine the plasma stability, pharmacokinetics, in vivo toxicity, and antitumor activity of PL-MLP in human xenograft models of GI-derived tumors. Methods: MLP was incorporated with nearly 100% efficiency in pegylated liposomes with hydrogenated phosphatidylcholine as the main component with or without cholesterol (Ch). Mean vesicle size was 45-65 nm for liposome preparations downsized by homogenization, and 80-100 nm for those downsized by extrusion, the latter displaying narrower polydispersity. MLP to phospholipid molar ratio was 5% (∼20 μg MMC-equivalents/μmol). Therapeutic studies were carried out in 3 tumor models (HCT15 colon Ca, N87 gastric Ca, and Panc-1 pancreatic Ca) implanted s.c. in CD1 nude mice. Treatment was administered i.v. into mice with established tumors. Results: PL-MLP was very stable when incubated in plasma, and whole blood with a maximum of 5% of MLP undergoing activation to free MMC. In the presence of a strong reducing agent (dithiothreitol, 0.5 mM), MLP was massively activated to free MMC. Pharmacokinetic studies in mice revealed huge differences in key parameters (t, Cl, Vss) between free MMC and PL-MLP. The longest t were observed for extruded and/or Ch-containing preparations. PL-MLP was ∼3-fold less toxic than free MMC at MMC-equivalent doses. PL-MLP was significantly more effective in delaying tumor growth and resulted in more tumor regressions than irinotecan in the HCT15 and N87 models, and than gemcitabine in the Panc-1 model. Conclusions: Delivery of MLP in pegylated liposomes is more effective than conventional chemotherapy used in the treatment of GI-derived tumor models, and may represent an effective tool for treatment of these malignancies in the clinical setting with improved safety over free MMC. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Teva Teva