A Parenteral Econazole Formulation Using a Novel Micelle-to-Liposome Transfer Method: In Vitro Characterization and Tumor Growth Delay in a Breast Cancer Xenograft Model

Abstract

The purpose of this study was to develop a parenteral liposomal formulation of econazole, a poorly water-soluble compound not previously available in an intravenous form. We are investigating econazole as an anticancer agent based on its unique mechanism of action to which cancer cells are preferentially sensitive. An intravenous formulation of econazole was desired for preclinical toxicity and efficacy studies of econazole. Liposomal econazole was prepared using a novel micelle exchange technique to incorporate the drug into the lipid bilayer of pre-formed liposomes using a poly(ethylene) glycol-linked phospholipid, distearoyl phosphatidylethanolamine (DSPE-PEG). This method allowed for stable and efficient drug incorporation into DPPC and DMPC liposomes at a final drug:lipid ratio of 0.05 (w/w) and increased solubility in saline from <0.1 to 5 mg/ml. Stability over 14 days at 4 degrees C in buffer was demonstrated as well as in vitro plasma stability at 37 degrees C. Plasma elimination studies of micelle-loaded liposomal econazole showed a half-life of approximately 35 min and plasma AUC of 281 microg/ml min. In MCF-7 human breast cancer xenografts in Rag2M mice. Liposomal econazole did not induce significant hepatoxicity, renal toxity or weight loss compared to empty liposomes. Tumor growth was slightly delayed in liposomal econazole-treated mice, with approximately 10-day lag time to reach 300 mm(3) compared to vehicle controls. The micelle transfer method provided an efficient means of preparing liposomal econazole suitable for intravenous administration. Liposomal econazole was successfully administered to tumor bearing mice at 50 mg/kg, and no significant toxicities attributable to econazole were observed.