Development and optimization of an injectable formulation of copper diethyldithiocarbamate, an active anticancer agent

Abstract

Mohamed Wehbe,1,2 Malathi Anantha,1 Minghan Shi,3,4 Ada Wai-yin Leung,1 Wieslawa H Dragowska,1 Léon Sanche,3,4 Marcel B Bally1,2,5,6 1Experimental Therapeutics, British Columbia Cancer Agency, 2Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC, 3Department of Nuclear Medicine and Radiobiology, Faculty of Medicine and Health Science, 4Faculté de médecine et des sciences de la santé, Center for Research in Radiotherapy, Department of Nuclear Medicine and Radiobiology, Université de Sherbrooke, Sherbrooke, Québec, QC, 5Department of Pathology and Laboratory Medicine, University of British Columbia, 6Faculty of Medicine, Center for Drug Research and Development, Vancouver, BC, Canada Abstract: Copper diethyldithiocarbamate (Cu(DDC)2) is the active anticancer agent generated when disulfiram (DSF) is provided in the presence of copper. To date, research directed toward repurposing DSF as an anticancer drug has focused on administration of DSF and copper in combination, efforts that have proven unsuccessful in clinical trials. This is likely due to the inability to form Cu(DDC)2 at relevant concentrations in regions of tumor growth. Little effort has been directed toward the development of Cu(DDC)2 because of the inherent aqueous insolubility of the complex. Here, we describe an injectable Cu(DDC)2 formulation prepared through a method that involves synthesis of Cu(DDC)2 inside the aqueous core of liposomes. Convection-enhanced delivery of a Cu(DDC)2 formulation prepared using 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC)/cholesterol liposomes into a rat model of F98 glioma engendered a 25% increase in median survival time relative to vehicle-treated animals. In a murine subcutaneous MV-4–11 model, treatment resulted in a 45% reduction in tumor burden when compared to controls. Pharmacokinetic studies indicated that the Cu(DDC)2 was rapidly eliminated after intravenous administration while the liposomes remained in circulation. To test whether liposomal lipid composition could increase Cu(DDC)2 circulation lifetime, a number of different formulations were evaluated. Studies demonstrated that liposomes composed of DSPC and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-n-(carboxy[polyethylene glycol]-2000) (95:5) enhanced Cu(DDC)2 concentrations in the circulation as reflected by a 4.2-fold increase in plasma AUC(0-∞) relative to the DSPC/cholesterol formulation. The anticancer activity of this Cu(DDC)2 formulation was subsequently evaluated in the MV-4–11 model. At its maximum tolerated dose, this formulation exhibited comparable activity to the DSPC/cholesterol formulation. This is the first report demonstrating the therapeutic effects of an injectable Cu(DDC)2 formulation in vivo. Keywords: disulfiram, copper diethyldithiocarbamate, cancer, copper complexes, liposomes

Keywords

• disulfiram
• copper diethyldithiocarbamate
• cancer
• copper complexes
• liposomes.