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

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.

Pancreatic cancer stem cell proliferation is strongly inhibited by diethyldithiocarbamate-copper complex loaded into hyaluronic acid decorated liposomes

“…Cu(DDC) 2 containing liposomes were prepared by using the method described by Wehbe et al [45,51], which provides the formation of the active Cu In order to prepare hyaluronic acid decorated liposomes, the conjugates HA 4800 -DPPE or HA 17000 -DPPE, in molar ratio of 3 or 5%, were added during the hydration phase of lipid film. In this way, the phospholipidic chain was incorporated into the liposome membrane, while the HA was exposed toward the aqueous phase.…”

Hydroxycobalamin catalyzes the oxidation of diethyldithiocarbamate and increases its cytotoxicity independently of copper ions

“…DDC at millimolar concentrations (0,5-1 мМ) is used as a Cu,Zn-SOD inhibitor, which produces a prooxidant effect; however, under some conditions, it exhibits antioxidant and antiapoptotic properties [11] , [12] . Under in vivo conditions, DDC appears in the bloodstream as a result of the metabolism of the anti-alcohol drug disulfiram (DSF) and undergoes further transformations in the liver and kidneys [13] , [14] , [15] . There is substantial evidence in the literature indicating that, due to the binding of copper ions, DTC produce a pronounced cytotoxic effect [13] , [14] , [16] , [17] , [18] .…”

“…It was found that the active metabolite of DSF when it is used in combination with copper is a dithiocarb-copper complex [17] , [34] . Because this complex can damage normal tissues, different ways to increase the DSF toxicity without the use of copper ions and to protect the adjacent tissues by encapsulating the components into micro- and nanoparticles are developed to date [15] , [35] , [36] .…”

“…The enhancement of the cytotoxic effect of DDC by Cbl detected in the study may be taken as the basis in the design of novel antitumor drugs. The use of modern ways of isolating active components by incapsulation (incorporation into liposomes as well as micro- and nanoparticles) [15] , [36] , [39] , [40] , [41] will enable one to avoid a possible unfavorable effect of the combination of DDC with Cbl on normal tissues. The goal of this work was to establish the mechanism by which HOCbl enhances the cytotoxic effect of DDC.…”

Biomimetic metal-organic nanoparticles prepared with a 3D-printed microfluidic device as a novel formulation for disulfiram-based therapy against breast cancer

“…Therefore, co-administration of DSF and Cu 2+ in two separate formulations usually yielded a very low concentration of the active ingredient, Cu(DDC) 2, in the tumor region and resulted in only marginal anticancer efficacy. Therefore, the delivery of preformed Cu(DDC) 2 in a single formulation is a more effective method to achieve a higher Cu(DDC) 2 concentration in tumor and improve the anticancer efficacy [6].…”