Abstract
The development of copper-drug complexes (CDCs) is hindered due to their very poor aqueous solubility. Diethyldithiocarbamate (DDC) is the primary metabolite of disulfiram, an approved drug for alcoholism that is being repurposed for cancer. The anticancer activity of DDC is dependent on complexation with copper to form copper bis-diethyldithiocarbamate (Cu(DDC)2), a highly insoluble complex that has not been possible to develop for indications requiring parenteral administration. We have resolved this issue by synthesizing Cu(DDC)2 inside liposomes. DDC crosses the liposomal lipid bilayer, reacting with the entrapped copper; a reaction that can be observed through a colour change as the solution goes from a light blue to dark brown. This method is successfully applied to other CDCs including the anti-parasitic drug clioquinol, the natural product quercetin and the novel targeted agent CX-5461. Our method provides a simple, transformative solution enabling, for the first time, the development of CDCs as viable candidate anticancer drugs; drugs that would represent a brand new class of therapeutics for cancer patients.
Highlights
Over the past decade, the number of copper complexes with anticancer activity has been increasing and a number of reviews have detailed their synthesis and development [1,2,3]
DSF is unable to interact with copper, activity of DSF depends on its degradation to DDC
DDC as well as Cu(DDC)2 exhibited little activity when added to normal human bronchial epithelial cells (HBEpC), suggesting specificity of Cu(DDC)2 against cancer cells
Summary
The number of copper complexes with anticancer activity has been increasing and a number of reviews have detailed their synthesis and development [1,2,3]. Copper-drug complexes (CDCs) have not been approved for use in patients. A significant challenge associated with the development of CDCs is their extremely low aqueous solubility, making it difficult to establish the utility of these copper-complexes in preclinical models or patients. Development of intravenous dosage formulations requires the use of solubilising agents to create products suitable for use. The therapeutic promise of CDCs has largely been based on data obtained with compounds solubilized in dimethyl.
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