title: Nanoscale Reaction Vessels Designed for Synthesis of Copper-Drug Complexes Suitable for Preclinical Development.
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.
authors.affiliation: Experimental Therapeutics, British Columbia Cancer Research Centre, Vancouver, British Columbia, Canada.|Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Wehbe
authors.affiliation: Experimental Therapeutics, British Columbia Cancer Research Centre, Vancouver, British Columbia, Canada.
authors.forename: Malathi
authors.initials: M
authors.lastname: Anantha
authors.affiliation: Experimental Therapeutics, British Columbia Cancer Research Centre, Vancouver, British Columbia, Canada.
authors.forename: Ian
authors.initials: I
authors.lastname: Backstrom
authors.affiliation: Experimental Therapeutics, British Columbia Cancer Research Centre, Vancouver, British Columbia, Canada.|Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Ada
authors.initials: A
authors.lastname: Leung
authors.affiliation: Experimental Therapeutics, British Columbia Cancer Research Centre, Vancouver, British Columbia, Canada.
authors.forename: Kent
authors.initials: K
authors.lastname: Chen
authors.affiliation: Experimental Therapeutics, British Columbia Cancer Research Centre, Vancouver, British Columbia, Canada.
authors.forename: Armaan
authors.initials: A
authors.lastname: Malhotra
authors.affiliation: Department of Chemistry, University of Uppsala, 3 Husargatan (B7), Uppsala, Sweden.
authors.forename: Katarina
authors.initials: K
authors.lastname: Edwards
authors.affiliation: Experimental Therapeutics, British Columbia Cancer Research Centre, Vancouver, British Columbia, Canada.|Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia, Canada.|Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.|Center for Drug Research and Development, Vancouver, British Columbia, Canada.
authors.forename: Marcel B
authors.initials: MB
authors.lastname: Bally
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D000975:Antioxidants / Q000737:chemistry / Q000494:pharmacology; D052160:Benzothiazoles / Q000737:chemistry / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D007464:Clioquinol / Q000737:chemistry / Q000494:pharmacology; D003300:Copper / Q000737:chemistry* / Q000378:metabolism; D004050:Ditiocarb / Q000737:chemistry* / Q000378:metabolism; D005260:Female; D006801:Humans; D008081:Liposomes; D051379:Mice; D036103:Nanotechnology; D009287:Naphthyridines / Q000737:chemistry / Q000494:pharmacology; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology*; D011794:Quercetin / Q000737:chemistry / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D000975:Antioxidants; D052160:Benzothiazoles; C557717:CX 5461; D008081:Liposomes; D009287:Naphthyridines; D003300:Copper; D007464:Clioquinol; D004050:Ditiocarb; D011794:Quercetin