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Copper-based therapeutics : creating a formulation platform to facilitate development of an emerging drug class

University of British Columbia

Copper-based therapeutics (CBTs) are a promising class of drug candidates that have been shown to have anti-cancer activity. One of the major challenges associated with developing this emerging class of medicines, however, is their poor aqueous solubility (< 1 mg/mL). This has impeded the transition of these agents from preclinical candidate drugs to lead candidates suitable for use in humans. This thesis describes a novel method for preparing copper-based therapeutics suitable for parenteral administration. The method involves synthesis of the copper complexes in the core of liposomes nanoscaled spherical structures with an aqueous core surrounded by a lipid bilayer). The method provides a simple, transformative solution enabling the development of CBTs as viable candidate anticancer drugs—a brand new class of therapeutics for cancer patients. The potential of this technology was exemplified with several compounds. Diethyldithiocarbamate (DDC) is the primary metabolite of disulfiram, an approved drug for alcoholism that is being repurposed for cancer. The anti-cancer activity of DDC is dependent on complexation with copper (Cu(DDC)₂), which is a highly insoluble complex. An injectable Cu(DDC)₂ formulation was prepared through synthesis of Cu(DDC)₂ inside the aqueous core of liposomes, and the resultant formulation exhibited significant therapeutic activity in two different rodent models of cancer. Clioquinol (CQ) is an approved anti-microbial agent that has potential anti-cancer activity. The activity of CQ is enhanced in some cancer cell lines when complexed to copper. The copper-CQ complex (Cu(CQ)₂) is sparingly soluble in aqueous solution but it is demonstrated that Cu(CQ)₂ can be synthesized inside liposomes. The therapeutic activity of the resultant formulations was, however, not significant. In an effort to identify cancer indications that may benefit most from treatment with CBTs, the therapeutic potential of DDC, pyrithione (Pyr), plumbagin (Plum), 8-hydroxyquinoline (8-HQ) and CQ copper complexes was determined in a panel of cancer cell lines that differed in their sensitivity to cisplatin. Cu(DDC)₂, Cu(Pyr)₂, Cu(Plum)₂ and Cu(8-HQ)₂ showed IC₅₀ values less than that of cisplatin in all tested cell lines. This work suggests that future studies with CBTs for cancer should focus on platinum refractory cancers.

Text

2017-10-17

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/63320

Pharmaceutical Sciences

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/