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Drug Deliv Transl Res. 2018 Feb;8(1):239-251. doi: 10.1007/s13346-017-0455-7.

Development of a copper-clioquinol formulation suitable for intravenous use.

Author information

1
Experimental Therapeutics, British Columbia Cancer Agency, 675 West 10th Avenue, Vancouver, BC, V5Z 1L3, Canada. mwehbe@bccrc.ca.
2
Faculty of Pharmaceutical Sciences, University of British Columbia, 2146 East Mall, Vancouver, BC, V6T 1Z3, Canada. mwehbe@bccrc.ca.
3
Experimental Therapeutics, British Columbia Cancer Agency, 675 West 10th Avenue, Vancouver, BC, V5Z 1L3, Canada.
4
Faculty of Pharmaceutical Sciences, University of British Columbia, 2146 East Mall, Vancouver, BC, V6T 1Z3, Canada.
5
Department of Pathology and Laboratory Medicine, University of British Columbia, 2211 Wesbrook Mall, Vancouver, BC, V6T 2B5, Canada.
6
Center for Drug Research and Development, Vancouver, BC, V6T 1Z4, Canada.

Abstract

Clioquinol (CQ) is an FDA-approved topical antifungal agent known to kill cancer cells. This facilitated the initiation of clinical trials in patients with refractory hematologic malignancies. These repurposing efforts were not successful; this was likely due to low intracellular levels of the drug owing to poor absorption and rapid metabolism upon oral administration. CQ forms a sparingly soluble copper complex (Cu(CQ)2) that exhibits enhanced anticancer activity in some cell lines. We have utilized a novel method to synthesize Cu(CQ)2 inside liposomes, an approach that maintains the complex suspended in solution and in a format suitable for intravenous administration. The complex was prepared inside 100-nm liposomes composed of 1,2-distearoyl-sn-glycero-3-phosphocholine/cholesterol (55:45). The therapeutic activity of the resultant formulation was evaluated in two subcutaneous tumor models (glioblastoma and ovarian cancers) but was not active. We also assessed the ability of the Cu(CQ)2 formulation to increase copper delivery to cancer cells in vitro and its potential to be used in combination with disulfiram (DSF). The results suggested that addition of Cu(CQ)2 enhanced cellular copper levels and the activity of DSF in vitro; however, this combination did not result in a statistically significant reduction in tumor growth in vivo. These studies demonstrate that a Cu(CQ)2 formulation suitable for intravenous use can be prepared, but this formulation used alone or in combination with DSF was not efficacious. The methods described are suitable for development formulations of other analogues of 8-hydroxyquinoline which could prove to be more potent.

KEYWORDS:

Cancer; Clioquinol; Copper; Copper complexes; Disulfiram; Liposomes

PMID:
29247315
PMCID:
PMC5756275
DOI:
10.1007/s13346-017-0455-7
[Indexed for MEDLINE]
Free PMC Article

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