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

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.

• Authors: Moe Wehbe, Armaan K Malhotra, Malathi Anantha, Cody Lo, Wieslawa H Dragowska, Nancy Dos Santos, Marcel B Bally
• Journal: Drug delivery and translational research (Drug Deliv Transl Res) Vol. 8 Issue 1 Pg. 239-251 (02 2018) ISSN: 2190-3948 [Electronic] United States
• PMID: 29247315 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antifungal Agents
• Antineoplastic Agents
• Liposomes
• Phosphatidylcholines
• Copper
• Clioquinol
• Cholesterol
• 1,2-distearoyllecithin
• Disulfiram

Topics

• Administration, Intravenous
• Animals
• Antifungal Agents (administration & dosage, chemistry, pharmacokinetics, therapeutic use)
• Antineoplastic Agents (administration & dosage, chemistry, pharmacokinetics, therapeutic use)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Cholesterol (chemistry)
• Clioquinol (administration & dosage, chemistry, pharmacokinetics, therapeutic use)
• Copper (administration & dosage, chemistry, pharmacokinetics, therapeutic use)
• Disulfiram (administration & dosage, chemistry, therapeutic use)
• Drug Therapy, Combination
• Humans
• Liposomes
• Mice
• Neoplasms (drug therapy, pathology)
• Phosphatidylcholines (chemistry)
• Tumor Burden (drug effects)