Evaluating the Anticancer Properties of Liposomal Copper in a Nude Xenograft Mouse Model of Human Prostate Cancer: Formulation, In Vitro, In Vivo, Histology and Tissue Distribution Studies
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Although Cu complexes have been investigated as anticancer agents, there has been no description of Cu itself as a cancer killing agent. A stealth liposomal Cu formulation (LpCu) was studied in vitro and in vivo.
LpCu was evaluated in prostate cancer origin PC-3 cells by a metabolic cytotoxicity assay, by monitoring ROS, and by flow cytometry. LpCu efficacy was evaluated in vivo using intratumoral and intravenous injections into mice bearing PC-3 xenograft tumors. Toxicology was assessed by performing hematological and blood biochemistry assays, and tissue histology and Cu distribution was investigated by elemental analysis.
LpCu and free Cu salts displayed similar levels of cell metabolic toxicity and ROS. Flow cytometry indicated that the mechanisms of cell death were both apoptosis and necrosis. Animals injected i.t. with 3.5 mg/kg or i.v. with 3.5 and 7.0 mg/kg LpCu exhibited significant tumor growth inhibition. Kidney and eye were the main organs affected by Cu-mediated toxicities, but spleen and liver were the major organs of Cu deposition.
LpCu was effective at reducing tumor burden in the xenograft prostate cancer model. There was histological evidence of Cu toxicity in kidneys and eyes of animals treated at the maximum tolerated dose of LpCu 7.0 mg/kg.
KEY WORDSliposomes copper reactive oxygen species cancer therapy toxicity
Dynamic light scattering
Dulbecco’s modified eagle medium
Dulbecco’s phosphate buffered saline
Enhanced permeability and retention
Fetal bovine serum
Hank’s balanced salt solution
2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid buffer
Stealth formulation of liposomal Cu
Large unilamellar vesicle
Maximum tolerated dose
Phosphate buffered saline
Reactive oxygen species
Wisconsin veterinary diagnostic laboratory
This research was supported by NIH grants R00CA136970 and R01DK099596, and startup funds from the University of Wisconsin-Madison, School of Pharmacy. We are grateful to Professor Manish Patankar and Dr. Arvinder Kapur (Dept. of Ob/Gyn, University of Wisconsin-Madison), and the UWCCC Flow Cytometry Laboratory for invaluable assistance with all the flow cytometry assays. We would also like to thank the WVDL Chemistry Section for performing all the elemental tissue analyses.
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