title: Polymer micelle formulations of proteasome inhibitor carfilzomib for improved metabolic stability and anticancer efficacy in human multiple myeloma and lung cancer cell lines.
abstract: Carfilzomib (CFZ) is a second-generation proteasome inhibitor drug approved for the treatment of multiple myeloma. Contrary to its excellent antimyeloma activity, CFZ has shown only limited efficacy in patients with solid malignancies. This lack of efficacy has been attributed in part to rapid degradation of CFZ in the body, possibly hindering the ability of CFZ to access the proteasome target in solid tumors. We hypothesized that polymer micelles, a currently Food and Drug Administration-approved nanoparticle drug delivery formulation, may protect CFZ from metabolic degradation and thus expand the clinical utility of the drug as an anticancer agent. To test our hypothesis, we prepared CFZ-entrapped polymer micelle particles with various compositions and drug release profiles and examined the extent of the CFZ metabolism in vitro using mouse liver homogenates. We also assessed the cytotoxic activities of the CFZ-entrapped micelle formulations in human cancer cell lines derived from B lymphocytes (RPMI-8226) and the lung (H460). Our data indicated that polymer micelle-based formulations can improve metabolic stability and cytotoxic effects of CFZ compared with free CFZ in human cancer cell lines tested. Taken together, these results suggest that polymer micelles may have potential as a delivery system for CFZ with an extended therapeutic utility for nonhematologic malignancies in the future.
authors: Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, Kentucky (L.A., D.R., K.B.K., Y.B.); Department of Pharmacy Practice, College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois (D.H., H.J.); and College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Korea (W.L.).
authors: Lin
authors: L
authors: Ao
authors: Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, Kentucky (L.A., D.R., K.B.K., Y.B.); Department of Pharmacy Practice, College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois (D.H., H.J.); and College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Korea (W.L.).
authors: Derek
authors: D
authors: Reichel
authors: Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, Kentucky (L.A., D.R., K.B.K., Y.B.); Department of Pharmacy Practice, College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois (D.H., H.J.); and College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Korea (W.L.).
authors: Di
authors: D
authors: Hu
authors: Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, Kentucky (L.A., D.R., K.B.K., Y.B.); Department of Pharmacy Practice, College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois (D.H., H.J.); and College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Korea (W.L.).
authors: Hyunyoung
authors: H
authors: Jeong
authors: Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, Kentucky (L.A., D.R., K.B.K., Y.B.); Department of Pharmacy Practice, College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois (D.H., H.J.); and College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Korea (W.L.).
authors: Kyung Bo
authors: KB
authors: Kim
authors: Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, Kentucky (L.A., D.R., K.B.K., Y.B.); Department of Pharmacy Practice, College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois (D.H., H.J.); and College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Korea (W.L.).
authors: Younsoo
authors: Y
authors: Bae
authors: Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, Kentucky (L.A., D.R., K.B.K., Y.B.); Department of Pharmacy Practice, College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois (D.H., H.J.); and College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Korea (W.L.) wooin.lee@snu.ac.kr.
authors: Wooin
authors: W
authors: Lee
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology*; D045744:Cell Line, Tumor / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004337:Drug Carriers; D005026:Ethylene Glycols; D005260:Female; D006801:Humans; D008099:Liver / Q000378:metabolism; D008175:Lung Neoplasms / Q000188:drug therapy*; D008810:Mice, Inbred C57BL; D008823:Micelles; D009101:Multiple Myeloma / Q000188:drug therapy*; D009842:Oligopeptides / Q000378:metabolism / Q000494:pharmacology*; D011091:Polyesters; D061988:Proteasome Inhibitors / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D004337:Drug Carriers; D005026:Ethylene Glycols; D008823:Micelles; D009842:Oligopeptides; D011091:Polyesters; D061988:Proteasome Inhibitors; C476300:poly(epsilon-caprolactone)-b-poly(ethylene glycol); C524865:carfilzomib