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Doxorubicin and Paclitaxel-Loaded Lipid-Based Nanoparticles Overcome Multidrug Resistance by Inhibiting P-Glycoprotein and Depleting ATP

¹ Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, Kentucky; ² Department of Anatomical Science/Neurobiology, School of Medicine, University of Louisville, Louisville, Kentucky; and ³ Division of Molecular Pharmaceutics, Center for Nanotechnology in Drug Delivery, UNC Eshelman School of Pharmacy and ⁴ UNC Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina

Request for reprints: Russell J. Mumper, University of North Carolina Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7360. Phone: 919-966-1271; Fax: 919-966-0197; E-mail: mumper{at}email.unc.edu.

Key Words: anticancer drugs • cancer • polyoxyethylene 20-stearyl ether (Brij 78) • endocytosis • ATP

To test the ability of nanoparticle formulations to overcome P-glycoprotein (P-gp)–mediated multidrug resistance, several different doxorubicin and paclitaxel-loaded lipid nanoparticles were prepared. Doxorubicin nanoparticles showed 6- to 8-fold lower IC₅₀ values in P-gp–overexpressing human cancer cells than those of free doxorubicin. The IC₅₀ value of paclitaxel nanoparticles was over 9-fold lower than that of Taxol in P-gp–overexpressing cells. A series of in vitro cell assays were used including quantitative studies on uptake and efflux, inhibition of calcein acetoxymethylester efflux, alteration of ATP levels, membrane integrity, mitochondrial membrane potential, apoptosis, and cytotoxicity. Enhanced uptake and prolonged retention of doxorubicin were observed with nanoparticle-based formulations in P-gp–overexpressing cells. Calcein acetoxymethylester and ATP assays confirmed that blank nanoparticles inhibited P-gp and transiently depleted ATP. I.v. injection of pegylated paclitaxel nanoparticles showed marked anticancer efficacy in nude mice bearing resistant NCI/ADR-RES tumors versus all control groups. Nanoparticles may be used to target both drug and biological mechanisms to overcome multidrug resistance via P-gp inhibition and ATP depletion. [Cancer Res 2009;69(9):3918–26]