Journal
JOURNAL OF PHARMACEUTICAL SCIENCES
Volume 98, Issue 3, Pages 945-958Publisher
ELSEVIER SCIENCE INC
DOI: 10.1002/jps.21479
Keywords
diblock copolymers; micelle; polymeric drug delivery systems; surfactants; P-glycoprotein; multidrug resistance
Funding
- Canadian Institutes of Health Research (CIHR)
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Overexpression of P-glycoprotein (Pgp) is one of the major limitations in cancer chemotherapy. Previous work has shown that amphiphilic diblock copolymers composed of methoxypolyethylene glycol-block-polycaprolactone (MePEG-b-PCL) diblock copolymers enhanced the cellular accumulation of Pgp substrates by modulating the function of this drug efflux transporter. The objective of this work was to determine whether MePEG-b-PCL diblock copolymers modulated Pgp function in multidrug resistant (MDR) cancer cells. The diblock copolymer enhanced the accumulation of various Pgp substrates in Pgp overexpressing MDR cells but did not influence substrate accumulation in non-Pgp expressing cells. Treatment of MDR cells with the diblock copolymer enhanced paclitaxel (ptx) and doxorubicin (dox) accumulation. Following uptake, ptx was rapidly effluxed from MDR cells whereas diblock copolymer treatment retained dox inside MDR cells. Treatment of MDR cells with the diblock copolymer reversed drug resistance to dox but not ptx. However, resistance to ptx was reversed by verapamil, which indicated that a sustained inhibition of Pgp was required for ptx to induce cytotoxicity in MDR cells. Taken together, these results highlight the potential of MePEG-b-PCL diblock copolymer to reverse drug resistance in MDR cancer cells through inhibition of Pgp function, making it a promising candidate for overcoming MDR. (C) 2008 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:945-958, 2009
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