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Enhanced effect of pH-sensitive mixed copolymer micelles for overcoming multidrug resistance of doxorubicin

Paper ID Volume ID Publish Year Pages File Format Full-Text
5950 450 2014 11 PDF Available
Title
Enhanced effect of pH-sensitive mixed copolymer micelles for overcoming multidrug resistance of doxorubicin
Abstract

P-glycoprotein (P-gp) mediated drug efflux has been recognized as a key factor contributing to the multidrug resistance (MDR) in tumor cells. To address this issue, a new pH-sensitive mixed copolymer micelles system composed of hyaluronic acid-g-poly(l-histidine) (HA-PHis) and d-α-tocopheryl polyethylene glycol 2000 (TPGS2k) copolymers was developed to co-deliver doxorubicin (DOX) and TPGS2k into drug-resistant breast cancer MCF-7 cells (MCF-7/ADR). The DOX-loaded HA-PHis/TPGS2k mixed micelles (HPHM/TPGS2k) were characterized to have a unimodal size distribution, high DOX loading content and a pH dependent drug release profile due to the protonation of poly(l-histidine). As compared to HA-PHis micelles (HPHM), the HPHM/TPGS2k showed higher and comparable cytotoxicity against MCF-7/ADR cells and MCF-7 cells, respectively. The enhanced MDR reversal effect was attributed to the higher amount of cellular uptake of HPHM/TPGS2k in MCF-7/ADR cells than HPHM, arising from the inhibition of P-gp mediated drug efflux by TPGS2k. The measurements of P-gp expression level and mitochondrial membrane potential indicate that the blank HPHM/TPGS2k inhibited P-gp activity by reducing mitochondrial membrane potential and depletion of ATP but without inhibition of P-gp expression. In vivo study of micelles in tumor-bearing mice indicate that HPHM/TPGS2k could reach the tumor site more effectively than HPHM. The pH-sensitive mixed micelles system has been demonstrated to be a promising approach for overcoming the MDR.

Keywords
pH-sensitive; Copolymer micelles; Multidrug resistance; Hyaluronic acid; d-α-tocopheryl polyethylene glycol succinate; P-glycoprotein
First Page Preview
Enhanced effect of pH-sensitive mixed copolymer micelles for overcoming multidrug resistance of doxorubicin
Publisher
Database: Elsevier - ScienceDirect
Journal: Biomaterials - Volume 35, Issue 37, December 2014, Pages 9877–9887
Authors
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Subjects
Physical Sciences and Engineering Chemical Engineering Bioengineering