Enhanced Intercellular Retention Activity of Novel PH-sensitive Polymeric Micelles in Wild and Multidrug Resistant MCF-7 Cells

Overview

Journal Pharm Res

Specialties Pharmacology
Pharmacy

Date 2007 Mar 27

PMID 17385015

Citations 26

Authors

Ghazal Mohajer

Eun Seong Lee

You Han Bae

Affiliations

Soon will be listed here.

Abstract

Purpose: The purpose of this work was to demonstrate the advantage of using pH-sensitive polymeric mixed micelles (PHSM) composed of poly(L: -histidine) (polyHis)/poly(ethylene glycol) (PEG) and poly(L: -lactic acid) (pLLA)/PEG block copolymers with folate conjugation to increase drug retention in wild-type and MDR tumor cells.

Materials And Methods: Both wild-type and multidrug resistant (MDR) human breast adenocarcinoma (MCF-7) cell lines were used to investigate the accumulation and elimination of doxorubicin (DOX), PHSM with folate (PHSM/f), and pH-insensitive micelles composed of pLLA/PEG block copolymer with folate (PHIM/f).

Results: Cells treated with PHSM/f showed decelerated elimination kinetics compared to cells treated with PHIM/f. MDR cells treated with drug-containing PHSM/f for 30 min retained 80% of doxorubicin (DOX) even after incubation for 24 h in the absence of drug. On the other hand, cells treated with drug-containing PHIM/f retained only 40% of DOX within the same period of time. Flow cytometry and confocal microscopy confirmed these results.

Conclusions: Cellular entry of the micelles occurred via receptor-mediated endocytosis using folate receptors. The pH-induced destabilization of PHSM/f led to rapid distribution of drug and polymer throughout the cells, most likely due to polyHis-mediated endosomal disruption. This reduced the likelihood of drug efflux via exocytosis from resistant tumor cells.

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