QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: jpet.106.101154v1 317/3/1372    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Wong, H. L. Articles by Wu, X. Y. Search for Related Content PubMed PubMed Citation Articles by Wong, H. L. Articles by Wu, X. Y.

CHEMOTHERAPY, ANTIBIOTICS, AND GENE THERAPY

A Mechanistic Study of Enhanced Doxorubicin Uptake and Retention in Multidrug Resistant Breast Cancer Cells Using a Polymer-Lipid Hybrid Nanoparticle System

Leslie Dan Faculty of Pharmacy, University of Toronto, Ontario, Canada (H.L.W., R.B., H.Y.X., K.B., X.Y.W.); and Ontario Cancer Institute, Toronto, Ontario, Canada (A.M.R.)

The objectives of this study were to evaluate the potential of a polymer-lipid hybrid nanoparticle (PLN) system to enhance cellular accumulation and retention of doxorubicin (Dox), a widely used anticancer drug and an established P-glycoprotein (Pgp) substrate, in Pgp-overexpressing cancer cell lines and to explore the underlying mechanisms. Nanoparticles containing Dox complexed with a novel anionic polymer (Dox-PLN) were prepared using an ultrasound method. Two Pgp-overexpressing breast cancer cell lines (a human cell line, MDA435/LCC6/MDR1, and a mouse cell line, EMT6/AR1) were used to investigate the effect of nanoparticles on cellular uptake and retention of Dox. Endocytosis inhibition studies and fluorescence microscopic imaging were performed to elucidate the mechanisms of cellular drug uptake. Treatment of Pgp-overexpressing cell lines with Dox-PLNs resulted in significantly enhanced Dox uptake and more substantial increases in drug retention after the end of treatment compared with free Dox solutions (p < 0.05). Fluorescence microscopic images showed improved nuclear localization of Dox and uptake of lipid when the drug was delivered in the Dox-PLN form to MDA435/LCC6/MDR1 cells. Endocytosis inhibition studies revealed that phagocytosis is an important pathway in the membrane permeability of the nanoparticles. These findings suggest that some of the Dox physically associated with the nanoparticles bypass the membrane-associated Pgp when delivered as Dox-PLNs, and in this form, the drug is better retained within the Pgp-overexpressing cells than the free drug. The present study suggests a new mechanism for overcoming drug resistance in Pgp-overexpressing tumor cells using lipid-based nanoparticle formulations.

Address correspondence to: Dr. Xiao Yu Wu, Graduate Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, 19 Russell Street, University of Toronto, ON, Canada M5S 2S2.

This article has been cited by other articles:

				X. Dong, C. A. Mattingly, M. T. Tseng, M. J. Cho, Y. Liu, V. R. Adams, and R. J. Mumper Doxorubicin and Paclitaxel-Loaded Lipid-Based Nanoparticles Overcome Multidrug Resistance by Inhibiting P-Glycoprotein and Depleting ATP Cancer Res., May 1, 2009; 69(9): 3918 - 3926. [Abstract] [Full Text] [PDF]

				K. Cho, X. Wang, S. Nie, Z. Chen, and D. M. Shin Therapeutic Nanoparticles for Drug Delivery in Cancer Clin. Cancer Res., March 1, 2008; 14(5): 1310 - 1316. [Abstract] [Full Text] [PDF]