Abstract

The treatment of multi-drug resistant (MDR) cancer is a clinical challenge. Many MDR cells over-express epidermal growth factor receptor (EGFR). We exploit this expression through the development of EGFR-targeted, polymer blend nanocarriers for the treatment of MDR cancer using paclitaxel (a common chemotherapeutic agent) and lonidamine (an experimental drug; mitochondrial hexokinase 2 inhibitor). An orthotopic model of MDR human breast cancer was developed in nude mice and used to evaluate the safety and efficacy of nanoparticle treatment. The efficacy parameters included tumor volume measurements from day 0 through 28 days post-treatment, terminal tumor weight measurements, tumor density and morphology assessment through hematoxylin and eosin staining of excised tumors, and immunohistochemistry of tumor sections for MDR protein markers (P-glycoprotein, Hypoxia Inducible Factor, EGFR, Hexokinase 2, and Stem Cell Factor). Toxicity was assessed by tracking changes in animal body weight from day 0 through 28 days post-treatment, by measuring plasma levels of the liver enzymes ALT (Alanine Aminotransferase) and LDH (lactate dehydrogenase), and by white blood cell and platelet counts. In these studies, this nanocarrier system demonstrated superior efficacy relative to combination (paclitaxel/lonidamine) drug solution and single agent treatments in nanoparticle and solution form. The combination nanoparticles were the only treatment group that decreased tumor volume, sustaining this decrease until the 28 day time point. In addition, treatment with the EGFR-targeted lonidamine/paclitaxel nanoparticles decreased tumor density and altered the MDR phenotype of the tumor xenografts. These EGFR-targeted combination nanoparticles were considerably less toxic than solution treatments. Due to the flexible design and simple conjugation chemistry, this nanocarrier system could be used as a platform for the development of other MDR cancer therapies; the use of this system for EGFR-targeted, combination paclitaxel/lonidamine therapy is an advance in personalized medicine.

Notes

Published as: Milane L, Duan Z, Amiji M (2011) Therapeutic Efficacy and Safety of Paclitaxel/Lonidamine Loaded EGFR-Targeted Nanoparticles for the Treatment of Multi-Drug Resistant Cancer. PLoS ONE 6(9): e24075. doi:10.1371/journal.pone.0024075

This study was supported by the National Cancer Institute, National Institutes of Health through grants R01 CA-119617 and R01 CA-119617S1 (ARRA Supplement), and R21 CA-135594.

Keywords

multi-drug resistance (MDR), cancer, epidermal growth factor receptor (EGFR), polymer blend nanocarriers, paclitaxel, lonidamine, breast cancer

Subject Categories

Nanomedicine, Drug resistance in cancer cells, Multidrug resistance, Paclitaxel, Lonidamine

Disciplines

Oncology | Pharmaceutics and Drug Design

Publisher

Public Library of Science

Publication Date

9-8-2011

Rights Information

Copyright 2011

Restrictions

This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Rights Holder

Lara Jabr-Milane, Zhenfeng Duan, Mansoor M. Amiji

journal.pone.0024075.s001.tif (900 kB)
Figure S1: Toxicity analysis at day 0, day 14, and day 28

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Additional Files

journal.pone.0024075.s001.tif (900 kB)
Figure S1: Toxicity analysis at day 0, day 14, and day 28

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