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.
multi-drug resistance (MDR), cancer, epidermal growth factor receptor (EGFR), polymer blend nanocarriers, paclitaxel, lonidamine, breast cancer
Nanomedicine, Drug resistance in cancer cells, Multidrug resistance, Paclitaxel, Lonidamine
Oncology | Pharmaceutics and Drug Design
Public Library of Science
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.
Lara Jabr-Milane, Zhenfeng Duan, Mansoor M. Amiji
Jabr-Milane, Lara S.; Duan, Zhenfeng; and Amiji, Mansoor M., "Therapeutic efficacy and safety of paclitaxel/lonidamine loaded EGFR-targeted nanoparticles for the treatment of multi-drug resistant cancer" (2011). Bouvé Faculty Publications. Paper 27. http://hdl.handle.net/2047/d20001021
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Additional Filesjournal.pone.0024075.s001.tif (900 kB)
Figure S1: Toxicity analysis at day 0, day 14, and day 28