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.