Date(s) - 08/18/2014
Nanotechnology-based strategies are needed to improve the dismal prognosis of diffusive infiltrative pontine glioma (DIPG). DIPGs are suitable candidates to magnetically mediated energy delivery (MagMED) through targeted magnetic nanoparticles due to the following facts: (i) they have been shown to exhibit potential biomarkers in cell surfaces, such as transmembrane proteins, (ii) these potential biomarkers are overexpressed in several clinical studies without compromising expression in normal brain tissues, and (iii) potential targeting ligands can promote receptor-mediated endocytosis. Current cancer research on targeted nanoparticles involves various Epidermal Growth Factor Receptor-based targeting moieties due to FDA approval of antibody immunotherapies. Because Epidermal Growth Factor Receptor (EGFR) and its mutant form EGFRvIII are overexpressed in a significant fraction of DIPG cases, there is a potential motivation to test efficacy of MagMED in treating DIPG using EGFR-targeted MNPs in vitro and in vivo. EGFR, a 170 kDa glycoprotein member of the ErbB family, possesses an extracellular ligand-binding domain which can bind EGF ligands leading to receptor mediated endocytosis. In this study, iron oxide magnetic nanoparticles coated with polyethylene glycol are tested in vitro and in vivo in a rat model, and conjugated with EGF to activate lysosomal death pathways in glioma cells upon the application of an alternating magnetic field (AMF). In addition, we will study the significance of the magnetic relaxation mechanisms in the nanoscale energy delivery of non-targeted and targeted magnetic nanoparticles in the presence of AMFs to promote lysosomal fragilization and programmed cell death in vitro. We expect to demonstrate the delivery of EGFR-targeted magnetic nanoparticles to a DIPG rat model and their effect on cell survival in vitro and translate these results to an in vivo preclinical animal model of DIPG.