Novel immunological treatment approaches are required that attack the molecular and biological features of invasive malignant gliomas. The magnetic nanoparticle has emerged as a potential multifunctional clinical tool for cancer cell-specific detection, treatment, and monitoring. Such multitasking is not possible with existing therapies. Current magnetic nanoparticle technology relies on iron-oxide nanoparticles (IONPs). Various formulations of iron oxide nanoparticles (IONPs) have been developed for drug delivery schemes, magnetic cell separation and cell targeting, magnetic resonance imaging (MRI) contrast enhancement, and hyperthermia treatment of cancer. Use of these particles is limited due to their weak magnetic properties. The PI has recently introduced a new generation of biocompatible metallic nanoparticles (FeNPs) that are highly magnetic. These nanoparticles (10 nm) are much more effective at MRI contrast enhancement and local hyperthermia than standard IONPs.
In this proposal, the PI builds on this new nanotechnology by applying it to brain cancer for imaging and therapeutic purposes. The central hypothesis of the proposal is that FeNPs, conjugated to a glioblastoma-specific EGFRvIII antibody (EGFRvIIIAb), will be used for MRI contrast enhancement of human glioblastoma cells and generation of local hyperthermia to allow for both in vitro and in vivo targeted imaging and therapy of glioblastoma multiforme (GBM).
EGFRvIII is a truncated, constitutively active version of the epidermal growth factor receptor (EGFR) that is overexpressed by glioblastoma cells and not normal cells. Targeting of the EGFRvIII deletion mutant forms the basis of ongoing immunotherapy clinical trials for patients with newly diagnosed GBM which the PI is participating in.
The proposal highlights important preliminary data where standard IONPs are conjugated to a EGFRvIII antibody (EGFRvIII-IONPs) and used for glioblastoma cell imaging and convection-enhanced delivery (CED) to mice implanted with human EGFRvIII expressing glioblastoma tumors. Convection-enhanced delivery (CED) of magnetic nanoparticles in a mouse glioma model results in MRI contrast of the nanoparticles. In addition, CED permits optimal distribution of IONPs in the brain. Dispersion of the nanoparticles over days, after the infusion has finished, may potentially target infiltrating tumor cells outside the tumor mass. Evidence is also provided on the use of cancer stem cell (CSC) containing neurospheres harvested from actual glioblastoma patients for generation of invasive brain tumors in a mouse model.
In Aim 1, FeNPs will undergo conjugation to the EGFRvIII antibody (EGFRvIII-FeNPs) after they are coated with an amphiphilic triblock polymer upon synthesis. This conjugation has already been performed with the use of IONPs. In Aim 2, the established glioma cell line U87MG(EGFRvIII), which expresses EGFRvIII, will be used for GBM cell imaging in vitro by MRI. In Aim 3, glioblastoma cells will be treated with FeNPs with or without local hyperthermia generation to determine cell survival and proliferation. The PI has determined that the FeNPs can generate local hyperthermia when exposed to an alternating magnetic field. In Aim 4, athymic nude mice will undergo stereotactic intracranial implantation with U87-MG(EGFRvIII) or EGFRvIII-expressing neurosphere cells followed by CED of FeNPs and treatment with an alternating magnetic field.
Upon completion of these aims we will translate these findings into a potential human clinical trial for the treatment of patients with GBM.