EGFRvIII Antibody Conjugated Magnetic Nanoparticles for Targeted Imaging and Therapy of Glioblastoma

Costas G. Hadjipanayis, M.D., Ph.D.

Funded in September, 2009: $200000 for 3 years
LAY SUMMARY . ABSTRACT . BIOGRAPHY .

LAY SUMMARY

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Testing a promising technology for visualizing, targeting and killing brain glioma cells

A newly developed technique that can both image deadly brain glioma cells and also potentially kill those cells will be tested in a mouse model of glioblastoma. 

Deadly brain glioblastoma remains resistant to treatment.  A potential therapeutic target is an “epidermal growth factor receptor” that is found on the cancerous but not normal brain cells. The magnetic nanoparticle has emerged as a potential clinical tool for detecting cancer cells through imaging, for treating the cancer, and for monitoring the effects of treatment. While current technology relies on iron oxide nanoparticles for targeting the tumor cells and delivering potential therapies to them, these nanoparticles have weak magnetic properties. In contrast, metallic nanoparticles that the investigators recently developed are highly magnetic. They hypothesize that these metallic nanoparticles, bound to antibodies that specifically target epidermal growth factor receptors on the cancer cells, can both facilitate MRI imaging of glioblastoma cells and killing them.

Preliminary data in a mouse model of glioblastoma indicate that a technique called “convection-enhanced delivery” permits optimal distribution of the metallic nanoparticles to cancerous cells in the brain that is visible through MRI imaging. Moreover, the nanoparticles’ continued dispersion may potentially target infiltrating tumor cells outside of the tumor mass.  In this study, the investigators will: 1) bind the nanoparticles to the antibody that targets and attacks epidermal growth factor receptors on the cancer cells; 2) use MRI imaging to determine whether the nanoparticles bind to and therefore label the cells; 3)  see whether the metallic nanoparticles kill the tumor cells by generating local hyperthermia (heating them to death) when exposed to an alternating magnetic field; and 4) determine whether the nanoparticles kill human glioblastoma cells that have been introduced into the mouse model.

Significance:  If this new metallic nanoparticle technique effectively labels glioblastoma cells so that they can be seen by MRI imaging, and kills the cells by heating them to death in this mouse model, the research may lead to treatment of patients with this deadly cancer.

ABSTRACT

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EGFRvIII Antibody Conjugated Magnetic Nanoparticles for Targeted Imaging and Therapy of Glioblastoma

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.

INVESTIGATOR BIOGRAPHIES

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Costas G. Hadjipanayis, M.D., Ph.D.

Dr. Costas G. Hadjipanayis is Assistant Professor in the Dept. of Neurological Surgery at Emory University School of Medicine.  Dr. Hadjipanayis received his medical degree from Jefferson Medical College at Thomas Jefferson University in 1998.  He completed his general surgery internship and neurosurgical residency at the University of Pittsburgh in 2006.  While completing his neurosurgical training he obtained a Ph.D. degree in the Biochemistry and Molecular Genetics program at the University of Pittsburgh.  Upon completion of his residency, he spent time at the University of California San Francisco (UCSF) studying surgical neuro-oncology including cortical and subcortical brain mapping.  Dr. Hadjipanayis joined the Dept. of Neurological Surgery at Emory University in 2007.  His clinical and research focus is on central nervous system tumors, including brain and spinal tumors.  He has a special surgical interest with minimally invasive neurosurgery and neuro-endoscopy.  Dr. Hadjipanayis is a neurosurgeon-scientist who is actively involved with clinical trials for brain tumor patients at the Winship Cancer Institute at Emory University.  He is currently the director of the Brain Tumor Nanotechnology Laboratory at Emory University.  His lab is actively studying the development of multifunctional nanoparticle agents (magnetic nanoparticle and chemotherapy based nanoparticles) for the targeted imaging and therapy of malignant brain tumors.  His research focus also involves the study of glioma stem cells (GSCs) harvested from patient brain tumors at the time of surgical resection.  His lab is actively studying the implantation of GSCs in rodents and formation of invasive human glioblastoma xenografts for novel therapeutics development.  His lab has studied the delivery and use of recombinant Herpes Simplex Virus (HSV-1) vectors for the therapy of brain cancer (malignant gliomas).  He is interested in direct delivery of therapeutic agents to brain tumors by convection-enhanced delivery (CED) and has developed a mouse model for this purpose.