EGFRvIII Antibody Conjugated Iron Oxide Nanoparticles for MRI Guided Convection-Enhanced Delivery and Targeted Therapy of Glioblastoma

• Type of Material: Article
• Authors: Constantinos G Hadjipanayis, Emory University; Revaz Machaidze, Emory University; Milota Kaluzova, Emory University; Liya Wang, Emory University; Albert Jesse Schuette Jr, Emory University; Hongwei Chen, Emory University; Xinying Wu, Emory University; Hui Mao, Emory University
• Language: English
• Date: 2010-08-01
• Publisher: American Association for Cancer Research
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2010, American Association for Cancer Research
• Final Published Version (URL): http://cancerres.aacrjournals.org/content/70/15/6303
• Title of Journal or Parent Work: Cancer Research
• ISSN: 0008-5472
• Volume: 70
• Issue: 15
• Start Page: 6303
• End Page: 6312
• Grant/Funding Information: National Institute of Neurological Disorders and Stroke : NINDS; This work was supported in part by grants from the NIH (NS053454 to CGH; 54 CA119338-01, Center for Cancer Nanotechnology in Excellence Program to HM, P50CA128301-01A10003 to HM and CGH), EmTech Bio, Inc. (to HM), Southeastern Brain Tumor Foundation (to CGH), the Georgia Cancer Coalition, Distinguished Cancer Clinicians and Scientists Program (to CGH), and the Dana Foundation (to CGH).
• Keywords: Glioblastoma; EGFR; MRI; Convection-Enhanced Delivery; Magnetic Nanoparticles
• Research Categories: Health Sciences, Oncology

Abstract

The magnetic nanoparticle has emerged as a potential multifunctional clinical tool that can provide cancer cell detection by magnetic resonance imaging (MRI) contrast enhancement as well as targeted cancer cell therapy. A major barrier in the use of nanotechnology for brain tumor applications is the difficulty in delivering nanoparticles to intracranial tumors. Iron oxide nanoparticles (IONPs; 10 nm in core size) conjugated to a purified antibody that selectively binds to the epidermal growth factor receptor (EGFR) deletion mutant (EGFRvIII) present on human glioblastoma multiforme (GBM) cells, were used for therapeutic targeting and MRI contrast enhancement of experimental glioblastoma both in vitro and in vivo after convection-enhanced delivery (CED). A significant decrease in glioblastoma cell survival was observed after nanoparticle treatment and no toxicity was observed with treatment of human astrocytes (P<0.001). Lower EGFR phosphorylation was found in glioblastoma cells after EGFRvIIIAb-IONP treatment. Apoptosis was determined to be the mode of cell death after treatment of GBM cells and glioblastoma stem cell (GSC)-containing neurospheres with EGFRvIIIAb-IONPs. MRI-guided CED of EGFRvIIIAb-IONPs allowed for the initial distribution of magnetic nanoparticles within or adjacent to intracranial human xenograft tumors and continued dispersion days later. A significant increase in animal survival was found after CED of magnetic nanoparticles (P<0.01) in mice implanted with highly tumorigenic glioblastoma xenografts (U87ΔEGFRvIII). IONPs conjugated to an antibody specific to the EGFRvIII deletion mutant constitutively expressed by human glioblastoma tumors can provide selective MRI contrast enhancement of tumor cells and targeted therapy of infiltrative glioblastoma cells after CED.