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Radiosensitivity enhancement of radioresistant glioblastoma by epidermal growth factor receptor antibody-conjugated iron-oxide nanoparticles

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Abstract

The epidermal growth factor receptor deletion variant EGFRvIII is known to be expressed in a subset of patients with glioblastoma (GBM) tumors that enhances tumorigenicity and also accounts for radiation and chemotherapy resistance. Targeting the EGFRvIII deletion mutant may lead to improved GBM therapy and better patient prognosis. Multifunctional magnetic nanoparticles serve as a potential clinical tool that can provide cancer cell targeted drug delivery, imaging, and therapy. Our previous studies have shown that an EGFRvIII-specific antibody and cetuximab (an EGFR- and EGFRvIII-specific antibody), when bioconjugated to IONPs (EGFRvIII-IONPs or cetuximab-IONPs respectively), can simultaneously provide sensitive cancer cell detection by magnetic resonance imaging (MRI) and targeted therapy of experimental GBM. In this study, we investigated whether cetuximab-IONPs can additionally allow for the radiosensitivity enhancement of GBM. Cetuximab-IONPs were used in combination with single (10 Gy × 1) or multiple fractions (10 Gy × 2) of ionizing radiation (IR) for radiosensitization of EGFRvIII-overexpressing human GBM cells in vitro and in vivo after convection-enhanced delivery (CED). A significant GBM antitumor effect was observed in vitro after treatment with cetuximab-IONPs and subsequent single or fractionated IR. A significant increase in overall survival of nude mice implanted with human GBM xenografts was found after treatment by cetuximab-IONP CED and subsequent fractionated IR. Increased DNA double strands breaks (DSBs), as well as increased reactive oxygen species (ROS) formation, were felt to represent the mediators of the observed radiosensitization effect with the combination therapy of IR and cetuximab-IONPs treatment.

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Acknowledgments

We thank Dr. Robert C. Long for his significant contribution in acquiring and processing the MRI data and for helpful scientific image interpretations discussions. We also thank the Pathology Core Lab of Winship Cancer Institute of Emory University for helping with all the histology data. This work was supported by grants from the NIH (NS053454), Southeastern Brain Tumor Foundation (SBTF), Georgia Cancer Coalition Distinguished Cancer Clinicians and Scientific Program, Robbins Scholar Award from the Winship Cancer Institute of Emory University, AANS/CNS Section on Tumors/BrainLab International Research Fellowship and Dana Foundation.

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The authors declare no conflict of interest.

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Authors and Affiliations

  1. Brain Tumor Nanotechnology Laboratory, Department of Neurosurgery, Emory University School of Medicine, Winship Cancer Institute of Emory University, Atlanta, GA, 30322, USA

    Alexandros Bouras, Milota Kaluzova & Costas G. Hadjipanayis

  2. Winship Brain Tumor Center of Emory University, Winship Cancer Institute of Emory University, Atlanta, GA, 30322, USA

    Costas G. Hadjipanayis

  3. Department of Neurosurgery, Emory University School of Medicine, 1365B Clifton Rd. NE, Suite 6200, Atlanta, GA, 30322, USA

    Costas G. Hadjipanayis

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  1. Alexandros Bouras
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Correspondence to Costas G. Hadjipanayis.

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Bouras, A., Kaluzova, M. & Hadjipanayis, C.G. Radiosensitivity enhancement of radioresistant glioblastoma by epidermal growth factor receptor antibody-conjugated iron-oxide nanoparticles. J Neurooncol 124, 13–22 (2015). https://doi.org/10.1007/s11060-015-1807-0

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