Oncotarget

Research Papers:

Targeted therapy of glioblastoma stem-like cells and tumor non-stem cells using cetuximab-conjugated iron-oxide nanoparticles

Milota Kaluzova, Alexandros Bouras, Revaz Machaidze and Costas G. Hadjipanayis _

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Oncotarget. 2015; 6:8788-8806. https://doi.org/10.18632/oncotarget.3554

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Abstract

Milota Kaluzova1, Alexandros Bouras1, Revaz Machaidze1,3 and Costas G. Hadjipanayis1,2

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

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

3 Present address: Brigham and Women’s Hospital, Neurosurgery, Boston, MA, USA

Correspondence to:

Costas G. Hadjipanayis, email:

Keywords: glioblastoma stem-like cells (GSCs), iron-oxide nanoparticles (IONPs), cetuximab, magnetic resonance imaging (MRI), convection-enhanced delivery (CED)

Received: February 06, 2015 Accepted: February 10, 2015 Published: March 12, 2015

Abstract

Malignant gliomas remain aggressive and lethal primary brain tumors in adults. The epidermal growth factor receptor (EGFR) is frequently overexpressed in the most common malignant glioma, glioblastoma (GBM), and represents an important therapeutic target. GBM stem-like cells (GSCs) present in tumors are felt to be highly tumorigenic and responsible for tumor recurrence. Multifunctional magnetic iron-oxide nanoparticles (IONPs) can be directly imaged by magnetic resonance imaging (MRI) and designed to therapeutically target cancer cells. The targeting effects of IONPs conjugated to the EGFR inhibitor, cetuximab (cetuximab-IONPs), were determined with EGFR- and EGFRvIII-expressing human GBM neurospheres and GSCs. Transmission electron microscopy revealed cetuximab-IONP GBM cell binding and internalization. Fluorescence microscopy and Prussian blue staining showed increased uptake of cetuximab-IONPs by EGFR- as well as EGFRvIII-expressing GSCs and neurospheres in comparison to cetuximab or free IONPs. Treatment with cetuximab-IONPs resulted in a significant antitumor effect that was greater than with cetuximab alone due to more efficient, CD133-independent cellular targeting and uptake, EGFR signaling alterations, EGFR internalization, and apoptosis induction in EGFR-expressing GSCs and neurospheres. A significant increase in survival was found after cetuximab-IONP convection-enhanced delivery treatment of 3 intracranial rodent GBM models employing human EGFR-expressing GBM xenografts.


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