title: Targeted therapy of glioblastoma stem-like cells and tumor non-stem cells using cetuximab-conjugated iron-oxide nanoparticles.
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.
authors: Brain Tumor Nanotechnology Laboratory, Department of Neurosurgery, Emory University School of Medicine, Winship Cancer Institute of Emory University, Atlanta, GA, USA.
authors: Milota
authors: M
authors: Kaluzova
authors: Brain Tumor Nanotechnology Laboratory, Department of Neurosurgery, Emory University School of Medicine, Winship Cancer Institute of Emory University, Atlanta, GA, USA.
authors: Alexandros
authors: A
authors: Bouras
authors: Brain Tumor Nanotechnology Laboratory, Department of Neurosurgery, Emory University School of Medicine, Winship Cancer Institute of Emory University, Atlanta, GA, USA.|Present address: Brigham and Women's Hospital, Neurosurgery, Boston, MA, USA.
authors: Revaz
authors: R
authors: Machaidze
authors: Brain Tumor Nanotechnology Laboratory, Department of Neurosurgery, Emory University School of Medicine, Winship Cancer Institute of Emory University, Atlanta, GA, USA.|Winship Brain Tumor Center of Emory University, Winship Cancer Institute of Emory University, Atlanta, GA, USA.
authors: Costas G
authors: CG
authors: Hadjipanayis
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000188:drug therapy*; D002478:Cells, Cultured; D000068818:Cetuximab / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D004337:Drug Carriers; D004354:Drug Screening Assays, Antitumor; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D058185:Magnetite Nanoparticles / Q000008:administration & dosage* / Q000633:toxicity; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D058990:Molecular Targeted Therapy; D009363:Neoplasm Proteins / Q000032:analysis; D014411:Neoplastic Stem Cells / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects; D011092:Polyethylene Glycols / Q000008:administration & dosage; D018874:Spheroids, Cellular; D023041:Xenograft Model Antitumor Assays
chemical_list: D004337:Drug Carriers; D058185:Magnetite Nanoparticles; D009363:Neoplasm Proteins; D011092:Polyethylene Glycols; D000068818:Cetuximab
keywords: cetuximab; convection-enhanced delivery (CED); glioblastoma stem-like cells (GSCs); iron-oxide nanoparticles (IONPs); magnetic resonance imaging (MRI)