title: EGFRvIII antibody-conjugated iron oxide nanoparticles for magnetic resonance imaging-guided convection-enhanced delivery and targeted therapy of glioblastoma.
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 (IONP; 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-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 (U87DeltaEGFRvIII). 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.
authors.affiliation: Brain Tumor Nanotechnology Laboratory, Department of Neurosurgery, Emory University School of Medicine, Atlanta, Georgia 30322, USA. chadjip@emory.edu
authors.forename: Costas G
authors.initials: CG
authors.lastname: Hadjipanayis
authors.forename: Revaz
authors.initials: R
authors.lastname: Machaidze
authors.forename: Milota
authors.initials: M
authors.lastname: Kaluzova
authors.forename: Liya
authors.initials: L
authors.lastname: Wang
authors.forename: Albert J
authors.initials: AJ
authors.lastname: Schuette
authors.forename: Hongwei
authors.initials: H
authors.lastname: Chen
authors.forename: Xinying
authors.initials: X
authors.lastname: Wu
authors.forename: Hui
authors.initials: H
authors.lastname: Mao
mesh_terms: D000818:Animals; D000918:Antibody Specificity; D017209:Apoptosis / Q000187:drug effects; D001253:Astrocytes / Q000187:drug effects; D001932:Brain Neoplasms / Q000175:diagnosis / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000276:immunology* / Q000378:metabolism; D005290:Ferric Compounds / Q000008:administration & dosage* / Q000737:chemistry; D005909:Glioblastoma / Q000175:diagnosis / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D006801:Humans; D018796:Immunoconjugates / Q000008:administration & dosage* / Q000737:chemistry / Q000276:immunology; D008279:Magnetic Resonance Imaging; D051379:Mice; D008819:Mice, Nude; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry; D015398:Signal Transduction; D014183:Transplantation, Heterologous
chemical_list: D005290:Ferric Compounds; D018796:Immunoconjugates; C410723:epidermal growth factor receptor VIII; C000499:ferric oxide; D066246:ErbB Receptors