Introduction: The epidermal growth factor receptor (EGFR) represents the most common alteration present in glioblastoma (GBM) tumors. Iron-oxide nanoparticles (IONPs) conjugated to antibodies specific to the EGFR can be used for magnetic resonance imaging (MRI) contrast enhancement and therapeutic targeting of GBM. We hypothesize that the treatment of experimental GBM with cetuximab-conjugated IONPs can result in radiosensitivity enhancement both in vitro and in vivo after convection-enhanced delivery (CED) in a rodent glioma model.
Methods: Human GBM cells overexpressing the EGFR deletion mutant, EGFRvIII, were treated with control (HBSS; Hanks’ solution), free IONPs, cetuximab (a wt EGFR monoclonal antibody that also cross-reacts with EGFRvIII), bioconjugated cetuximab-IONPs and subsequent irradiation (IR; 10 Gy) in vitro. MTT proliferation assay was performed. Immunohistochemical staining was performed to examine the presence of DNA double-strand breaks (DSBs) induced by IR after each treatment (30 min and 4 h). Animal survival studies were performed in 4 different groups of athymic nude mice after implantation of U87MG EGFRvIII cells and treatment with CED of control (HBSS), IONPs, cetuximab, bioconjugated cetuximab-IONPs and subsequent whole brain IR (10 Gy).
Results: Decreased GBM cell survival as well as increased formation of DNA DSBs was observed in vitro after treatment with bioconjugated cetuximab-IONPs and subsequent IR, compared to other treatment groups. An increase in overall animal survival was found in animals who underwent CED of cetuximab-IONPs and subsequent whole brain IR in comparison to other animal groups.
Conclusions: IONPs bioconjugated to antibodies specific to the EGFR can provide MRI contrast enhancement of GBM cells and targeted therapy of GBM tumors after CED, as well as radiosensitivity enhancement of GBM tumors. This approach could represent a possible new paradigm for GBM therapy.
Patient Care: Glioblastoma multiforme (GBM) tumors are extremely aggressive in a locally invasive fashion due to the presence of infiltrating tumor cells that extend beyond the area of the main tumor mass and are difficult to detect by magnetic resonance imaging. Imaging and targeted therapy of infiltrating GBM cells by bioconjugated magnetic nanoparticles could lead to better local tumor control and extend the survival of patients with GBM.
Learning Objectives: By the conclusion of this session participants should be able to: 1. Describe the importance of magnetic nanoparticles as a potential multifunctional clinical agent for future cancer therapy. 2. Discuss in small groups the current limitations and the future perspectives of magnetic nanoparticles in malignant gliomas therapy. 3. Identify a potentially effective treatment by using bioconjugated magnetic nanoparticles for targeted therapy as well as MRI contrast enhancement and radiosensitivity enhancement of malignant gliomas.