Abstract B37: Photothermal therapy of glioblastoma multiforme using multiwalled carbon nanotubes optimized for diffusion in extracellular space

Abstract

Abstract Glioblastoma multiforme (GBM) is the most common and most lethal primary brain tumor with a 5 year overall survival rate of approximately 5%. Currently, no therapy is curative and all have significant side effects. Focal thermal ablative therapies that heat malignant tissue to ablative temperatures (>55°C) to induce tumor cell death are being investigated as a novel treatment modality. Such thermal ablative therapies can be enhanced by using nanotechnology, with the addition of nanoparticles. Carbon nanotube mediated thermal therapy (CNMTT) uses lasers that emit near infrared radiation to excite carbon nanotubes (CNTs) localized to the tumor volume to generate localized heat needed for thermal ablation. Clinical translation of CNMTT for GBM will require development of effective strategies to deliver CNTs to tumors, clear structure-activity and structure-toxicity evaluation, and an understanding of the effects of inherent and acquired thermotolerance on the efficacy of treatment. In our studies, we look at the effects of different coatings on multiwalled CNT (MWCNTs) diffusion and show that a dense coating of phospholipid-poly(ethylene glycol) on MWCNTs allows for better diffusion through brain ECM-mimicking hydrogels, while maintaining the ability to achieve ablative temperatures after laser exposure. We investigate the effects of phospholipid-poly(ethylene glycol) coated MWCNTs on the heat shock response in GBM and show that they do not induce a HSR in GBM cell lines. Activation of the HSR in GBM cells via exposure to sub-ablative temperatures or short term treatment with an inhibitor of heat shock protein 90 (17-(dimethylaminoethylamino)-17-demethoxygeldanamycin (17-DMAG)), induces a protective heat shock response that results in thermotolerance and protects against CNMTT. Finally, we evaluate the potential for CNMTT to selectively heat GBM multicellular spheroids comparing different methods of heat generation in a three dimensional spheroid model. These data provide pre-clinical insight into key parameters needed for translation of CNMTT including nanoparticle delivery through a three-dimensional volume, cytotoxicity, and efficacy for treatment of thermotolerant GBM. Citation Format: Brittany Eldridge, Brian Bernish, Cale Fahrenholtz, Ravi Singh. Photothermal therapy of glioblastoma multiforme using multiwalled carbon nanotubes optimized for diffusion in extracellular space. [abstract]. In: Proceedings of the AACR Special Conference on Engineering and Physical Sciences in Oncology; 2016 Jun 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2017;77(2 Suppl):Abstract nr B37.