Nanoparticle-Enhanced Radiation Therapy for DIPG

ABSTRACT Peter Chiarelli, MD DPhil, is a clinician-scientist in the field of pediatric neurosurgery, who is focused on the application of photochemical techniques to treat disease of the human brain. This K08 mentored career development award will provide the advanced training and mentorship within the fields of biological sciences, including design and refinement of tumor models, application/evaluation of biological assays, and practical use of advanced microscopy for biological systems. Supplementing this critical training gap will provide the resources for success as an independent investigator in the translational application of novel technologies grounded in the realm of physical chemistry. RESEARCH CONTEXT: Diffuse intrinsic pontine glioma (DIPG) is a tumor of the brainstem that occurs in children, with no available option for safe surgical resection, and no effective current chemotherapeutic strategy. The development of alternative therapies for this incurable brain cancer is a priority among pediatric neuro-oncology consortia. A new approach for the treatment of DIPG is proposed, grounded on successful pre-clinical work with a different high-grade brain tumor (murine xenograft model of supratentorial glioblastoma). This method takes advantage of the radiation which is already necessary for children with DIPG, and uses targeted ~35 nm biocompatible poly(ethylene glycol)(PEG)-coated iron oxide core-shell nanoparticles (NPs) to modify the effects of incident radiation by inducing Auger photoelectron ejection from the nanoparticle core. Through the biochemical targeting of NPs to the tumor cells, the effect of radiation is spatially enhanced within sub-micron distances from the NP, allowing the possibility of lower overall radiation doses to be delivered with greater tumor cytotoxicity. This research project will use a reliable murine model of DIPG, and apply targeted iron oxide-PEG NPs through two different methods: intravenous (IV) delivery, and convection-enhanced delivery (CED) to the brain. A mechanistic exploration of the NP-Auger effect will also be carried out using 2-dimensional thin films, to better understand the spatial extent over which photoelectron ejection exerts a biological effect. The goal of developing this technology is the translation to human pediatric clinical trials for DIPG, and to achieve the first substantial improvement in outcome observed over the past 3+ decades. CAREER DEVELOPMENT PLAN: Dr. Chiarelli will complete coursework on the advanced tumor biology in animal models, methods in benchtop molecular biology, and quantitative imaging (cell culture and tissue). This coursework will be integrated with the sequence of specific aims included in this proposal, so that training can be directly applied to the research. An interdisciplinary team of mentors with expertise spanning clinical neuro-oncology, live-cell imaging, DIPG biology, biomaterials design, and physical chemistry of 2-D surfaces has been assembled to provide close mentorship for Dr. Chiarelli, and the guidance necessary for clinical translation of the included work, presentation at professional meetings, as well as progress towards independent funding (R01 submission).