This project is addressing the critical challenges facing the glioma field on multiple levels: (i) To overcome toxicity, insufficient specificity and delivery of targeted therapies (e.g., (R)TK inhibitors), efforts focus on gene silencing using novel small interfering RNA (siRNA)-conjugated gold nanoparticles (RNA-Au NPs). This alternative and highly promising new agent exhibits enhanced cellular/tissue uptake, reduced off-target effects, and improved biostability and compatibility compared to conventional molecular RNAi and other polymer and nanoconstructs. (ii) This single-entity RNAi nano-reagent will target concomitantly activated RTKs and Bcl2L12 as GBM signature lesions and functionally validated modulators of therapeutic resistance and neurologically debilitating necrogenesis. (iii) We will pre-clinically validate RTK- and Bcl2L12-targeting NPs (RTK-, L12-RNA-Au NPs) in physiologically highly relevant BTSC and derived orthotopic explant model systems. (iv) The group will extend our pre-clinical validation efforts from orthotopic xenograft models to studies of tumor regression in a refined, acute-onset, highly penetrant GBM mouse model to assess efficacy of RNA-Au NPs in the setting of an intact immune system and a physiologically more relevant tumor microenvironment.

AuraSense, LLC—a new gene regulation platform company that has licensed some of the early advances in RNA-Au NP therapy—and Abraxis, Inc., is guiding the translational aspects of the project and playing a pivotal role in commercialization of the nano-RNAi platforms as anti-glioma therapeutics.