Targeted nano-boron based boron neutron capture therapy for glioma treatment

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Project Summary Gliomas represent one of the most fatal and difficult to treat cancers. Despite the aggressive therapies, including surgical resection, radiotherapy and chemotherapy the median survival time for patients remains very poor. Boron neutron capture therapy (BNCT) is a noninvasive therapy for treating locally invasive malignant tumors such as glioma. BNCT is a robust therapy with clear advantages as it relies on the nuclear capture and fission reactions. Despite clear advantages, BNCT have not been as effective in the clinic due to inability to achieve adequate amounts of Boron-10 (an active drug) concentration selectively in the target cancer cells, which remains an unsolved problem. The studies proposed here are intended to fill a critical void using a nanomedicine-based approach, which is uniquely poised to offer a solution to this unsolved problem. We have developed nanodrugs for imaging and treatment of the primary and metastatic brain tumors. Here we propose a novel nanodrug (Nano-10Boron), based on a natural, nontoxic and biodegradable polymer carrying in excess of 300 molecules of Boron-10 enriched 4-boronophenylalanine (BPA) to cross blood-brain barrier (BBB) and actively target and deliver high Bopron-10 concentration to glioma cells for effective BNCT. In Aim 1, we will establish optimum functionating lead Nano-10Boron. This will be achieved by synthesizing next-generation Nano-10Borons with varied loading of BPA and a tumor targeting and BBB transport peptide Angiopep-2 (Ap2). In our preliminary studies, we used 12 Ap2 molecules and 300 BPA molecules covalently attached to PMLA to form a first-generation Nano-10Boron. Our goal is to prepare a lead Nano-10Boron with maximum allowable number of BPA molecules to enhance intracellular Boron-10 concentrations to boost the treatment outcome. Aim 2 will focus on establishing an ideal time window for neutron flux irradiation for greater BNCT effect. PK of our first-generation Nano-10Boron is about 1.44 h (see preliminary results for details) whereas, PK of free BPA used in clinical studies ranges in few minutes. Additionally, PMLA based nanodrugs utilizes active targeting and remains in tumor for relatively longer period, while clearing out from the systemic circulation providing grater tumor uptake. Studies outlines in this aim will determine the optimum time window when we have the highest Boron-10 concentrations in tumor vs surrounding healthy brain, facilitating effective BNCT response while minimizing any potential off targeting toxicity to the healthy brain. Aim 3 will utilize the lead Nano-10Boron to treat glioma baring mice to improve the survival. Lead Nano-10Boron will be injected at the optimum dose developed in the previous aim followed by irradiation with low energy neutrons to treat glioma baring animals and improve the survival time. The proposed work will solve the long-standing problem of Boron-10 delivery, thereby making BNCT a practical therapy for glioma treatment, improve patient survival and enhance the quality of life. The results of this study could lay the groundwork for a novel treatment option for glioma for clinical applications. Page 1