Project Summary The goal of this Fast Track STTR project is to determine proof-of-principle and efficacy of a novel blood brain barrier (BBB) penetrating therapeutic nanoparticle for the potential treatment of otherwise intractable brain tumors like glioblastoma multiforme (GBM). This project seeks to demonstrate that novel, targetable nanoparticles can delivery therapeutic substances to human brain tumor cells and reduce tumor burden in brain cancer and prolong patient survival. The therapeutic cargos are encapsulated cytotoxic drugs for otherwise intractable brain tumors. After exiting the brain vasculature, upon recognition by the tumor cell, the nanoparticle binds, gets taken into the cell (endocytosed) and the nanoparticle cargo is released, ultimately allowing availability of the drug to kill the cancer cell. This project fits well within the mission of the NCI, to develop new nanotechnology-based therapeutics, especially for high-risk tumors. Historically successful cancer chemotherapy, while vastly increasing survival in non- CNS tumors, has failed to do so for brain tumors in children and adults alike. GBM remains the most malignant primary central nervous system tumor, where the median overall survival is 15–23 months and 5-year survival is less than 6%. The incidence of brain metastases is increasing with an estimated 69,950 adults age 40+ in 2021 in the US alone. Brain tumors represent the highest per-patient initial cost of care for any cancer group. Estimations from Surveillance, Epidemiology, and End Results (SEER) on annualized mean net cost of care approach $150,000 per patient. These patients have the highest annualized mean net costs for last-year-of-life care, relative to other cancers, at $135,000 to $210,000 (depending on age and gender). There us thus dramatic unmet need to prevent morbidity and mortality while improving an otherwise dismal survival rate. Treatment-resistant metastases are the ultimate cause of death in most cancer patients. For brain cancer treatment, systemic therapy for metastases is generally ineffective due to the inability to get therapeutic doses across the blood brain barrier. A reliable, low- toxic, highly effective therapy is urgently needed to treat patients with primary tumors and treatment-resistant metastases. The specific aims of this proposal are therefore efficient encapsulation cancer drugs inside the targeted HPLNs that cross the blood brain barrier, demonstrate safety and efficacy in killing cancer cells in a spectrum of humanized xenograft mouse models of human GBM. NanoValent's goal, at the conclusion of the Fast Track proposal is to have a promising optimized formulation that can be that can ultimately be GMP manufactured and submitted for IND approval with the FDA.