Project Summary/Abstract: Transitional cell carcinoma (TCC) of the bladder is the fifth most common form of cancer in the U.S., with over 80,000 new cases expected in 2019. For early-stage carcinomas, patients receive intravesical bacillus Calmette-Guerin (BCG) immunotherapy, or transurethral resection of the bladder tumor (TURBT) with intravesical chemotherapy. Both are associated with a high rate of recurrence and eventual progression. BCG fails many patients who are immunocompromised or who experience adverse reactions, while TURBT with chemotherapy fails because the chemotherapeutic agent is not sufficiently retained in the bladder to penetrate lesions that aren’t resected. Thus, there is a need for an improved drug formulation for early-stage (CIS, Ta, T1, T2) TCC capable of 1) penetrating the tumor beyond the superficial cell layers, and 2) increasing the dwell/contact time between the chemotherapeutic agent and the cancer cells. To that end, NanoMedTrix (NMTx) has developed a particle based on mesoporous silica nanoparticles (MSN) that carries known chemotherapeutic agents and is designed to improve their specificity, dwell time, and tumor penetration. Our Phase I SBIR project exceeded our goals and demonstrated the safety and efficacy of the MSN particles in carrying and releasing epirubicin in vivo in a murine TCC orthotopic model and in vitro using cultured human TCC cells. Through our participation in the NIH I-CORPS program we spoke with key opinion leaders (urologic oncologists) in the clinical bladder cancer space. As a result, we are completing our Phase I work using the MSN to deliver clinically relevant doses of gemcitabine, docetaxel, and mitomycin-c in the same model. Following our Phase I success, our Phase II SBIR is designed to complete the acquisition of data required by the FDA for initiation of IND approval of NMTx MSN in human clinical trials. Specific Aim 1 describes the necessary in vitro tasks: optimizing particle chemistry and validating our larger canine model using cultured cells and canine TCC organoids. Specific Aim 2 describes completion of murine orthotopic studies and the start of pre-clinical trials in dogs with spontaneously occurring TCC. Specific Aim 3 lays out our plan for carrying out cGMP synthesis, packaging, and analysis of our IND. Beyond setting the stage for FDA IND approval and first-in-human clinical trials, Phase II completion will strengthen our position with investors/partners in the pharmaceutical industry, with whom we will partner in SBIR Phase IIB, Phase III and beyond to expand clinical trials and ultimately commercialize the technology. We are continuing to work with the urology contacts we made in I-CORPS who are eager to participate in clinical trials, and we have received interest from Pharma companies (Bristol-Myers Squibb, Urovant, and others). Our proprietary technology will provide licensees with improved performance from established chemotherapeutics that have already gone off-pa...