S. Sweeney, J. Assouline
Keywords: mesoporous silica nanoparticles, drug delivery, transitional cell carcinoma, bladder cancer, ultrasound
Summary: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 has developed a material based on mesoporous silica nanoparticles (MSN) that carries known chemotherapeutic agents and is designed to improve their specificity, dwell time, and tumor penetration. In murine toxological models, we evaluated the safety of ingested, intravenous, and intravesical MSN. Using a short peptide identified by phage display library, we improved specificity for bladder cancer cells relative to normal bladder epithelium in vitro and in vivo. We then demonstrated the ability of our materials to improve tumor imaging when using ultrasound or MRI. Subsequently our Phase I SBIR project 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. We then used the MSN to deliver clinically relevant doses of gemcitabine, docetaxel, and mitomycin-c in the same model. Ongoing and future studies include scaling up of manufacture for larger pre-clinical and, ultimately, clinical trial quantities. Our production capability has increased to 100 grams of MSN with equivalent particle characteristics as measured (TEM, pXRD, DLS) compared to smaller batches. We are also testing a range of particle encapsulation to tailor the release timing of drugs from the MSN cores.