Ultrasound-based diagnostic and monitoring of bladder cancer treatment with drug released from nanoparticles

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Project Summary/Abstract Transitional cell carcinoma (TCC) of the bladder is the fifth most common form of cancer in the United States, with over 79,000 new cases expected for 2017. For early stage carcinomas, the most common treatment regimen is to initially perform transurethral resection of bladder tumor (TURBT) using an invasive cystoscopic approach with non-specific fluorescent dyes to highlight the lesions. Even then, small lesions are often missed leading to the cancer recurring in up to 70% of patients and further progresses to advanced cancer in up to 20% of patients following TURBT. Compared to cystoscopy, high resolution ultrasound (HRUS) is low-cost, minimally invasive, and provides an in-depth view of the smooth muscle layer and surrounding tissues of the bladder with spatial resolution as low as 30 m. Despite advances in HRUS, current imaging systems are limited to anatomical data, as it can neither provide functional or molecular imaging data, nor facilitate any interventional approach, alone. The implementation of a targeted contrast enhancement is necessary to elevate the data acquired from even the most advanced system. Clinically approved ultrasound contrast agents operate on the principle that the speed of sound is drastically different high molecular weight gases than in soft tissue. While highly echogenic, these agents are too large and too short-lived to be useful for functional imaging. To improve upon this approach, sub-micron ultrasound agents are being used experimentally, though the resulting agents are limited and have not been applied to TCC. Clinical applications resulting from this approach will benefit by 1) improvement of current screening methods (expedited, cheaper and dynamic), and 2) facilitation of specific delivery of intravesical treatment, specifically with non-invasive monitoring. We propose a material based on mesoporous silica nanoparticles (MSN), functionalized for diagnostic HRUS as well as interventional imaging following delivery of a therapeutic agent. We propose a rigorous in vitro / in vivo testing methodology to characterize the MSN and optimize its diagnostic and therapeutic capabilities. Upon completion the MSN would fulfill a desperately needed alternative to the current invasive and TCC treatment. If successful, the end product represents a highly marketable cost effective material that can be deployed clinically, ultimately improving patient outcomes. Our team of biomedical engineers, radiologists, urology researchers and clinicians are uniquely poised to carry out this research. The use of biocompatible materials and a short peptide for targeting, as opposed to many pre-clinical studies which involve monoclonal antibodies, ensures that the proposed material is of immediate clinical and commercial relevance. This proposal paves the way for SBIR Phase II studies, in which long-term survival and the scale-up of synthesis for commercial purposes will be evaluated.