PROJECT OVERVIEW This project will focus on the application of nanotechnology to the unique problems of pancreatic adenocarcinoma (PAC). Unlike what is observed in other solid tumors, pancreafic cancer cells exist as foci embedded in an abundant dense hypovascular fibrofic stroma. Development of this dense stroma begins with eariy premalignant disease (pancreatic intraepithelial neoplasia (PanIN)) and continues through tumor progression. A primary goal of this project will be to develop nanotechnologies that can either penetrate or accumulate in the abundant stroma that characterizes pancreafic cancer. The ability to specifically deliver therapies to the pancreafic tumors will also allow the use of therapies directed at appropriate targets in individual patients, opening the door to individualized therapies. Unfortunately, the current preclinical tumor models for PAC do not develop stroma and thus do not accurately represent the microenvironment found in the human disease. Recentiy, we have developed novel preclinical mouse models, both xenografts and genetic, which accurately mimic this fibrofic microenvironment. We will use these novel and unique model systems to develop optimized nanotechnologies that target and accumulate within pancreafic stromal networks for therapy. Imaging, and prevenfion of PAC. Thus, we will effectively turn what was a barrier to therapeutic delivery into a reservoir for preventive and therapeutic agents. Alternatively, we will suppress the biological activity of the stromal cells to prevent cancer progression or to render the cancer more amenable to cancer cell directed therapies. Together these studies will, for the first fime, ufilize nanocarriers to penetrate the barrier surrounding pancreafic tumors to achieve clinically significant goals,