Multifunctional Nanoparticles in Diagnosis and Therapy

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DESCRIPTION (provided by applicant): Pancreatic ductal adenocarcinoma is the fourth most common cause of cancer-related mortality in the United States, accounting for nearly 31,000 deaths each year. The vast majority of patients present with locally advanced or unresectable disease, and currently available conventional therapeutic approaches have been minimally successful in ameliorating the dismal prognosis of this malignancy. Nanobiotechnology provides unprecedented opportunities for addressing many of the current pitfalls in the diagnosis and therapy of pancreatic cancer. The current proposal represents a multi-institutional platform partnership between groups with extensive expertise in nanomaterial synthesis and delivery, pancreatic cancer biology, and small animal imaging. Multifunctional hybrid ceramic-polymeric nanoparticles, specifically indium phosphide quantum dots (InP Q-DOTS) and organically modified silica (ORMOSIL) nanoparticles have been developed for comprehensive preclinical evaluation in pancreatic cancer models. Specific Aim 1 of this proposal entails the synthesis of long-circulating (PEGylated), surface-functionalized Q-DOTS and dye-doped ORMOSIL nanoparticles incorporating PET probes ("nanoPET"), for improved imaging of early and metastatic pancreatic cancer in vivo. Specific Aim 2 of this proposal entails synthesis of long-circulating, surface-functionalized ORMOSIL nanoparticles encapsulating the small molecule inhibitor rapamycin (nanorapamycin) for systemic drug delivery to pancreatic cancer. A systematic approach is proposed, including an "optimization" phase comprised of in vitro experiments using human pancreatic cancer cell lines and in vivo studies using conventional subcutaneous xenografts; these studies will then lead into an "application" phase utilizing two preclinical models that faithfully recapitulate human pancreatic cancer biology, including the development of intra-abdominal metastases: first, a novel KRAS-driven transgenic mouse model of pancreatic cancer and second, a spontaneously metastasizing orthotopic xenograft model of human pancreatic cancer established in athymic mice. It is anticipated that clinical translation of these "smart" nanomaterials will lead to improved staging of pancreatic cancer at diagnosis, early detection in "at risk" individuals, and more potent therapeutic benefits for patients with advanced disease. The long-term goal of this proposal remains improvement in patient outcome for a malignancy with near-uniform lethality.