Development of Targeted Nanotechnology Platform for Pancreatic Cancer

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The management of pancreatic cancer (PanCa) is exceptionally difficult due to the extremely poor response to available therapeutic modalities. Poor survival is primarily because of suboptimal drug delivery and chemo- resistance due to excessive fibrosis and extracellular matrix deposition (desmoplasia) in pancreatic tumors. NF-κB, Wnt and Sonic Hedgehog (SHH) are key oncogenic signaling pathways that are involved in PanCa progression and chemo-resistance to drugs such as gemcitabine. Strategies for targeted suppression of these key oncogenic pathways in PanCa tumors, including metastases, are not well developed. Recent studies demonstrate that curcumin has potent inhibitory effects on aforementioned pathways and induces chemo- sensitization in PanCa cells. However, curcumin has poor pharmacokinetics and modifications to curcumin are needed for successful clinical use. Recently we have engineered a unique curcumin loaded multi-layered magnetic nanoparticle (MNP-CUR) formulation for magnetic resonance imaging (MRI) and therapeutic applications (Patent # PCT/US2011/063723). Our overall goal is to develop new strategies for targeted suppression of these key oncogenic signaling pathways in PanCa by utilizing a novel targeted magnetic nanoparticle (MNP) formulation. Recently, we have identified a novel transmembrane mucin, MUC13, which is highly expressed in PanCa but not in the normal pancreas. Additionally, we have generated novel monoclonal and humanized anti-MUC13 antibodies that can be used for targeted tumor specific delivery of drug loaded nanoparticles. Based on this compelling evidence we hypothesize that our novel antibody guided MNPs will enhance bioavailability of curcumin in tumors to attenuate tumor growth and sensitize pancreatic cancer cells to gemcitabine via suppression of NF-κB, Wnt, SHH signaling pathways and decreased desmoplastic reaction. Recent studies suggest a major role for tumor-stromal (paracrine) cross-talk in the pathobiology of PanCa. The accumulation of antibody guided MNP-CUR (Targeted Nanotechnology Platform) within tumors/metastases will provide sustained release of curcumin which will regulate autocrine and paracrine signaling between PanCa cells and stromal cells. The specific aims to test this hypothesis are: 1) To investigate the effect of MNP-CUR formulation on the regulation of molecular interactions occurring within the pancreatic tumor microenvironment; 2) To evaluate therapeutic and imaging efficacy of MNP-CUR formulation in PanCa xenograft and transgenic (PDA.MUC1) mouse models; and 3) To determine the theranostic efficacy of antibody guided MNP-CUR formulation in combination with gemcitabine in clinically relevant mouse models. The overall objective of this project is to develop an innovative targeted therapeutic and imaging approach for PanCa. Findings of this project will advance diagnosis and therapy of PanCa to reduce the morbidity and mortality caused by this devastating disease.