Pancreatic cancer is the fourth leading cause of cancer death in the US and remains the most difficult cancer type to treat with less than 5% of patients surviving 5 years after diagnosis. Chemotherapy and radiotherapy are the only options for these patients. However, the efficacy of systemic chemotherapy is limited by poor efficiency in the delivery and systemic toxicity. Recent research in personalized oncology has concentrated on tumor targeted delivery and controlled release of therapeutic agents with assistances of non-invasive imaging methods to monitor the delivery and accumulation of the drugs in the tumor and to assess the therapeutic response. In this project, we propose to develop and test a multi-functional imaging- delivery magnetic nanoparticle platform that combines the capabilities of demonstrated magnetic resonance imaging (MRI) contrast enhancement, receptor specific tumor targeting and optimized drug loading and release for MRI-guided systemic delivery of chemotherapy drug, gemcitabine, into pancreatic tumors. Our Specific Aim 1 focuses on the design, preparation and characterization of MRI-capable nanoparticles coated with functionalized anti-fouling stealth polymers that can conjugate targeting ligands and may reduce non-specific uptake of nanoparticles by normal tissues for improved tumor targeting efficiency. We will develop methods that can conjugate gemcitabine onto the tumor targeting nanoparticles for enzyme-activated intracellular release. The drug-nanoparticle complex will target the urokinase plasminogen activator receptor (uPAR), a cellular receptor highly expressed in pancreatic cancer and active tumor stromal cells, to facilitate the intratumoral and subcellular delivery of gemcitabine. With the goal of translating the proposed magnetic nanoparticle imaging-delivery platform into clinical applications, we will investigate the biodistribution, systemic toxicity and pharmacokinetics of this delivery platform in normal and tumor bearing mice. In Aim 2, we will develop novel MRI approaches that are designed for specific and sensitive detection of magnetic nanoparticle delivery vehicles in vivo. For MRI guided drug delivery applications, our objective is to design and test a set of MRI methods, such as ultra-short TE imaging, that not only enable us to track and follow the delivery vehicles with a high sensitivity and better visualization but also provide quantitative information on intra-tumoral delivery efficiency. New MRI methods to assess the tumor response to treatment will also be tested. In Aim 3, we will evaluate intratumoral distribution of nanoparticles, investigate their tumor targeted therapeutic effect, test and optimize the imaging capabilities of following and quantifying the delivery and accumulation of the drug in the targeted tumors as well as monitoring response to therapy in pancreatic cancer animal models using MRI.
NIH ExPorter
NIH ExPorter