Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis with the poorest 5-year survival of all gastrointestinal malignancies. Although numerous chemotherapeutic agents have been effective in inhibiting growth of PDAC in vitro or in mice, these agents fail when administered to human subjects in clinical trials. There are two principle reasons for this lack of effectiveness. First, it is difficult to provide an adequate dos of chemotherapeutic agents and avoid systemic toxicity because most agents used for PDAC are not 'tumor- selective', in that they fail to target specific proteins or receptors on the cancer surface. Without tumor specificity, parenteral chemotherapy administration leads to a low concentration of potentially effective agents reaching the cancer and a high incidence of toxicity to other organs. Second, certain promising treatments, such as RNAi, are broken down by nucleases in the blood stream;hence, these compounds have to be given in higher doses or protected from the environment in order to achieve effectiveness in disrupting tumor growth. Regarding targeting, characterization of tumor-specific receptor antigens has significantly improved cancer therapeutics in many malignancies. We have identified a membrane bound growth receptor in human pancreatic cancer cells called the cholecystokinin or CCK- receptor. Using this target, we have developed nontoxic, physiologic calcium phosphosilicate nanoparticles (NPs) with enhanced tumor uptake and delivery compared to untargeted vehicles. Our research team has developed a means to encapsulate either gene therapy or chemotherapeutic agents in NPs, representing a significant improvement over traditional methods. With regard to gene therapy, we have chosen two target genes that have been shown to drive growth of PDAC: gastrin and mutated Kras. We hypothesize that treatment of PDAC may be significantly improved through the application of nanotechnology using tumor-selective delivery vehicles in which drugs or gene therapy are protected through encapsulation. In order to test this hypothesis we plan to carry out the following Specific aims: 1) Optimize a new generation of PDAC-specific nanoparticles and verify improved encapsulation of therapeutic agents using single molecule spectroscopy and 2) Determine pharmacokinetic parameters for targeted NPs including the maximum tolerated dose, biodistribution and bioavailability, and 3) Examine the safety and efficiency of target-specific loaded nanoparticles to inhibit growth of pancreatic cancer cells in vitro and in vivo. Our long term goal is to develop novel effective strategies to improve therapy and survival of patients with this devastating malignancy.
Pancreatic cancer remains one if not the most resistant cancers to standard chemotherapy and has the worse prognosis of all solid tumors with a 5-year survival of less than 1%. Our research team includes a multidisciplinary approach of experts who have developed nontoxic, physiologic, biocompatible nanoparticles that are target specific in that they selectively bind to and are taken up into pancreatic cancer cells through cancer cell receptors. We have successfully filled these nanoparticles with tumor-specific gene therapies or chemotherapeutic agents and plan to test their safety and efficacy in a preclinical setting.
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