Cancer arising from organs within the peritoneal cavity (pancreatic, ovarian, colorectal, gastric, liver) accounts for more than 200,000 new cases annually. The cavity is also a common site for metastasis of advanced cancer originating from extra-abdominal sites. Intraperitoneal (IP) therapy provides a tumor targeting advantage, by maximizing the exposure of therapeutic agents to peritoneal tumors while minimizing its exposure to the host organs. Furthermore, the benefits of IP chemotherapy have been demonstrated in ovarian cancer patients. However, the efficacy of IP gene therapy is less well established. An important lesson learned from the ovarian cancer trials is the limited efficacy of IP chemotherapy in bulky disease. This indicates that the success of IP chemo-gene therapy is predicated on overcoming the barriers to drug and gene vector transport in tumor interstitium. Our laboratory has established high tumor cell density as a key barrier to intra-tumoral transport, and has since developed the tumor priming technology to promote particulate delivery and interstitial transport in solid tumors. This technology uses paclitaxel to induce apoptosis, expand the interstitial space, and consequently promote greater penetration and more even dispersion of particulates in tumor matrix. The goal of this application is to use the recent advances in gene therapy and particulate delivery platforms to develop intraperitoneal (IP) tumor-targeting chemo-gene therapy. Based on the result of preliminary study, we propose to apply the tumor priming microparticles (TPM) technology to develop IP gene therapy using small interference RNA (siRNA) to enhance penetration and dispersion in the tumor interstitium. In this project, we will first determine the feasibility of using TPM as a tumor-selective delivery platform to promote delivery and penetration of liposomal siRNA into tumors. The studies will be conducted using siGLO, a fluorescent 22 nucleotide RNA duplex that does not interfere or compete with functional siRNA. The experiment results will identify the optimal formulation of cationic liposomal siGLO, and define the conditions for using IP TPM to promote siRNA penetration and dispersion in IP tumors. We will further test whether the established technologies can enhance the therapeutic efficacy of survivin siRNA in the treatment of intraperitoneal tumor. PUBLIC HEALTH RELEVEANCE:The current proposal is to develop a novel therapeutic approach to treat cancer, with a focus on cancers of the peritoneal cavity in particular. ? ? ?
