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.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Small Business Innovation Research Grants (SBIR) - Phase I (R43)
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Special Emphasis Panel (ZRG1-ONC-L (10))
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Andalibi, Ali
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Optimum Therapeutics, LLC
San Diego
United States
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Wang, Jie; Lu, Ze; Wang, Junfeng et al. (2015) Paclitaxel tumor priming promotes delivery and transfection of intravenous lipid-siRNA in pancreatic tumors. J Control Release 216:103-10
Wang, Jie; Lu, Ze; Yeung, Bertrand Z et al. (2014) Tumor priming enhances siRNA delivery and transfection in intraperitoneal tumors. J Control Release 178:79-85
Li, Yinghuan; Wang, Jie; Wientjes, M Guillaume et al. (2012) Delivery of nanomedicines to extracellular and intracellular compartments of a solid tumor. Adv Drug Deliv Rev 64:29-39
Li, Yinghuan; Wang, Jie; Gao, Yue et al. (2011) Relationships between liposome properties, cell membrane binding, intracellular processing, and intracellular bioavailability. AAPS J 13:585-97
Wang, Jie; Lu, Ze; Gao, Yue et al. (2011) Improving delivery and efficacy of nanomedicines in solid tumors: role of tumor priming. Nanomedicine (Lond) 6:1605-20
Wong, Ho Lun; Shen, Zancong; Lu, Ze et al. (2011) Paclitaxel tumor-priming enhances siRNA delivery and transfection in 3-dimensional tumor cultures. Mol Pharm 8:833-40
Lu, Ze; Wang, Jie; Wientjes, M Guillaume et al. (2010) Intraperitoneal therapy for peritoneal cancer. Future Oncol 6:1625-41
Wang, Jie; Lu, Ze; Wientjes, M Guillaume et al. (2010) Delivery of siRNA therapeutics: barriers and carriers. AAPS J 12:492-503