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.
Thesaurus Terms: (8s-Cis)-10-[(3-Amino-2,3,6-Trideoxy-Alpha-L-Lyxo-Hexopyranosyl)Oxy]-7,8,9,10-Tetrahydro-6,8,11-Trihydroxy-8-(Hydroacetyl)-1-Methoxy-5,12-Naphthacenedione; 14-Hydroxydaunomycin; 3-D; 3-Dimensional; 5,12-Naphthacenedione, 10-((3-Amino-2,3,6-Trideoxy-Alpha-L-Lyxo-Hexopyranosyl)Oxy)-7,8,9,10-Tetrahydro-6,8,11-Trihydroxy-8-(Hydroxyacetyl)-1-Methoxy-, (8s-Cis)-; Api4; Abdomen; Abdominal; Abscission; Accounting; Adriamycine; Advanced Cancer; Advanced Malignant Neoplasm; Affect; Anzatax; Apoptosis; Apoptosis Inhibitor 4; Apoptosis Inhibitor Survivin; Apoptosis Pathway; Ascitic Fluid; Asotax; Birc5; Baculoviral Iap Repeat-Containing 5 (Survivin); Baculoviral Iap Repeat-Containing Protein 5; Binding; Binding (Molecular Function); Bristaxol; Bulky Disease; Caliber; Cancer Patient; Cancer Of The Ovary; Cancer Of The Peritoneum; Cancers; Cell Death, Programmed; Cell Density; Cells; Characteristics; Charge; Chemicals; Clinical Trials; Clinical Trials, Phase I; Clinical Trials, Phase Iii; Clinical Trials, Unspecified; Collaborations; Colon Or Rectum; Colorectal; Dox; Data; Density, Cell; Diameter; Dose; Doxorubicin; Doxorubicina; Drug Formulations; Drugs; Epr-1; Early-Stage Clinical Trials; Endocytosis; Endosomes; Excision; Exposure To; Extirpation; Formulation; Formulations, Drug; Gastrointestinal Tract, Pancreas; Gene Products, Rna; Gene Transfer Clinical; Gene Transfer Procedure; Gene-Tx; Genes; Genetic Intervention; Goals; Greater Sac Of Peritoneum; Half-Life; Half-Lifes; Human; Human, General; Hydroxyl Daunorubicin; Hydroxyldaunorubicin; Iap4; Intervention, Genetic; Intraperitoneal Chemotherapy; Intravenous; Laboratories; Learning; Lipids; Liposomal; Liposomes; Liver; Location; Lysosomes; Malignant Neoplasms; Malignant Ovarian Neoplasm; Malignant Ovarian Tumor; Malignant Peritoneal Neoplasm; Malignant Tumor; Malignant Tumor Of The Ovary; Malignant Neoplasm Of Ovary; Man (Taxonomy); Man, Modern; Measures; Medical; Medication; Metastasis; Metastasize; Metastatic Neoplasm; Metastatic Tumor; Modification; Molecular Biology, Gene Therapy; Molecular Interaction; Neoplasm Metastasis; Nucleotides; Organ; Ovarian; Paclitaxel; Paclitaxel (Taxol); Pancreas; Pancreatic; Particulate; Penetration; Peritoneal; Peritoneal Cavity; Peritoneal Effusion; Peritoneal Fluid; Pharmaceutic Preparations; Pharmaceutical Preparations; Phase 1 Clinical Trials; Phase 3 Clinical Trials; Phase I Clinical Trials; Phase I Study; Phase Iii Clinical Trials; Post-Transcriptional Gene Silencing; Post-Transcriptional Gene Silencings; Posttranscriptional Gene Silencing; Posttranscriptional Gene Silencings; Praxel; Property; Property, Loinc Axis 2; Proteins; Public Health; Quelling; Rna; Rna Interference; Rna Silencing; Rna Silencings; Rna, Non-Polyadenylated; Rnai; Receptosomes; Removal; Research Design; Reticuloendothelial System; Ribonucleic Acid; Safety; Sampling; Secondary Neoplasm; Secondary Tumor; Sequence-Specific Posttranscriptional Gene Silencing; Site; Small Rna; Solid Neoplasm; Solid Tumor; South Carolina; Spinal Column; Spine; Stomach; Study Type; Surface; Surgical Removal; Taxol; Taxol (Old Nsc); Taxol A; Taxol Konzentrat; Technology; Testing; Therapeutic; Therapeutic Agents; Therapy, Dna; Time; Toxic Effect; Toxicities; Transfection; Treatment Efficacy; Tumor Cell; Tumor Cell Migration; Universities; Vertebral Column; Weight; Backbone; Base; Body System, Hepatic; Cancer Metastasis; Clinical Investigation; Drug/Agent; Experiment; Experimental Research; Experimental Study; Gastric; Gene Product; Gene Therapy; Genetic Therapy; Improved; In Vivo; Interstitial; Intraperitoneal; Intraperitoneal Therapy; Malignancy; Monolayer; Nano Particle; Nanoparticle; Neoplasm/Cancer; Neoplastic Cell; Novel Therapeutic Intervention; Nuclease; Organ System, Hepatic; Ovarian Cancer; Particle; Peritoneal Cancer; Phase 1 Study; Phase 1 Trial; Phase 3 Study; Phase 3 Trial; Phase I Trial; Phase Iii Trial; Protocol, Phase I; Protocol, Phase Iii; Public Health Medicine (Field); Research Study; Resection; Study Design; Study, Phase Iii; Success; Survivin; Therapeutic Efficacy; Therapeutically Effective; Tumor; Uptake; Vector
