Intraperitoneal Tumor-Targeting Chemo-gene Therapy

腹膜内肿瘤靶向化疗基因治疗

• 批准号: 7537132
• 负责人: ZE LU
• 金额: $ 12.26万
• 依托单位: OPTIMUM THERAPEUTICS, LLC
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-17 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7537132
• 关键词: 3-Dimensional; Abdomen; Accounting; Advanced Malignant Neoplasm; Affect; Apoptosis; Binding; Bulky Disease; Caliber; Cancer Patient; Cells; Characteristics; Charge; Chemicals; Clinical Trials; Collaborations; Colorectal; Condition; Data; Depth; Dose; Doxorubicin; Drug Formulations; Endocytosis; Endosomes; Excision; Exposure to; Genes; Goals; Greater sac of peritoneum; Half-Life; Human; Intravenous; Laboratories; Learning; Lipids; Liposomes; Liver; Location; Lysosomes; Malignant Neoplasms; Malignant neoplasm of ovary; Measures; Medical; Modification; Neoplasm Metastasis; Nucleotides; Organ; Ovarian; Paclitaxel; Pancreas; Particulate; Penetration; Peritoneal; Peritoneal Fluid; Pharmaceutical Preparations; Phase I Clinical Trials; Phase III Clinical Trials; Property; Proteins; Public Health; RNA; RNA Interference; Rate; Research Design; Reticuloendothelial System; Safety; Sampling; Site; Small RNA; Solid Neoplasm; South Carolina; Stomach; Surface; Technology; Testing; Therapeutic; Therapeutic Agents; Time; Toxic effect; Transfection; Treatment Efficacy; Universities; Vertebral column; Weight; base; density; gene therapy; improved; in vivo; interstitial; intraperitoneal; intraperitoneal therapy; monolayer; nanoparticle; neoplastic cell; novel therapeutics; nuclease; particle; peritoneal cancer; research study; size; success; survivin; tumor; uptake; vector

DESCRIPTION (provided by applicant): 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.

描述（申请人提供）：由腹腔内器官（胰腺、卵巢、结肠、胃、肝）引起的癌症每年新增病例超过20万例。腹腔也是源自腹外部位的晚期癌症转移的常见部位。腹腔内（IP）治疗提供了肿瘤靶向优势，通过最大限度地暴露于腹膜肿瘤，同时最大限度地减少其暴露于宿主器官。此外，在卵巢癌患者中已经证实了IP化疗的益处。然而，IP基因治疗的疗效尚不明确。从卵巢癌试验中得到的一个重要教训是，在体积较大的疾病中，IP化疗的疗效有限。这表明，IP化学-基因治疗的成功取决于克服肿瘤间质中药物和基因载体运输的障碍。我们的实验室已经建立了高肿瘤细胞密度作为肿瘤内运输的关键屏障，并开发了肿瘤启动技术来促进实体肿瘤中的颗粒传递和间质运输。该技术利用紫杉醇诱导细胞凋亡，扩大间隙，从而促进肿瘤基质中颗粒更大的渗透和更均匀的分散。本应用程序的目标是利用基因治疗和颗粒递送平台的最新进展来开发腹腔（IP）肿瘤靶向化学基因治疗。在初步研究的基础上，我们提出应用肿瘤启动微粒子（tumor priming microparticles， TPM）技术，利用小干扰RNA （small interference RNA, siRNA）增强肿瘤间质渗透和分散，开发IP基因治疗。在本项目中，我们将首先确定使用TPM作为肿瘤选择性递送平台促进脂质体siRNA进入肿瘤的递送和渗透的可行性。该研究将使用siGLO进行，这是一种22核苷酸的荧光RNA双工，不会干扰或与功能性siRNA竞争。实验结果将确定阳离子脂质体siGLO的最佳配方，并确定使用IP TPM促进siRNA在IP肿瘤中的渗透和分散的条件。我们将进一步测试所建立的技术是否可以提高survivin siRNA治疗腹膜内肿瘤的疗效。公共卫生相关性：目前的建议是开发一种新的治疗方法来治疗癌症，特别是腹膜腔的癌症。