Intraperitoneal Tumor-Targeting Chemo-gene Therapy

描述（由申请人提供）：腹膜腔内器官（胰腺、卵巢、结直肠、胃、肝）引起的癌症每年新发病例超过20万例。腹腔也是源自腹腔外部位的晚期癌症转移的常见部位。腹膜内（IP）治疗提供了肿瘤靶向优势，通过最大限度地增加治疗剂对腹膜肿瘤的暴露，同时最大限度地减少其对宿主器官的暴露。此外，IP化疗的益处已在卵巢癌患者中得到证实。然而，IP基因治疗的功效尚不清楚。从卵巢癌试验中吸取的一个重要教训是IP化疗在巨大疾病中的疗效有限。这表明IP化疗-基因治疗的成功取决于克服肿瘤组织中药物和基因载体转运的障碍。我们的实验室已经建立了高肿瘤细胞密度作为肿瘤内转运的关键屏障，并开发了肿瘤引发技术，以促进实体瘤中的颗粒递送和间质转运。该技术使用紫杉醇诱导细胞凋亡，扩大间质空间，从而促进颗粒在肿瘤基质中更大的渗透和更均匀的分散。本申请的目的是利用基因治疗和微粒递送平台的最新进展来开发腹膜内（IP）肿瘤靶向化学基因治疗。基于初步的研究结果，我们提出了应用肿瘤引发微粒（TPM）技术，开发IP基因治疗，使用小干扰RNA（siRNA），以提高在肿瘤细胞中的渗透和分散。在这个项目中，我们将首先确定使用TPM作为肿瘤选择性递送平台以促进脂质体siRNA递送和渗透到肿瘤中的可行性。研究将使用siGLO进行，siGLO是一种荧光22核苷酸RNA双链体，不干扰功能性siRNA或与之竞争。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肿瘤中渗透和分散的条件。我们将进一步测试已建立的技术是否可以增强Survivin siRNA治疗腹腔内肿瘤的疗效。公共卫生释放：目前的建议是开发一种新的治疗方法来治疗癌症，特别是腹膜腔癌症。

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.