Intraperitoneal Tumor-Targeting Chemo-gene Therapy

描述(申请人提供)：由腹膜腔内器官(胰腺、卵巢、结直肠、胃、肝)引起的癌症每年新增病例超过20万例。腔内也是来自腹外的晚期癌症转移的常见部位。通过最大限度地增加治疗药物对腹膜肿瘤的暴露，同时最小化其对宿主器官的暴露，腹膜内(IP)治疗提供了一种肿瘤靶向优势。此外，IP化疗的好处已在卵巢癌患者中得到证实。然而，IP基因治疗的疗效还不是很确定。从卵巢癌试验中学到的一个重要教训是，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药物和基因载体在肿瘤间质中转运的障碍。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，并自那以后开发了肿瘤启动技术来促进实体瘤中的颗粒输送和间质转运。这项技术使用紫杉醇来诱导细胞凋亡，扩大间质空间，从而促进颗粒在肿瘤基质中的更大渗透和更均匀的分散。这一应用的目标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肿瘤靶向化疗基因治疗。根据初步研究的结果，我们建议应用肿瘤启动微粒(TPM)技术来开发使用小干扰RNA(SiRNA)的IP基因治疗，以增强对肿瘤间质的渗透和分散。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的可行性，以促进脂质体siRNA的递送和渗透到肿瘤中。这项研究将使用Siglo进行，Siglo是一种荧光22核苷酸RNA双链，不干扰或竞争功能siRNA。实验结果将确定阳离子脂质体Siglo的最佳处方，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提高Survivin siRNA在治疗腹膜内肿瘤方面的疗效。公共卫生研究报告：目前的建议是开发一种新的治疗方法来治疗癌症，尤其是腹腔癌。

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.