TCP-1靶向多肽在胃癌肿瘤血管上的特异靶点鉴定及其靶向传输抗肿瘤药物的研究

项目名称： TCP-1靶向多肽在胃癌肿瘤血管上的特异靶点鉴定及其靶向传输抗肿瘤药物的研究

项目编号： No.81473269

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 曹之宪

作者单位： 常州大学

项目金额： 50万元

中文摘要： 本研究旨在研究靶向TCP-1多肽在胃癌肿瘤上的结合位点，以及将其开发应用为肿瘤的生物指标和增强化疗药物的靶标。利用噬菌体展示实验，我们分离鉴定了一个小分子多肽并命名为TCP-1。该多肽特异性地靶向于由人胃癌细胞株MKN45诱导的原位胃癌组织的血管上，而非其他正常组织器官。这些结果表明肿瘤血管上存在某个特异的靶点。该靶点可被用作胃癌早期检测的生物指标及化疗药物靶向传输的靶点。我们将运用蛋白质交互作用沉淀试验（Pull-down assay）寻找到TCP-1在MKN45细胞膜上的特异靶点，并深入研究该靶点。该靶点的鉴定将会给胃癌的治疗带来新的方向──利用TCP-1多肽作为药物载体靶向给药。本项目中，我们将运用基因重组技术耦合TCP-1多肽和TNF-alpha以期开发出新的靶向制剂用于治疗胃癌等癌症。TCP-1多肽在肿瘤组织上的结合位点的鉴定将有助于靶向治疗胃癌，也会给癌症病人的个体化用药。

中文关键词： 作用机制；靶向多肽；胃癌；结合位点；肿瘤坏死因子

英文摘要： The aims of this study are to identify the binding molecule in gastric tumor blood vessels and develop a biomarker and a drug target to enhance chemotherapy. Using phage display biopanning technology, our previous study identified a small peptide (CTPSPFSHC) termed TCP-1 that specifically bound to blood vessels of tumors induced orthotopically by a human gastric cancer cell line (MKN45) but not to other tissues or subcutaneous MKN45 xenograft in mice. These findings suggest that there is a specific binding site in tumor blood vessels. With these findings, identification of this molecule could have significant clinical implications in the treatment of gastric cancer (GC). In this regard, the binding molecule could be a specific biomarker for GC and used as a molecule for drug targeting during chemotherapy. Our preliminary data also showed that the same binding capacity of TCP-1 was found on the cell membrane of MKN45. With this important information, we shall use TCP-1 to pull down the binding molecule from these membranes, in order to identify and also define the properties of this molecule. The identity of this binding molecule will be confirmed in the gastric tumor vasculature in animals. This molecule will be a guide for GC treatment using TCP-1 as a carrier for anticancer drugs in targeted drug therapy. In this study, we shall employ tumor necrosis factor alpha (TNF-alpha) which has been identified to have potent anti-angiogenic activity but possess severe systemic toxicity. We shall couple TCP-1 with TNF-alpha using recombinant technology in the hope that new anticancer agents for GC could be developed. This TCP-1/TNF-alpha could also enhance the efficacy of other clinical anticancer drugs, e.g. 5-fluorouracil and irinotecan through destruction and removal the vascular barrier and/or stabilization of the tumor vascular system. These novel therapeutic strategies will not only enhance the anticancer action of TNF-alpha on tumor blood vessels but also produce synergistic effects with other anticancer drugs together with lower systemic toxicity. This could greatly increase the viability of chemotherapy in humans. Identification of the binding molecule for TCP-1 at tumors is useful for targeted and guided therapy for GC. This serves as a good example for personalized medicine in cancer patients.

英文关键词： Mechanisms;Targeted peptide;Gastric cancer;Binding molecules;TNF-alpha