基于αvβ3整合素途径的[cRGD-PTX]pH敏感纳米水凝胶覆膜支架提高新疆特高发疾病食管癌治疗效果及其机制研究

The esophageal cancer is a high incidence disease in China , and the esophageal cancer is also the high prevanlence diease in Xinjiang. The minorities in Xinjiang have some specail eating habits, and the high incidence may be caused by the habits. For example, the high incidence of the esophageal cancer in kazakh is very serious. The nutritional support and the effectiveness of the chemotherapy for the patients are the key issues which will affect the therapeutic effect of the esophageal cancer, especially for prolonging the survival period of patients who are in the advanced stage and can not be treated by the surgery. Angiogenesis is an important mechanism for the esophageal carcinoma invasion, and the tumor cell homing could be managed by the interaction of the abnormal expression of the integrin on the vasculature with the extracellular matrix. The hydrogel laoding the paclitaxel and the cyclic RGD is prepared, then the stent coated with the hydrogel will be constructed. The covered stent preparation can not only do good for the patients to swallow food but also helps the drug to contact with the tumor site directly. The drug could be released slowly near the tumor, and the paclitaxel could be targeted to the tumor by the interaction of the cyclic RGD peptide with the integrin αvβ3 at the same time , which will help the paclitaxel to improve the efficacy and reduce the toxic and side effects. The effectiveness of the coverd stent for the esophageal cancer will be investigated in vitro and in vivo, and the molecular mechanism of the ECM reconstruction related with the integrinαvβ3 and the Changes of the tumor microenvironment will be studied , which will help us to know how [cRGD-PTX] system interact with them .

我国是食管癌高发国家,新疆少数民族的饮食习惯影响食管癌成为新疆的特高发疾病,其中哈萨克族食管癌发病率尤高。病人的营养支持和化疗效果是影响食管癌治疗效果的核心问题，特别对延长无法采用手术治疗的中晚期病人的生存周期方面有着重要的意义。拟制备紫杉醇-cRGD自组装pH敏感纳米水凝胶进而构建覆膜含药食管支架。制备的覆膜食管支架可以方便病人进食，含药层与肿瘤部位直接接触并缓慢释放出药物，同时通过cRGD-αvβ3途径实现化疗药物对食管肿瘤细胞的抗侵袭和靶向杀伤，利用肿瘤细胞酸性环境进一步刺激载体pH响应释药，提高药物疗效并降低毒副作用。支架在治疗结束后生物降解，无需手术取出。体内外观察含药pH敏感纳米水凝胶及其覆膜支架对靶向肿瘤的杀伤效应，研究以αvβ3整合素为核心的ECM重构相重构相关的肿瘤微环境变化和分子生物学机制，了解[cRGD-PTX]多肽纳米水凝胶自组装体及其覆膜支架与以上机制的联系。

食管癌是常见的消化道肿瘤，全世界每年约增加40万病例，每年约有35万人死于食管癌，是死亡率排名第六的常见恶性肿瘤之一。食管支架置入术已成为治疗患者的食管狭窄的重要手段，随着技术的发展，生物可降解支架由于能在短期内支撑管腔，最终在体内降解，而被广泛研究。然而目前可降解食管支架只能实现物理上的机械扩张，而不能从根本达到抗肿瘤效果。为了解决以上问题，本研究制备了紫杉醇-cRGD自组装pH敏感纳米水凝胶，并利用该水凝胶成功构建了覆膜含药可降解食管支架。本研究利用固相合成法设计并合成了一系列具有pH敏感性的多肽，这些多肽能够通过自组装形成稳定的水凝胶，并且在肿瘤微环境条件下逐渐瓦解释放出紫杉醇，从而发挥抗肿瘤作用。对该多肽水凝胶进行一系列的理化性质研究，包括成胶能力，透射电镜，圆二色谱，流变学研究和体外药物释放研究，结果显示cRGD自组装pH敏感纳米水凝胶具有良好的pH响应性和可注射性，能够自组装形成致密的纤维网络结构，纤维之间相互交联从而形成稳定的水凝胶。体外药物释放实验结果表明该多肽水凝胶具有良好的药物装载能力，其释放行为具有pH依赖性。通过CCK-8法考察覆膜含药可降解食管支架对正常食管细胞的细胞相容性，结果表明该体系具有良好的生物相容性。构建小鼠食管癌模型，体内抗肿瘤研究结果表明覆膜含药可降解食管支架在肿瘤部位靶向释放紫杉醇，抑制肿瘤生长，并且对主要脏器没有毒副作用，在体内具有一定的生物安全性。我们的研究为食管癌的治疗提供了一个新的方向。