整合素αvβ6靶向PLGA纳米微球在结肠癌肝转移化疗及影像诊断中的作用研究

Colon cancer has an evident tendency of liver metastasis, which results in a poor prognosis of colon cancer. Targeted PLGA nanoparticles as a nano-carrier system can deliver drugs or contrast agents to the tumor location, enhancing tumor chemo-sensitivity and tumor imaging. This project, which is based on our long-term research of the relationship between integrin αvβ6 and colon cancer, is to explore new means of liver cancer targeting the diagnosis and treatment of colon cancer using integrin αvβ6 as a target for PLGA nanoparticles. Preliminary data indicated that the expression of integrin αvβ6 in liver metastasis of colon cancer was significantly increased. Furthermore, we found that the integrin αvβ6 targeting immunoliposomes had significant specificity on integrin αvβ6-positive colon cancer, and could enhance the efficacy of chemotherapy in colon cancer. Therefore, we deduce that αvβ6-targeting PLGA nanoparticles could deliver drugs or contrast agents specifically to liver metastases of colon cancer and promote the enrichment of drugs or contrast agents, which finally enhance the efficacy of chemotherapy and the imaging effect. In this study, we intend to investigate the role of αvβ6 targeting PLGA nanoparticles in the diagnosis and chemotherapy in liver metastases of colon cancer through cell experiments and the model of liver metastasis. Our research will provide a potential reference for the target diagnosis and chemotherapy in liver metastases of colon cancer.

结肠癌具有明显的肝转移倾向，肝转移是影响结肠癌预后的主要因素。靶向PLGA纳米微球作为纳米载体能够将化疗药物或造影剂特异性转运至肿瘤病灶，增强肿瘤化疗敏感性或显影效果。本课题是在我们长期对整合素αvβ6与结肠癌关系研究的基础上，以αvβ6为靶点制备PLGA纳米微球，探寻结肠癌肝转移靶向诊疗新手段。前期实验证实结肠癌肝转移组织中αvβ6的表达明显升高；我们还发现以αvβ6为靶点的脂质体载体对αvβ6阳性的结肠癌具有显著特异性，并能提高结肠癌的化疗效果。由此我们推断，αvβ6靶向PLGA纳米微球可将化疗药物或造影剂特异性的转运至结肠癌肝转移病灶，促进药物或造影剂在肝转移部位富集，提高化疗疗效和增强显影效果。本研究拟通过细胞实验，以及利用结肠癌肝转移模型全面深入的研究αvβ6靶向PLGA纳米微球在结肠癌肝转移化疗及影像诊断中的作用，为建立以αvβ6为靶点的结肠癌肝转移诊疗提供实验基础及理论依据。

结肠癌是最常见的消化道恶性肿瘤之一，约20%的结肠患者在确诊时就已发生肝转移，并且预后较差。结肠癌肝转移的研究一直是世界肿瘤研究领域的一大难点。本课题在前期关于整合素αvβ6与结肠癌恶性生物学行为关系研究基础上，对整合素肝转移机制及以整合素αvβ6为靶点的结肠癌肝转移治疗的系统研究。研究发现整合素αvβ6与IL-6在结肠癌组织中高表达，二者具有明显的相关性；整合素αvβ6与IL-6的表达与结肠癌的T分期、N分期、TNM分期以及细胞分化程度密切相关；二者表达的患者生存期明显缩短，可以作为结肠癌预后不良的独立指标。作为与整合素αvβ6同亚型的整合素，整合素αvβ8同样在结肠癌组织中高表达，并且整合素αvβ8的表达与结肠癌的T分期、N分期、TNM分期以及细胞分化程度密切相关；其表达的患者生存期明显缩短，可以作为结肠癌预后不良的独立指标。不仅如此，结肠癌细胞中的整合素αvβ8能够通过与LAP结合从而活化TGF-β1，最终活化后的TGF-β1促进结肠癌细胞的迁移侵袭。在整合素αvβ6为靶点的结肠癌肝转移治疗研究中，我们发现整合素αvβ6靶向PLGA纳米微球对结肠癌细胞具有明显的特异性识别，能够显著提高5-FU对结肠癌细胞的抑制作用。同时，体内实验证实，整合素αvβ6靶向PLGA纳米微球装载5-FU后对结肠癌肝转移病灶具有明显的靶向性，且具有显著的抗肿瘤效果。本研究为整合素在肠癌细胞迁移运动机制的研究，以及为以αvβ6为靶点的结肠癌肝转移靶向治疗提供了理论依据。