以TF为靶点的靶向化疗轭合物5-Fu- HPEG- SPTT对结直肠癌的作用及其机制

Tumor vascular endothelial cell and cancer cell in colorectal cancer tumor have the specific overexpression of tissue factor(IF) receptor, what is more ,the overexpression of IF involves in colorectal cancer's canceration. So IF is "stem character" marker in cancer tumor vascular endothelial cell and cancer cell.We want to adopte a high affinity seven peptides as targete fragment, which is screened by phage technology, and couple with 5-Fluorouracil drug(5-Fu) to form 5-Fu-SPTT. Finally, conjugating to the surface of nano drug carriers, hyperbranchedpolymer-polyethylene glycol(HPEG), to form 5-Fu-SPPT-HPEG. The 5-Fu-SPPT-HPEG is a targeting chemotherapy conjugation, which can express 5-Fu and SPTT, which can release the cytotoxic and block the signal transdution of TF-PAP-1 to apoptosis and necrosis, respectively.In this case, we can achieve the goal of killing tumor cells and tumor vascular endothelial cells. This study will provide new idea and method to the anti-vascular's target chemotherapy of colorectal cancer.

结直肠癌肿瘤血管内皮细胞和癌细胞均有Tissue Factor（TF）受体特异性过度表达，TF过度表达参与了结直肠癌变过程，是结直肠癌细胞和肿瘤血管内皮细胞"干性"标志物。本课题选择纳米药物载体聚乙二醇接枝超枝化聚合物（HPEG）为药物输送平台，HPEG内部空腔包埋化疗药物5-氟尿嘧啶（5-Fu），然后利用我们采用噬菌体展示技术筛选的TF靶向小分子活性肽SPTT修饰载体表面，构建一种以TF为靶点的抗结直肠癌靶向化疗轭合物5-Fu- SPTT- HPEG；轭合物通过TF靶向肽的靶向作用，与表达TF的结直肠癌细胞和肿瘤血管内皮细胞特异性结合，轭合物在细胞内酸性环境下释放出5-Fu和SPTT，二者分别通过细胞毒素作用和阻断TF-PAR-1信号传导通路引起细胞凋亡和坏死，实现同时杀伤肿瘤细胞和肿瘤血管内皮细胞目的。该研究可为结直肠癌靶向化疗提供新的思路和方法。

结直肠癌肿瘤血管内皮细胞和癌细胞均有组织因子（Tissue Factor，TF）受体特异性过度表达，TF过度表达参与了结直肠癌变过程，是结直肠癌细胞和肿瘤血管内皮细胞“干性”标志物。本课题选择纳米药物载体聚乙二醇接枝超枝化聚合物（HPEG）为药物输送平台，HPEG内部空腔包埋化疗药物5-氟尿嘧啶（5-Fu），然后采用噬菌体展示技术筛选的TF靶向小分子活性肽SPTT修饰载体表面，构建一种以TF为靶点的抗结直肠癌靶向化疗轭合物5-Fu- SPTT- HPEG；轭合物通过TF靶向肽的靶向作用，与表达TF的结直肠癌细胞和肿瘤血管内皮细胞特异性结合，轭合物在细胞内酸性环境下释放出5-Fu和SPTT，二者分别通过细胞毒作用和阻断TF-PAR-1信号传导通路引起细胞凋亡和坏死，实现同时杀伤肿瘤细胞和肿瘤血管内皮细胞目的。该研究可为结直肠癌靶向化疗提供新的思路和方法。