抗血管新生是恶性肿瘤治疗的重要方法之一。VEGF和FGF2是肿瘤血管新生过程中关键生长因子，其信号通路依赖于细胞膜表面的硫酸乙酰肝素（HS）介导。HS类似物是VEGF/FGF2介导血管新生的潜在抑制剂。我们前期研究发现HS结构类似物低分子量岩藻糖基化硫酸软骨素（FCS）可显著抑制肿瘤血管新生，然而其系统的构效关系和作用机制尚未阐明。本课题以不同结构FCS为原料，通过化学降解和定向修饰构建FCS特征寡糖库，以VEGF和FGF2为靶点，基于计算机模拟、糖芯片和SPR等技术探讨FCS寡糖与VEGF/FGF2的作用位点和作用模式，基于细胞和斑马鱼模型进行FCS寡糖抗肿瘤和血管新生活性筛选，探讨FCS寡糖靶向VEGF/FGF2抑制肿瘤血管新生的构效关系，获得抗肿瘤FCS寡糖先导化合物，进一步在小鼠模型上进行抗乳腺癌转移的药效评价，并阐明作用机制，为靶点明确的抗肿瘤FCS寡糖药物的开发奠定基础。

Anti-tumor angiogenesis therapy is one of the important methods in the comprehensive treatment of malignant tumors. Vascular endothelial growth factor (VEGF) and fibroblast growth factor 2(FGF2) are the key growth factors in tumor angiogenesis, and their signaling activations are mediated by heparan sulfate (HS). The HS analogs are the potential inhibitors for VEGF/FGF2 mediated tumor angiogenesis. Our previous research showed the low molecular weight holothurian fucosylated chondroitin sulfate (FCS), a kind of HS analogs, could exert antitumor activity by inhibiting angiogenesis. However, the comprehensive structure-activity relationship and mechanism of FCS for anti-tumor angiogenesis has not yet been elucidated. In this study, the natural FCS extracted from different holothurian is depolymerized by chemical degradation and directional chemical modification. Series of oligosaccharides with clear structural properties are obtained to construct a characteristic oligosaccharide library. Furthermore, computer molecular simulation, glycochips and SPR are employed to study the interaction site and pattern of FCS oligosaccharides and VEGF/FGF2. Besides, FCS oligosaccharides with anti-tumor angiogenesis activity are screened and evaluated based on the constructed cell and zebrafish model. These results will elucidate the structure-activity relationship and mechanism of FCS oligosaccharides for anti-tumor angiogenesis. Finally, the screened lead compounds of FCS oligosaccharides will be tested on mouse model of breast cancer metastasis to evaluate their efficacy and mechanism. This study provides theoretical basis for the development of targeted anti-tumor marine FCS oligosaccharide drugs.