纳米金结合恩度使肝癌血管正常化及其机制

Repair of structural and functional abnormalities to normalize tumor vasculature can effectively transport oxygen and drugs to tumor cells and improve the efficacy of radiotherapy and chemotherapy. Currently, induced normalization of tumor vasculature has become a novel anti-tumor ideas. Studies have shown that Endostar can induce tumor vascular normalization, but its specificity is low. Gold nanoparticles as drug carriers can specifically target abnormal tumor vasculature, and our preliminary study showed that gold nanoparticles themselves can normalize transplanted hepatocellular carcinoma vasculature. So, whether gold nanoparticles can effectively combine Endostar induced normalization of tumor blood vessels and significantly improve the efficacy of chemotherapy, it is worth further study.The project intends to study in the early based on hepatocellular carcinoma xenograft model in nude mice, the first find of gold nanoparticles alone and load Endostar hepatocellular carcinoma vascular normalization window by small animal in vivo imaging combined with immunohistochemistry technique; further study gold nanoparticles alone and combined with Endostar improve the function of vascular normalization of hepatocellular carcinoma chemotherapeutic drug efficacy; Finally, quantitative proteomics technology systems to detect the expression of vascular normalization of hepatocellular carcinoma associated molecular changes, a comprehensive analysis of individual gold nanoparticles and load of endostatin molecule vascular normalization of hepatocellular carcinoma mechanisms. The present study would provide a new avenues into improving the efficacy of comprehensive cancer treatment.

修复结构和功能异常的肿瘤血管使其正常化，可有效地运输氧和药物到肿瘤细胞，提高放化疗疗效。目前，诱导肿瘤血管正常化已成为一种新颖的抗肿瘤思路。有研究显示恩度可以诱导肿瘤血管正常化，但其特异性低。纳米金作为药物载体可特异性靶向异常的肿瘤血管，而我们初步研究表明，纳米金本身也可使肝癌移植瘤血管正常化。那么，纳米金与恩度联合应用是否可有效的诱导肿瘤血管正常化并显著提高化疗疗效，值得进一步研究。本项目拟在前期研究基础上，在裸鼠肝癌移植瘤模型中，首先通过小动物活体成像结合免疫组化技术找到纳米金单独及结合恩度使肝癌血管正常化时间窗；进一步研究纳米金单独及结合恩度使肝癌血管正常化提高化疗药物疗效的功能；最后，结合定量蛋白质组学技术系统检测肝癌血管正常化相关分子表达变化，综合分析纳米金单独及结合恩度调节肝癌血管正常化机制。这将为提高肿瘤综合治疗疗效开辟新的途径。

修复结构和功能异常的肿瘤血管使其正常化，可有效地运输氧和药物到肿瘤细胞，提高放化疗疗效。本项目成功合成并鉴定纳米金-恩度复合体，体内实验结果表明，纳米金-恩度复合体能够提高恩度在小鼠肝癌移植瘤组织的聚集，增强恩度的肿瘤靶向性。纳米金-恩度复合体可以通过增强肿瘤血管完整性来降低血管通透性，进而增加肿瘤血流灌注，改善肿瘤组织缺氧，诱导短暂的肿瘤血管正常化。在肿瘤血管正常化时间窗内，联合5-氟尿嘧啶能进一步提高化疗疗效。其相关机制为纳米金-恩度复合体通过抑制血管内皮生长因子165和前梯度蛋白2信号通路，具体通过调节缺氧诱导因子-1α抑制前梯度蛋白2的表达，减少其介导的血管内皮细胞中基质金属蛋白酶2，钙粘蛋白，cMyc，p38和ERK1/2的磷酸化激活，从而抑制内皮细胞增殖、迁移和微管形成，使肿瘤血管正常化。研究进一步发现纳米金-恩度复合体使肿瘤血管正常化后，能够逆转肿瘤上皮-间充质转化，抑制黑色素瘤肺转移。为寻找实时无创监测肿瘤血管正常化时间窗的标记物，本项目发现血清前梯度蛋白2、血小板反应蛋白1和体素内不相干运动扩散加权磁共振成像可对肿瘤血管正常化时间窗进行微创或无创监测。该研究成果为肿瘤血管正常化理念在临床治疗中的进一步应用提供理论基础，为提高肿瘤综合治疗疗效开辟新的途径。