肝硬化多步癌变的血管生成及抗血管治疗：针对VEGF的USPIO纳米探针MR成像研究

The main objective is to investigate the angiogenesis regulation machanism of VEGF signal transduction passageway acting on the model of multistep carcinogenesis model of cirrhotic liver in Sprague-Dawley Rats, by MR molecular imaging using different USPIO-based MR molecular probes specific targeting to HIF-1, VEGF, Flk-1, respectively, and comparing with USPIO-RGD specific probe. The secondary objective is to investigate the possibility of anti- angiogenesis therapy on preventing or delaying the process of hepatic carcinogenesis by HIF-antibody on the model of Sprague-Dawley Rats. The expected Results obtained from this research will improve the recognization of effectiveness and machnisms of VEGF signal transduction passageway acting on multistep carcinogenesis process of HCC, improve the diagnostic ability of early stage HCC and precacerous lesions, and provide the experimental foundation of anti-angiogenesis therapy on preventing and treating the hepatic carcinogenesis.

本项目选择VEGF信号转导通路中对血管生成作用最强的几个环节包括HIF-1、VEGF及Flk-1作为分子靶点，利用各自单克隆抗体合成USPIO标记的特异性分子探针，并以USPIO-RGD探针为对比，利用SD大鼠肝硬化结节多步癌变模型进行在体MR分子靶向成像及靶向治疗，对肝硬化结节癌变过程中血管生成的规律、VEGF信号转导通路在此过程中的作用及可能机制、靶向抗血管生成治疗对预防或延缓肝硬化结节癌变的可行性等方面进行研究。本项目的完成将可能提高对肝硬化结节癌变过程中的VEGF信号传导通路发挥的作用及相关机理的认识，提高对早期肝细胞癌及癌前病变的诊治能力，并为抗血管生成靶向治疗药物在预防肝硬化癌变方面的作用提供实验依据。

本项目选择VEGF信号转导通路中对血管生成作用最强的几个环节HIF-1、VEGF作为分子靶点，利用各自单克隆抗体合成USPIO标记的特异性分子探针，并以USPIO探针为对比，利用裸鼠肝癌模型及SD大鼠肝硬化结节多步癌变模型进行在体MR分子靶向成像，对肝硬化结节癌变过程中血管生成的规律、VEGF信号转导通路在此过程中的作用及可能机制等方面进行研究。研究结果表明：（1）分子探针能被肿瘤组织特异性摄取，相较于USPIO能更有利于肿瘤显像；（2）调节血管生成的两个重要因子HIF-1和VEGF在HCC活体组织中均有高表达；（3）肝硬化癌变过程中，调节血管生成的HIF-1和VEGF蛋白的表达也表现出渐进性的增多。