靶向DLL4及VEGF-C纳米超声造影剂评价结肠癌肝转移疗效研究

The clinical application of Bavicazumab, the anti-angeogenic monoclonal antiboody, has improved the overall survival of patients with metastatic colon cancer. However, not all the patients have the survival benefits after Bavicazumab treatment. So, individualized treatment through choosing suitable patients for Bavicazumab treatment and evaluating the treatment effect timely and accurately becomes an important topic for imageology. Our primary study showed that contrast-enhanced ultrasound could reflect the blood supply change in tumor after Bavicazumab treatment. But the change could not be discriminated by naked eyes observation. It could be reflected only in tha quantitative parameters analysis and there was some overlap between the treatment group and control group. The important reason for it is that the ultrasound contrast agents (UCAs) we used has no special specificity and affinity to the targeting region. Preparing of nano- targeted- ultrsound contrast agents is the key technoloy to solve the problem. DLL4 and VEGF are the two most important factors to regulate tumor angiogenesis. Studies showed that the expression of DLL4 and VEGF-C in tumors was correlated with Bavicazumab treatment effect. So, in our study, we intend to prepare a new kind of UCAs with nano-material (triblock copolymer mPEG-PLGA-PLL) targeting to DLL4 and VEGF. The characteristics of the UCAs is observed with Nanotrac Particle Size Analyzer and Atomic force microscope. The new UCAs are used to perform contrast-enhanced ultrasound molecular imaging on the nude mice model with liver matastasis from colon cancer and to predict and evaluate Bavicazumab treatment effect. Our findings will provide scientific evidence for tumor individualized treatment.

抗血管生成药物贝伐单抗的应用明显提高转移性结肠癌患者的生存率，但并非所有患者对贝伐单抗治疗有效。个体化治疗是其研究方向，选择适合该疗法的患者及早期有效评价其疗效是影像学研究热点。我们前期研究显示超声造影可反映贝伐单抗治疗后肿瘤内血供变化，但肉眼观察无法分辨，仅从定量分析中反映，且定量信息在治疗组与对照组间存在重叠，这与目前所用超声造影剂特异性不强，对感兴趣区没有靶向亲和力有关。制备纳米靶向超声造影剂是解决该问题的技术关键。Notch家族及VEGF家族是调节肿瘤血管生成的关键因素，研究显示肿瘤DLL4及VEGF-C表达水平与贝伐单抗疗效相关。本研究以三嵌段共聚物为材料制备纳米级靶向DLL4及VEGF-C的超声造影剂，应用超细微粒粒度分析仪及原子粒显微镜对其表征；建立裸鼠结肠癌肝转移模型，应用新型靶向纳米造影剂进行超声造影分子成像，预测及早期评价贝伐单抗疗效，为肿瘤个体化治疗提供科据。

抗血管生成药物贝伐单抗的应用明显提高转移性结肠癌患者的生存率，但并非所有患者对贝伐单抗治疗有效。个体化治疗是其研究方向，选择适合该疗法的患者及早期有效评价其疗效是影像学研究热点。本研究应用超声造影定量分析评价结肠癌皮下瘤抗血管生成治疗疗效，结果显示超声造影及其定量分析可以有效、准确评价肿瘤治疗疗效；其中ROIsmall较ROItotal，曲线下面积参数较峰值强度及达峰时间更能准确反映肿瘤内血供变化。本研究进一步应用靶向超声造影剂成像，评价结肠癌肝转移瘤抗血管生成治疗疗效，结果显示与对照组相比，治疗组各个时间点超声造影信号强度均明显减低；靶向超声造影剂行超声造影分子成像，可以早期评价贝伐单抗疗效，为肿瘤个体化治疗提供科据。