多维示踪内皮靶向传递siRNA对于增强抗肝癌血管生成的初步研究

The non-surgical therapies of transcatheter arterial chemoembolization and radiofrequency ablation were easily to stimulate the hepatocellular carcinoma (HCC) cells to secrete VEGF, leading to pathological angiogenesis, recurrence and metastasis. Thus anti-angiogenesis therapy is of great significance for HCC. However, the existed problems of proteins of angiogenesis inhibitors used in clinical practice, such as great toxic side effect, poor single drug curative effect, as well as lack of sensitivity and effectiveness, made it hard to achieve the comprehensive control of HCC development. To solve the above-mentioned problem, RNA interference technique and AIE functionalized gold nano-gene carrier were combined to establish a multifunctional nanotheranostics system with highly collaborative. Herein, multimodal imaging was employed to track endothelial targeted delivery of siRNA, and radiotherapy was integrate with anti-angiogenesis gene therapy to improve the therapeutic effect. The actual effect of the multifunctional nanotheranostics system would be verified through a series of experiments including safety, stability, targeting ability and multimode imaging in vitro and in vivo. Moreover, these studies will undoubtedly have great significance for providing important scientific basis for improving the therapeutic effect of HCC.

动脉化疗栓塞、射频消融等非手术疗法极易刺激肝癌细胞大量分泌VEGF，导致病理性血管生成，引起复发及转移，因此抗肝癌血管生成治疗具有重大意义。然而目前临床所用的蛋白类血管抑制剂存在毒副作用大、单一用药疗效差、疗效评估缺乏实效性且不敏感等缺陷，难以实现对肝癌发生发展的综合控制。基于此，本项目拟将RNA干扰技术和AIE功能化的纳米金基因载体技术进行结合，构建一种内皮靶向传递siRNA的多功能高协同纳米诊疗系统，有机结合放疗与抗血管生成基因治疗，提高肝癌治疗效果；同时，多模态成像从多个维度跟踪和深入分析治疗效果，实现疗效的实时动态监测。通过一系列体外安全性、稳定性、靶向性、多模成像实验及肝癌模型鼠活体治疗实验，验证该多功能纳米高协同诊疗系统的实际功效，为最大程度地提高肝癌的治疗效果提供重要的科学依据。

动脉化疗栓塞、射频消融等非手术疗法极易刺激肝癌细胞大量分泌VEGF，导致病理性血管生成，引起复发及转移，因此抗肝癌血管生成治疗具有重大意义。然而目前临床所用的蛋白类血管抑制剂存在毒副作用大、单一用药疗效差、疗效评估缺乏实效性且不敏感等缺陷，难以实现对肝癌发生发展的综合控制。基于此，本项目设计了以谷胱甘肽（GSH）、血管生成靶向肽（cNGR）和聚赖氨酸短肽（CK9）为模板的Gd-DTPA功能化纳米金簇基因载体基于此，本项目设计了以谷胱甘肽（GSH）、血管生成靶向肽（cNGR）和聚赖氨酸短肽（CK9）为模板的Gd-DTPA功能化纳米金簇基因载体以实现多模态成像指导下的放疗与抗血管生成基因治疗的联合治疗。其中cNGR能提高纳米基因载体对血管内皮细胞的靶向性，增强其在肿瘤血管生成部位的聚集程度；CK9能提供VEGF-siRNA的负载位点，通过纳米载体特有的增强渗透滞留（EPR）效应和主动靶向功能实现VEGF-siRNA的定点投递，达到抗血管生成基因治疗的目的；载体中聚集的金元素具有放疗增敏、X射线计算机断层扫描成像（CT成像）和荧光成像（PL成像）功能；Gd-DTPA修饰能实现磁共振成像（MR成像），纳米载体的模块化特性将上述功能高效协同地组装于一体，达到放疗与抗血管生成基因治疗的有机结合，提高肝癌治疗效果；同时，多模态成像从多个维度跟踪和深入分析治疗效果，实现疗效的实时动态监测。通过体内外细胞实验及动物实验验证，我们成功构建了内皮靶向传递siRNA的多功能高协同纳米诊疗探，该纳米诊疗探针为最大程度地提高肝癌的治疗效果提供重要的科学依据。