通过可视化靶向纳米载体技术实现基因治疗和免疫治疗相结合的肝癌“诊断治疗一体化鸡尾酒疗法”

Hepatocellular carcinoma seriously endangers human health. In the early stage of the study, the gene therapy of hepatocellular carcinoma was carried out by using hepatoma cell targeted nanocomplex, and exact proliferation inhibition effect was achieved(Hepatology.2015). However, we find that because of the existence of cancer stem cell subsets and other factors, it is difficult to rely on a single mechanism, including gene therapy, which is difficult to achieve complete killing of all liver cancer cells. Therefore, in preliminary experiments an acid-sensitive nanocarrier was modified by CD3 antibody to target T cells, and a IL2 and IFNγ expression plasmid was carried, validate with in vivo tumor promoting cytokine-induced killer cells (CIK) formed effect, it can be used for immunotherapy of cancer. Different targeted modification of the same carrier is carried out in this project for combination of gene therapy and immune therapy of HCC,to verify the synergistic effect of "cocktail therapy" in the entire visual monitoring and provide new ideas for the development of efficient means for the treatment of hepatocellular carcinoma.

肝癌严重危害人类健康。申请人在前期研究中利用靶向肝癌细胞的纳米复合物进行肝癌的基因治疗，实现了确切的肝癌增殖抑制效果(Hepatology.2015)。然而，我们发现由于肝癌干细胞亚群等因素的存在，依靠针对包括基因治疗在内的单一机制的治疗手段难以实现对所有肝癌细胞的完全杀灭。所以在预实验中对酸敏纳米药物载体进行T细胞靶向化的CD3抗体修饰（ACS Nano.2012），并携带可促进内源性IL2和IFNγ表达的质粒，验证其具备在体内促进细胞因子诱导的肿瘤杀伤细胞（CIK）形成的效果，可以用于肝癌的免疫治疗。本项目拟通过对同一种多功能酸敏胞内控释“诊断治疗一体化”载体进行不同的靶向化修饰，将前期掌握的肝癌基因治疗手段与纳米体内诱导CIK形成的免疫治疗手段结合起来，在全程无创连续可视化监测下验证该“鸡尾酒疗法”在肝癌基因治疗和免疫治疗中产生的协同作用,为高效的肝癌综合治疗手段的开发提供新的思路。

本课题围绕“靶向化基因治疗手段可以保证对体内肝癌细胞进行高效的治疗基因传输，但是由于肝癌细胞亚型或肝癌干细胞的存在，单纯基因治疗不能杀灭肿瘤病灶中所有肿瘤细胞，结合免疫治疗可能通过不同机制的协同作用，实现更好的抗肿瘤效果”的科学问题进行研究。已完成了既定的研究计划。在研究中，通过综合运用具有肝癌细胞靶向或T淋巴细胞靶向的新型酸敏纳米复合物，在对肝癌细胞进行高效基因治疗的同时，在活体内诱导具有肝癌细胞免疫杀伤作用的CIK细胞的形成。在治疗过程由MRI和活体荧光等多种分子影像学手段可视化的前提下，对肝癌细胞进行基因治疗和免疫治疗不同治疗机制相结合的“鸡尾酒疗法”，实现了预期的治疗效果。

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