放射性槲皮素标记的纳米MOF复合体用于肝癌微波消融的增敏机制研究

Residual tumor recurrence after microwave ablation was serving as the crucial factors that affected the long-term curative effect for the treatment of hepatocellular carcinoma and there is no effective method to solve this problem. Recently, tumor microwave thermal ablation sensitization technology utilizing neoteric nanomaterials and inherent property of microwave has becoming the focus in minimally invasive therapeutic areas. Previous studies have shown that quercetin has excellent radiotherapy sensitization characteristics, and combined with radiotherapy can effectively inhibit tumor growth and recurrence. Therefore, this study proposes using radioactive quercetin labels nanoscale organic framework materials (MOF) to residual tumor after sensitization of microwave ablation of hepatocellular carcinoma is a new treatment strategies. The aim is to bring target, microwave ablation, radiation and other functions together into an organic functional group to realize the precision treatment of hepatocellular carcinoma. The research include：the establishment of a novel nano-sized metal organic framework nanomaterial (MOF) with radioactive quercetin to achieve our hypothesis; The particular MOF material can realized computed tomography (CT) image enhancement and further microwave thermal ablation by different methods; We detected the expression of key protein of HIF-1α/Survivin signal pathway to speculate possible mechanisms. This study is to provide new materials, new techniques and new ideas for the treatment of residual tumor after microwave ablation of hepatocellular carcinoma.

肝癌微波消融后肿瘤残存与复发是影响其中远期疗效的重要因素，目前尚无有效手段解决此问题。利用纳米材料与微波的相互作用所发展的肿瘤热消融增敏技术是目前研究的热点领域。前期研究表明：槲皮素具有优异的放疗增敏特性，结合放疗可有效抑制肝癌的生长及复发。因此，本研究提出利用放射性槲皮素标记纳米级有机框架材料（MOF）进行肝癌微波增敏消融后残余瘤的治疗，这是一种全新的精准治疗策略，目的是将靶向、微波消融、内放疗等多种功能集于一体，实现肝癌的精准治疗方案。研究内容包括：构建放射性槲皮素标记的纳米MOF复合体来实现协同治疗设想；通过影像学方法验证MOF独特的CT影像增强功能，通过多种手段评价治疗效果；通过检测HIF-1α/Survivin通路中的蛋白表达及调控推测其增敏机制。此项研究为肝癌微波消融后残余瘤的治疗提供了新材料、新技术和新思路。

本文以Zr-MOF降解产生的1，4-苯甲酸为碳酸酐酶IX(CAIX)抑制剂，槲皮素(Qu)做为辐射增敏剂，设计了一种稳定的纳米复合材料来克服缺氧性能，将Qu包埋在Zr-MOF结构中，实现协同增敏治疗。. 我们通过各项表征手段，将槲皮素和牛血清白蛋白负载到Zr-MOF上，证明Zr-MOF-QU和成功合成：其为平均直径为62 nm的对称纳米立方体且具有良好的分散性和稳定性。在体外实验中验证得出Zr-MOF-Qu材料的放疗增敏率(SER)约为2，其增敏机制的研究中证实了Zr-MOF-Qu抑制CAIX的表达，HIF-1α的表达抑制表明其实现微环境缺氧的改变，逐步提高肿瘤对RT的敏感性。体内实验中我们证实了Zr-MOF-QU的CT成像优势。数据表明纳米材料进入小鼠血液后，可在肿瘤组织中逐渐蓄积。它在12h达到峰值（163.98%）； 双致敏法的最终抑瘤率达88.9%。又通过免疫组化、Real-time PCR和Western blotting检测相关基因的表达验证了其增敏机制与改善微环境乏氧程度相关，可减轻肿瘤组织对放射损伤的抵抗力，增强肿瘤组织对放射损伤的敏感性，此外我们通过全身毒素验证得到Zr-MOF-QU有很好的生物安全性能。. 我们的研究提出了一种双重增敏策略，使用槲皮素修饰的Zr-MOF作为一种多功能方法，可以同时增强放疗疗效和CT成像。Zr-MOF-Qu作为CAIX抑制剂，通过减轻缺氧诱导的抵抗和微环境的改变，改善了辐射介导的细胞凋亡。我们的研究促进了生物医学应用中对这些协同治疗方法的进一步研究。