不可逆电穿孔（纳米刀）联合局部应用纳米金-阿霉素颗粒治疗大鼠原发性肝癌的实验研究

The incident of hepatocellular carcinoma (HCC) and mortality rate caused by HCC continue to rise worldwide. Few patients meet the criteria for surgical resection. Conventional transcatheter arterial chemoembolization(TACE), radio frequency ablation(RFA), microwave ablation, and cryoablation have shown limited efficacy in the treatment of inoperable HCC, especially in HCC close to vessels, biliary tract, gall bladder, and gastrointestinal tract that has poor blood supply. Irreversible electroporation (IRE) that is under clinical investigation for different cancers has shown great promise for solid tumors ablation. However, tumor recurrence rate remains high after IRE treatment due to the heterogeneous liver structure and the un-unified tissue conductivity to electric pulse. Tumor cells that exposed to reduced electric field are less affected and may survive IRE treatment, because apoptosis is unlikely to occur with some reversibly electroporated cell membrane. Doxorubicin-loaded, polyethylene glycol-coated hollow gold nanospheres (Dox@PEG-HAuNS) are nanoscale particles with high Dox loading efficiency and controlled Dox release, which facilitate their passing through the blood vessels and the cell membrane entrance, and enable intracellular release of DOX upon near infrared region (NIR) laser exposure. Theoretically, Dox@PEG-HAuNS can pass through the IRE induced perforations on cell membrane, thus kill cancer cells upon intracellular release of DOX. Therefore improved therapeutic efficacy with decreased tumor recurrence rate can be expected. We plan to test our hypothesis by combining intra-arterial injected Dox@PEG-HAuNS with IRE in an orthotopic rat model of HCC.

原发肝癌发病率高，手术切除率低，预后差。尤其靠近血管、胆道、胆囊、胃肠道的血供不丰富的肝癌，常规肝动脉化疗栓塞、射频消融、微波消融、冷冻消融等疗效不好。近年，不可逆电穿孔（IRE，纳米刀）治疗这类肝癌显示出良好的应用前景，但仍存在肿瘤灭活不彻底，局部复发率高的缺点，文献报道因为肿瘤组织各部位细胞结构存在差异，对电脉冲传导不均一，部分肿瘤细胞接受电脉冲偏低，发生可逆性电穿孔，未出现凋亡。纳米金-阿霉素颗粒体积微小，载药量大，可缓释药物，易于穿过血管壁及细胞膜进入细胞内，能在细胞内精准释放阿霉素。理论上，纳米金-阿霉素颗粒可以穿过纳米刀治疗过程中发生可逆电穿孔的肝癌细胞膜进入细胞内，释放阿霉素于细胞内，杀灭肝癌细胞，从而提高纳米刀治疗肝癌灭活程度、降低复发率。本课题拟建立大鼠原发肝癌模型，通过介入技术在肝癌局部应用纳米金-阿霉素颗粒，联合纳米刀治疗大鼠原发肝癌的动物实验研究来验证这一理论。

原发肝癌发病率高，手术切除率低，预后差。尤其靠近血管、胆道、胆囊、胃肠道血供不丰富的肝癌，常规肝动脉化疗栓塞、射频消融、微波消融、冷冻消融等疗效不理想。近几年，不可逆电穿孔治疗这类肝癌显示出良好的应用前景，但仍存在肿瘤灭活不彻底，局部复发率高的缺点，文献报道因为肿瘤组织各部位细胞结构存在差异，对电脉冲传导不均一，部分肿瘤细胞接受电脉冲偏低，发生可逆性电穿孔，未出现凋亡。纳米金-阿霉素颗粒体积微小，载药量大，可缓释药物，易于穿过血管壁及细胞膜进入细胞内，能在细胞内精准释放阿霉素。理论上，纳米金-阿霉素颗粒可以穿过纳米刀治疗过程中发生可逆电穿孔的肝癌细胞膜进入细胞内，释放阿霉素于细胞内，杀灭肝癌细胞，从而提高纳米刀治疗肝癌灭活程度、降低复发率。本课题拟建立大鼠原发肝癌模型，通过介入技术在肝癌局部应用纳米金-阿霉素颗粒，联合纳米刀治疗大鼠原发肝癌的动物实验研究来验证这一理论。本课题研究结果证实大鼠肝癌模型经纳米刀消融后，可以促进更多的纳米金-阿霉素颗粒进入肝癌组织，使肿瘤组织内阿霉素含量显著提高，进一步体内实验研究结果表明纳米刀消融联合肝动脉局部灌注纳米金-阿霉素颗粒可以有效抑制肝癌的增长，同时，具有良好的安全性。本课题研究结果为提高肝癌介入治疗有效性所探索的新的载药材料及介入治疗联合策略及未来临床的转化应用提供了可靠的动物实验参考依据。