增敏型褪黑素—纳米凝胶介入治疗肝癌的疗效及机制研究

Transcatheter arterial chemoembolization (TACE) is a common method for the treatment of hepatocellular carcinoma in the mid-advanced stage. However, hypoxia-induced HIF-1α high expression in the microenvironment after incomplete embolization, for which activating the downstream signaling pathways and increasing the expression of related factors of tumor angiogenesis, glucose metabolism and invasion and metastasis, then leading to residual, recurrence and metastasis of liver cancer after interventional embolization. Therefore, hypoxic tumor cells become an important therapeutic target. Recent studies found that melatonin can effectively inhibit HIF-1α-mediated tumor angiogenesis and metastasis, at the transcriptional and translational levels. As a sensitizer, ramelteon can further improve the anti-tumor effect of melatonin. In this study, we will construct ramelteon modified melatonin Melatonin-loaded Nanogel. Then experimental studies will both be carried out in vitro and transcatheter embolization treatment of animal liver cancer models in vivo. To evaluate the efficacy and clarify the mechanism of collaborative therapy, interventional molecular imaging and molecular biology and other means will be used. The study will provide the theoretical and practical basis for the clinical treatment of HCC, expected to provide a new method and a new way for the interventional treatment of liver cancer.

经肝动脉化疗栓塞是目前中晚期肝癌治疗的常规方法，而栓塞后肿瘤轻、中度缺血缺氧引起微环境中HIF-1α高表达，诱发下游信号通路中血管新生、糖代谢转换和浸润转移相关因子表达，进而导致肝癌介入栓塞术后残存、复发和转移，因此，缺氧的肿瘤细胞成为重要的治疗靶点。国内外最新研究发现，褪黑素可在转录与翻译水平有效抑制HIF-1α表达及其介导的肿瘤血管新生和转移；同时，增敏剂雷美替胺可进一步提高褪黑素的抗肿瘤疗效。本研究拟构建雷美替胺修饰的载褪黑素纳米凝胶，通过体外细胞实验和体内经导管栓塞治疗动物肝癌模型实验，使用先进的介入分子影像学和分子生物学等多种方法评价疗效并阐明其协同治疗机制，以发挥纳米凝胶良好的介入栓塞和缓释作用、褪黑素高效的生物靶向协同治疗作用，从而为提高肝癌介入治疗的整体疗效提供理论依据和实践基础，开辟一条肝癌综合介入治疗的新方法和新途径。

经肝动脉化疗栓塞是目前不可切除肝癌的有效治疗方式。然而，对血供丰富或血供异常的肿瘤，很难达到完全栓塞，导致不完全栓塞。不完全栓塞会引起肿瘤缺氧微环境的产生，缺氧引起微环境中HIF-1α高表达，诱发下游信号通路中血管新生、糖代谢转换和浸润转移相关因子表达，进而导致肝癌介入栓塞术后残存、复发和转移，因此，缺氧肿瘤微环境成为重要的治疗靶点。国内外最新研究发现，褪黑素可在转录与翻译水平有效抑制HIF-1α表达及其介导的肿瘤血管新生和转移；本研究拟构建载褪黑素的温敏纳米凝胶（PIB-M），通过体外细胞实验和体内经导管栓塞治疗VX2兔肝癌模型实验，使用先进的介入分子影像学和分子生物学等多种方法评价疗效并阐明其治疗机制，以发挥纳米凝胶良好的介入栓塞和缓释作用、褪黑素高效的生物靶向治疗作用。本研究结果显示1mM褪黑素可以通过靶向肿瘤缺氧微环境来抑制HepG2细胞及LM3细胞的增殖和转移。我们构建的100mg/ml的PIB-M在体外及VX2瘤兔肿瘤内均可以达到长时间释放效果。体内VX2瘤兔栓塞实验显示，PIB-M可以安全有效抑制肿瘤的生长及转移。本研究结果可以提高肝癌介入治疗的整体疗效提供理论依据和实践基础，从而开辟一条肝癌综合介入治疗的新方法和新途径。