EGCG-MOF-MoS2纳米复合材料用于肿瘤光热/免疫协同治疗研究

The incidence and mortality of cancer keep rising worldwide, and the therapeutic efficiency is hindered by the inflammatory tumor microenvironment (TME). Green tea catechin (EGCG) has excellent anti-inflammatory ability and proved to be able to inhibit immune checkpoint PD-L1 on cancer cells. Thus, EGCG has great potential as a good candidate for cancer immunotherapy. But the application of EGCG is limited by its low bioavailability. Photothermal nanoagents have been studied widely for the effective cancer therapy. Meanwhile, the photothermal therapy (PTT)-induced cell debris could lead for efficient cancer immunotherapy as cancer vaccine. However, the efficiency of single methodological oncotherapy strategy is limited. Therefore, multi-functional nanocomposites (NCs) that can achieve both PTT and EGCG-delivery at the same time have great potential for multi-model synergistic treatment of cancer. In this proposal, we proposed to prepare EGCG-MOF-MoS2 NCs, which will combine the excellent PTT effect of MoS2 NSs and the high loading efficiency of MOF on EGCG drug delivery, and achieve cancer treatment by PTT and immunotherapy in one shot. We will investigate this NCs’ PTT therapeutic efficiency, immunogenicity, TME-modulating capacity and PD-L1-based immunotherapeutic effects. At the end, we hope to achieve a high therapeutic efficiency on oncotherapy by using EGCG-MOF-MoS2 NCs as synergistic photothermal/immunotherapy agents.

肿瘤的炎性微环境严重阻碍免疫检查点阻断疗法的肿瘤治疗效率。茶多酚（EGCG）可下调肿瘤部位的炎性因子，并抑制肿瘤免疫检查点PD-L1的表达，从而提高肿瘤的免疫杀伤，但生物利用率极低。纳米光热试剂具有优异的肿瘤治疗效果，且热消融产生的细胞碎片具有免疫原性，可激活机体的肿瘤免疫杀伤。但单一模式的治疗方法效率有限。因此，本项目拟通过构建多功能纳米复合材料EGCG-MOF-MoS2 NCs，在利用介孔MOF（金属有机框架）纳米材料高效的药物负载率靶向递送EGCG提高其利用率的同时，与MoS2 NSs（硫化钼纳米片）优异的光热性能结合，进行肿瘤杀伤；并研究EGCG-MOF-MoS2 NCs的光热治疗和免疫原性诱导能力、调控肿瘤炎性微环境和抑制PD-L1表达的性能、及其光热/免疫协同治疗的效率。最终，本课题设计的纳米复合材料有望通过光热/免疫协同的手段，实现高效的肿瘤治疗。

炎症是肿瘤发生与发展的重要因素，是诱发肿瘤的重要条件。肿瘤存在复杂的微环境，并伴有众多免疫细胞的浸润和炎症因子的表达，但这些免疫细胞和细胞因子都被肿瘤细胞所挟持利用，促进肿瘤的生长和转移。其中，IL-1β是一个重要的多效性细胞因子，在乳腺癌、胰腺癌、肺癌等肿瘤细胞中都有发现，是肿瘤侵袭与转移的重要因子。IL-1β可以促进TNFα、IL-6、IL-8、CCL5和CCL2等多种细胞因子的表达与分泌，且与MDSCs等免疫抑制类免疫细胞在肿瘤部位的浸润相关，进而促进肿瘤生长。.茶多酚EGCG具有很好的免疫学效应，能够显著抑制炎症因子的表达与分泌。但是，EGCG较低的生物可利用率和短暂的体内半衰期限制了其医用与药用价值，依靠纳米技术提高EGCG的生物可利用性，是解决这一技术难点的途径之一。纳米技术可以提供更好的药物设计思路，以应对肿瘤的诊断和治疗。在此，我们构建了负载EGCG的纳米材料，有效的提高了肿瘤部位EGCG的富集率，降低了肿瘤部位IL-1β的分泌，有效减少MDSCs在肿瘤部位的浸润，改善肿瘤部位的免疫抑制微环境，进而抑制肿瘤生长。.同时，我们开发了TME响应性穿透纳米凝胶，通过可释放环糊精-药物包合物的纳米控释系统，改善了共载的雷西莫特和EGCG在肿瘤中的传递和渗透。纳米凝胶可以有效地促进树突状细胞的成熟，激活细胞毒性T淋巴细胞（CTL），并降低肿瘤组织中PD-L1的表达。纳米凝胶与OX40激动剂联合应用，进一步协同增强CTL的活化和浸润，接触调节性T细胞（Treg）的抑制作用。结果表明。肿瘤中活性CTL/Tregs的比值增加20.66倍，抑瘤率提升至91.56%，表明肿瘤成功地从冷肿瘤转变向热肿瘤，改善肿瘤部位的免疫抑制微环境，抗肿瘤免疫效果显著。