基于 pH 高敏感沸石咪唑酯骨架-8 的 1-MT 实现协同光热肿瘤免疫治疗。

BACKGROUND: A successful immune response against tumors depends on various cellular processes. Hence, there is an urgent need to construct a proficient nanoplatform for immunotherapy that can concurrently regulate the activities of various cells participating in the immune process. We have developed zeolitic imidazolate framework-8 (ZIF-8) formula, with good pH sensitivity, which is conducive to the release of drugs in the tumor site (acidic environment) and significantly improves immunotherapy. This is achieved through the coordinated action of different therapeutic agents, such as the photothermal agent polydopamine (PDA), the chemodrug camptothecin (CPT), and the immunomodulator 1-methyl-D-tryptophan (1-MT). MATERIALS AND METHODS: In this study, we evaluated the antitumor effect of PDA/(CPT + 1-MT) @ZIF-8 (PCMZ) nanoparticles (NPs) in vitro and in vivo and investigated the molecular mechanism of PCMZ NPs in tumor suppression via photothermal-chemo-immunotherapy. RESULTS: MTT and Annexin V-FITC/PI double staining apoptosis test showed that PCMZ NPs could induce apoptosis of 4T1 cell, and PCMZ NPs could cause 4T1 cell necrosis under 808 nm laser irradiation. The objective is to establish a unilateral breast cancer model in mice and investigate the effect of PCMZ NPs on tumor growth and tumor suppression in tumor bearing mice. The results showed that PCMZ NPs showed good heating effect in vivo and effectively inhibited tumor growth under 808 nm laser irradiation. In addition, PCMZ NPs could induce the immunogenic death of tumor cells, promote the maturation of DCs, inhibit IDO pathway, and finally differentiate T cells into cytotoxic T cells and helper T cells, so as to effectively activate the anti-tumor immune response. CONCLUSION: The PCMZ NPs, possessing good photothermal conversion capabilities due to join of PDA, effectively overcome two main challenges in immunotherapy: insufficient stimulation of the immune response and evasion of the immune system. This provides a robust platform against invasive cancer and recurrent tumors.

背景：成功的抗肿瘤免疫反应依赖于多种细胞过程。因此，迫切需要构建一种能够同时调节参与免疫过程的各种细胞活性的高效纳米平台用于免疫治疗。我们开发了具有良好 pH 敏感性的沸石咪唑酯骨架-8（ZIF-8）配方，有利于药物在肿瘤部位（酸性环境）的释放，并显著改善免疫治疗效果。这是通过不同治疗剂的协同作用实现的，例如光热剂聚多巴胺（PDA）、化疗药物喜树碱（CPT）和免疫调节剂 1-甲基-D-色氨酸（1-MT）。

材料和方法：在这项研究中，我们评估了 PDA/（CPT+1-MT）@ZIF-8（PCMZ）纳米颗粒（NPs）在体外和体内的抗肿瘤作用，并通过光热-化疗-免疫治疗研究了 PCMZ NPs 抑制肿瘤的分子机制。

结果：MTT 和 Annexin V-FITC/PI 双染色凋亡试验表明，PCMZ NPs 可以诱导 4T1 细胞凋亡，并且在 808nm 激光照射下 PCMZ NPs 可以引起 4T1 细胞坏死。目的是建立小鼠单侧乳腺癌模型，研究 PCMZ NPs 对荷瘤小鼠肿瘤生长和肿瘤抑制的影响。结果表明，PCMZ NPs 在体内具有良好的加热效果，并在 808nm 激光照射下有效抑制肿瘤生长。此外，PCMZ NPs 可以诱导肿瘤细胞的免疫原性死亡，促进 DCs 的成熟，抑制 IDO 途径，最终使 T 细胞分化为细胞毒性 T 细胞和辅助性 T 细胞，从而有效激活抗肿瘤免疫反应。

结论：由于加入了 PDA，PCMZ NPs 具有良好的光热转换能力，有效克服了免疫治疗中的两个主要挑战：免疫反应刺激不足和免疫系统逃避。这为对抗侵袭性癌症和复发性肿瘤提供了一个强大的平台。