National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China.
Zhuhai Precision Medical Center, Zhuhai People's Hospital (Zhuhai Hospital Affiliated with Jinan University), Zhuhai 519000, China.
Theranostics. 2021 Jan 1;11(4):1937-1952. doi: 10.7150/thno.45511. eCollection 2021.
Development of efficient therapeutic strategy to incorporate ultrasound (US)-triggered sonodynamic therapy (SDT) and ferroptosis is highly promising in cancer therapy. However, the SDT efficacy is severely limited by the hypoxia and high glutathione (GSH) in the tumor microenvironment, and ferroptosis is highly associated with reactive oxygen species (ROS) and GSH depletion. A manganese porphyrin-based metal-organic framework (Mn-MOF) was constructed as a nanosensitizer to self-supply oxygen (O) and decrease GSH for enhanced SDT and ferroptosis. and analysis, including characterization, O generation, GSH depletion, ROS generation, lipid peroxidation, antitumor efficacy and tumor immune microenvironment were systematically evaluated. Mn-MOF exhibited catalase-like and GSH decreasing activity . After efficient internalization into cancer cells, Mn-MOF persistently catalyzed tumor-overexpressed HO to produce O to relieve tumor hypoxia and decrease GSH and GPX4, which facilitated the formation of ROS and ferroptosis to kill cancer cells upon US irradiation in hypoxic tumors. Thus, strong anticancer and anti-metastatic activity was found in H22 and 4T1 tumor-bearing mice after a single administration of Mn-MOF upon a single US irradiation. In addition, Mn-MOF showed strong antitumor immunity and improved immunosuppressive microenvironment upon US irradiation by increasing the numbers of activated CD8 T cells and matured dendritic cells and decreaing the numbers of myeloid-derived suppressor cells in tumor tissues. Mn-MOF holds great potential for hypoxic cancer therapy.
开发将超声（US）触发的声动力学疗法（SDT）和铁死亡相结合的高效治疗策略在癌症治疗中极具前景。然而，SDT 的疗效受到肿瘤微环境中缺氧和高谷胱甘肽（GSH）的严重限制，铁死亡与活性氧（ROS）和 GSH 耗竭密切相关。构建了一种基于锰卟啉的金属-有机框架（Mn-MOF）作为纳米敏化剂，以自供氧（O）和降低 GSH，从而增强 SDT 和铁死亡。通过细胞摄取、细胞内 O 生成、GSH 耗竭、ROS 生成、脂质过氧化、抗肿瘤疗效和肿瘤免疫微环境等分析，系统评价了 Mn-MOF 的性能。Mn-MOF 表现出类过氧化氢酶和 GSH 降低活性。Mn-MOF 高效内化进入癌细胞后，持续催化肿瘤过表达的 HO 产生 O 以缓解肿瘤缺氧并降低 GSH 和 GPX4，这有利于在缺氧肿瘤的 US 照射下形成 ROS 和铁死亡来杀死癌细胞。因此，在 H22 和 4T1 荷瘤小鼠单次 US 照射后单次给予 Mn-MOF 即可显示出强烈的抗癌和抗转移活性。此外，Mn-MOF 通过增加肿瘤组织中活化的 CD8 T 细胞和成熟的树突状细胞的数量，降低髓系来源抑制细胞的数量，在 US 照射下显示出强大的抗肿瘤免疫和改善免疫抑制微环境的作用。Mn-MOF 具有治疗缺氧癌症的巨大潜力。
