Manganese porphyrin-based metal-organic framework for synergistic sonodynamic therapy and ferroptosis in hypoxic tumors

被引:205
|
作者
Xu, Qingbo [1 ,2 ]
Zhan, Guiting [1 ]
Zhang, Zelong [1 ]
Yong, Tuying [1 ]
Yang, Xiangliang [1 ,3 ,4 ]
Gan, Lu [1 ,3 ,4 ]
机构
[1] Huazhong Univ Sci & Technol, Coll Life Sci & Technol, Natl Engn Res Ctr Nanomed, Wuhan 430074, Peoples R China
[2] Jinan Univ, Zhuhai Hosp, Zhuhai Peoples Hosp, Zhuhai Precis Med Ctr, Zhuhai 519000, Peoples R China
[3] Huazhong Univ Sci & Technol, Sch Chem & Chem Engn, Hubei Key Lab Bioinorgan Chem & Mat Med, Wuhan 430074, Peoples R China
[4] Huazhong Univ Sci & Technol, Coll Life Sci & Technol, Minist Educ, Key Lab Mol Biophys, Wuhan 430074, Peoples R China
来源
THERANOSTICS | 2021年 / 11卷 / 04期
基金
中国国家自然科学基金;
关键词
metal-organic framework; catalase-like activity; GSH depletion; reactive oxygen species; sonodynamic therapy; ferroptosis; NANOPARTICLES; GENERATION; SCAVENGERS; OXYGEN;
D O I
10.7150/thno.45511
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
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. Methods: A manganese porphyrin-based metal-organic framework (Mn-MOF) was constructed as a nanosensitizer to self-supply oxygen (O-2) and decrease GSH for enhanced SDT and ferroptosis. In vitro and in vivo analysis, including characterization, O-2 generation, GSH depletion, ROS generation, lipid peroxidation, antitumor efficacy and tumor immune microenvironment were systematically evaluated. Results: Mn-MOF exhibited catalase-like and GSH decreasing activity in vitro. After efficient internalization into cancer cells, Mn-MOF persistently catalyzed tumor-overexpressed H2O2 to in-situ produce O-2 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. Conclusions: Mn-MOF holds great potential for hypoxic cancer therapy.
引用
收藏
页码:1937 / 1952
页数:16
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