Pretargeted Mitochondrial Delivery of Organoarsenicals for Cancer Immunotherapy
文献类型：期刊论文
| 作者 | Wang, Run1,3; Tian, Yuyang2; Lu, Xuliang2; Fang, Leyi2; Miao, Yinxing2; Fang, Daqing1; Li, Yingxia3; Liu, Hong1,3; Ye, Deju2 |
| 刊名 | JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
 |
| 出版日期 | 2025-10-22 |
| 卷号 | 147期号:42页码:38534-38548 |
| ISSN号 | 0002-7863 |
| DOI | 10.1021/jacs.5c12201 |
| 英文摘要 | Mitochondrial targeting of organoarsenic compounds shows potential for cancer therapy, but current delivery approaches face significant challenges such as poor tumor selectivity and systemic toxicity, leading to dose-limiting side effects and reduced therapeutic efficacy. In this study, we present a subcellular pretargeted delivery strategy designed to selectively and efficiently accumulate organoarsenic therapeutics within tumor cell mitochondria. This approach leverages P-TCO-TPP, an alkaline phosphatase (ALP)-responsive small-molecule probe containing a phosphate-caged near-infrared merocyanine fluorophore, trans-cyclooctene (TCO), and triphenylphosphonium (TPP) groups. This enables the in situ self-assembly of mitochondria-targeting nanoparticles upon ALP-mediated dephosphorylation. These mitochondria-localized nanoparticles then rapidly capture tetrazine-arsenic conjugates (Tz-As) via bioorthogonal inverse electron demand Diels-Alder (IEDDA) reaction, resulting in a >5-fold increase in mitochondrial arsenic accumulation. This, in turn, leads to mitochondrial proteins labeling, thioredoxin reductase inhibition, severe mitochondrial dysfunction, and immunogenic cell death in tumor cells. Notably, this strategy achieves strong antitumor efficacy with minimal toxicity in both subcutaneous cervical HeLa and orthotopic breast 4T1 tumor models. Furthermore, combining this strategy with anti-PD-L1 immunotherapy induces complete 4T1 tumor regression in 40% of mice, extended survival, and nearly prevents pulmonary metastasis. This subcellular pretargeted strategy offers a robust platform for precision mitochondrial drug delivery, enhancing therapeutic potential of various cytotoxic agents in cancer immunotherapy. |
| WOS关键词 | ARSENIC COMPOUNDS ; OXIDATIVE STRESS ; CELLS ; METABOLISM ; TARGET ; PROBE |
| 资助项目 | National Natural Science Foundation of China[2023YFF1205104] ; National Natural Science Foundation of China[2021YFA0910003] ; National Key R&D Program of China[22407130] ; National Key R&D Program of China[22274074] ; National Key R&D Program of China[22137003] ; National Natural Science Foundation of China[BK20232020] ; Natural Science Foundation of Jiangsu Province[KG202503] ; Fundamental Research Funds for the Central Universities[2023Y9284] ; Innovation of Science and Technology in Fujian Province[5431ZZXM2408] ; State Key Laboratory of Analytical Chemistry for Life Science |
| WOS研究方向 | Chemistry |
| 语种 | 英语 |
| WOS记录号 | WOS:001592892400001 |
| 出版者 | AMER CHEMICAL SOC |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/321678]  |
| 专题 | 国家级研究中心_原创新药研究全国重点实验室 |
| 通讯作者 | Li, Yingxia; Liu, Hong; Ye, Deju |
| 作者单位 | 1.Chinese Acad Sci, State Key Lab Drug Res, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China 2.Nanjing Univ, Chem & Biomed Innovat Ctr ChemBIC, Sch Chem & Chem Engn, State Key Lab Analyt Chem Life Sci, Nanjing 210023, Peoples R China 3.Fudan Univ, Sch Pharm, Shanghai 201203, Peoples R China |
| 推荐引用方式 GB/T 7714 | Wang, Run,Tian, Yuyang,Lu, Xuliang,et al. Pretargeted Mitochondrial Delivery of Organoarsenicals for Cancer Immunotherapy[J]. JOURNAL OF THE AMERICAN CHEMICAL SOCIETY,2025,147(42):38534-38548. |
| APA | Wang, Run.,Tian, Yuyang.,Lu, Xuliang.,Fang, Leyi.,Miao, Yinxing.,...&Ye, Deju.(2025).Pretargeted Mitochondrial Delivery of Organoarsenicals for Cancer Immunotherapy.JOURNAL OF THE AMERICAN CHEMICAL SOCIETY,147(42),38534-38548. |
| MLA | Wang, Run,et al."Pretargeted Mitochondrial Delivery of Organoarsenicals for Cancer Immunotherapy".JOURNAL OF THE AMERICAN CHEMICAL SOCIETY 147.42(2025):38534-38548. |
入库方式： OAI收割
来源：上海药物研究所
浏览0
下载0
收藏0
其他版本
除非特别说明，本系统中所有内容都受版权保护，并保留所有权利。