title: Simultaneously Inducing and Tracking Cancer Cell Metabolism Repression by Mitochondria-Immobilized Rhenium(I) Complex.
abstract: Mitochondrial metabolism is essential for tumorigenesis, and the development of cancer is usually accompanied by alternations of mitochondrial function. Emerging studies have demonstrated that targeting mitochondria and mitochondrial metabolism is an effective strategy for cancer therapy. In this work, eight phosphorescent organometallic rhenium(I) complexes have been synthesized and explored as mitochondria-targeted theranostic agents, capable of inducing and tracking the therapeutic effect simultaneously. Complexes 1b-4b can quickly and efficiently penetrate into A549 cells, specifically localizing within mitochondria, and their cytotoxicity is superior to cisplatin against the cancer cells screened. Notably, complex 3b [Re(CO)3(DIP) (py-3-CH2Cl)]+containing thiol-reactive chloromethylpyridyl moiety for mitochondria immobilization shows higher cytotoxicity and selectivity against cancer cells than other Re(I) complexes without mitochondria-immobilization properties. Mechanistic studies show that complexes 1b-4b induce a cascade of mitochondria-dependent events including mitochondrial damage, mitochondrial respiration inhibition, cellular ATP depletion, reactive oxygen species (ROS) elevation, and caspase-dependent apoptosis. By comparison, mitochondria-immobilized 3b causes more effective repression of mitochondrial metabolism than mitochondrial-nonimmobilized complexes. The excellent phosphorescence and O2-sensitive lifetimes of mitochondria-immobilized 3b can be utilized for real-time tracking of the morphological changes of mitochondria and mitochondrial respiration repression during therapy process, accordingly providing reliable information for understanding anticancer mechanisms.
authors.affiliation: MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, School of Chemistry, Sun Yat-Sen University , Guangzhou 510275, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Yang
authors.affiliation: MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, School of Chemistry, Sun Yat-Sen University , Guangzhou 510275, China.
authors.forename: Ji-Xian
authors.initials: JX
authors.lastname: Zhao
authors.affiliation: MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, School of Chemistry, Sun Yat-Sen University , Guangzhou 510275, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Cao
authors.affiliation: MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, School of Chemistry, Sun Yat-Sen University , Guangzhou 510275, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Hao
authors.affiliation: MOE Key Laboratory of Model Animals for Disease Study, Model Animal Research Center of Nanjing University , Nanjing 210061, China.
authors.forename: Danxia
authors.initials: D
authors.lastname: Zhou
authors.affiliation: MOE Key Laboratory of Model Animals for Disease Study, Model Animal Research Center of Nanjing University , Nanjing 210061, China.
authors.forename: Zhenji
authors.initials: Z
authors.lastname: Gan
authors.affiliation: MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, School of Chemistry, Sun Yat-Sen University , Guangzhou 510275, China.
authors.forename: Liang-Nian
authors.initials: LN
authors.lastname: Ji
authors.affiliation: MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, School of Chemistry, Sun Yat-Sen University , Guangzhou 510275, China.
authors.forename: Zong-Wan
authors.identifier: http://orcid.org/0000-0001-7131-1154
authors.initials: ZW
authors.lastname: Mao
mesh_terms: D000970:Antineoplastic Agents; D017209:Apoptosis; D045744:Cell Line, Tumor; D006801:Humans; D008928:Mitochondria; D017382:Reactive Oxygen Species; D012211:Rhenium
chemical_list: D000970:Antineoplastic Agents; D017382:Reactive Oxygen Species; D012211:Rhenium
keywords: PLIM; metabolism repression; mitochondria dysfunction; mitochondria immobilization; organometallic rhenium complex; theranostic