Simultaneously Inducing and Tracking Cancer Cell Metabolism Repression by Mitochondria-Immobilized Rhenium(I) Complex

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 mitochondria' 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 lb-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-CH(2)C1)](+) 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 lb-4b induce a cascade of mitochondria-dependent events including mitochondria' respiration inhibition, cellular ATP depletion, reactive oxygen species (ROS) elevation, and caspase-dependent apoptosis. By comparison, mitochondria-immobilized 3b causes more effective repression of mitochondria' metabolism than mitochondrial-nonimmobilized complexes. The excellent phosphorescence and O-2-sensitive lifetimes of mitochondria immobilized 3b can be utilized for real-time tracking of the morphological changes of mitochondria and mitochondria' respiration repression during therapy process, accordingly providing reliable information for understanding anticancer mechanisms.