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 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.