Light-Up Mitophagy in Live Cells with Dual-Functional Theranostic Phosphorescent Iridium(III) Complexes

Abstract

Phosphorescent Ir(III) complexes are expected to be new multifunctional theranostic platforms that enable the integration of imaging capabilities and anticancer properties. Mitophagy is an important selective autophagic process that degrades dysfunctional mitochondria. Until now, the regulation of mitophagy is still poorly understood. Herein, we present two phosphorescent cyclometalated iridium(III) complexes (Ir1 and Ir2) that can accumulate in mitochondria and induce mitophagy. Because of their intrinsic phosphorescence, they can specially image mitochondria and track mitochondrial morphological alterations. Mechanism studies show that Ir1 and Ir2 induce mitophagy by depolarization of mitochondrial membrane potential, depletion of cellular ATP, perturbation in mitochondrial metabolic status, and induction of oxidative stress. Moreover, no sign of apoptosis is observed in Ir1- and Ir2-treated cells under the same conditions that an obvious mitophagic response is initiated. We demonstrate that Ir1 is a promising theranostic agent that can induce mitophagy and visualize changes in mitochondrial morphology simultaneously.

Lysosome‐targeted Cyclometalated Iridium (III) Anticancer Complexes Bearing Phosphine‐Sulfonate Ligands

“…The emission maxima of all Ir (III) complexes can be tuned from 474 to 510 nm by varying the type of substituents on P,O‐chelating ligand frameworks. A vibronic structure containing two almost horizontal emission peaks is clearly observed in the emission spectra of these complexes, which indicates that there are noticeable 3 π‐π* LC transitions in the excited states of these complexes . It is possible that the complexes will be quenched in aqueous solution.…”

“…The ligand substituent effect exhibits little variation on these absorption bands. Complexes Ir1 ‐ Ir4 exhibit strong absorption at 250–350 nm due to spin‐allowed 1 π‐π* 1 LC transitions and weak absorption at 350–450 nm assigned to a mixture of 1 MLCT, 1 LLCT, 3 MLCT, 3 LLCT, and 3 π‐π* LC transitions …”

“…Among these compounds, cyclometalated Ir (III) complexes received great attention for their many advantageous characteristics, such as good physicochemical stability, photophysical properties and facile color tuning, which make them useful for a range of applications such as cellular imaging and the investigation of intracellular fate of anticancer agents . So far, cyclometalated iridium and ruthenium anticancer complexes have been widely used as probes and imaging agents due to their high photo stability, intense emission, and large Stokes shifts . They also show different anticancer mechanisms from the platinum anticancer agents.…”

“…Recently, a lot of cyclometalated Ir (III) anticancer drugs have been investigated . For instance, cyclometalated Ir (III)‐β‐carboline complexes have shown sensitivity to acidic environments and potent selectivity toward cancer cells.…”

Recent Progress on the Exploration of the Biological Utility of Cyclometalated Iridium(III) Complexes

“…Actually, the mitochondrial targeting has various effects on the cell physiology as well as apoptosis. The Mao group recently investigated the biological effects of cyclometalated Ir(III) complexes having a 2,2′‐bisimidazole ligand ( 49 in Scheme ) . They found that the complexes were localized within the mitochondria of A549 cells, eliciting mitochondrial dysfunctions.…”