Photocatalytic anticancer profile of a IrIII photocatalyst (Ir3) with strong light absorption, high turnover frequency, and excellent biocompatibility is reported. Ir3 showed selective photo‐cytotoxicity against cisplatin‐ and sorafenib‐resistant cell lines while remaining dormant to normal cell lines in the dark. Ir3 exhibited excellent photo‐catalytic oxidation of cellular co‐enzyme, the reduced nicotinamide adenine dinucleotide phosphate (NADPH), and amino acids via a single electron transfer mechanism. The photo‐induced intracellular redox imbalance and change in mitochondrial membrane potential resulted in necrosis and apoptosis of cancer cells. Importantly, Ir3 exhibited high biocompatibility and photo‐catalytic anticancer efficiency as evident from in vivo zebrafish and mouse cancer models. To the best of our knowledge, Ir3 is the first IrIII based photocatalyst with such a high biocompatibility and photocatalytic anticancer therapeutic effect.

Quantifying the content of metal‐based anticancer drugs within single cancer cells remains a challenge. Here, we used single‐cell inductively coupled plasma mass spectrometry to study the uptake and retention of mononuclear (Ir1) and dinuclear (Ir2) IrIII photoredox catalysts. This method allowed rapid and precise quantification of the drug in individual cancer cells. Importantly, Ir2 showed a significant synergism but not an additive effect for NAD(P)H photocatalytic oxidation. The lysosome‐targeting Ir2 showed low dark toxicity in vitro and in vivo. Ir2 exhibited high photocatalytic therapeutic efficiency at 525 nm with an excellent photo‐index in vitro and in tumor‐bearing mice model. Interestingly, the photocatalytic anticancer profile of the dinuclear Ir2 was much better than the mononuclear Ir1, indicating for the first time that dinuclear metal‐based photocatalysts can be applied for photocatalytic anticancer treatment.

The rapid efflux of Pt‐based chemotherapeutics by cancer cells is one of the major causes of drug resistance in clinically available drugs. Therefore, both the high cellular uptake as well as adequate retention efficiency of an anticancer agent are important factors to overcome drug resistance. Unfortunately, rapid and efficient quantification of metallic drug concentration in individual cancer cells still remains a tricky problem. Herein, with the help of newly developed single cell inductively coupled plasma mass spectrometry (SC‐ICP‐MS), we have found that the well‐known Ru(II)‐based complex, Ru3, displayed remarkable intracellular uptake and retention efficiency in every single cancer cell with high photocatalytic therapeutic activity to overcome cisplatin resistance. Moreover, Ru3 has shown sensational photocatalytic anticancer properties with excellent in‐vitro and in‐vivo biocompatibility under light exposure.

Four photo‐catalysts of the general formula [Ir(CO6/ppy)2(L)]Cl where CO6=coumarin 6 (Ir1–Ir3), ppy=2‐phenylpyridine (Ir4), L=4′‐(3,5‐di‐tert‐butylphenyl)‐2,2′ : 6′,2′′‐terpyridine (Ir1), 4′‐(3,5‐bis(trifluoromethyl)phenyl)‐2,2′ : 6′,2′′‐terpyridine (Ir2 and Ir4), and 4‐([2,2′ : 6′,2′′‐terpyridin]‐4′‐yl)‐N,N‐dimethylaniline (Ir3) were synthesized and characterized. These photostable photo‐catalysts (Ir1–Ir3) showed strong visible light absorption between 400–550 nm. Upon light irradiation (465 and 525 nm), Ir1–Ir3 generated singlet oxygen and induced rapidly photo‐catalytic oxidation of cellular coenzymes NAD(P)H. Ir1–Ir3 showed time‐dependent cellular uptake with excellent intracellular retention efficiency. Upon green light irradiation (525 nm), Ir2 provided a much higher photo‐index (PI=793) than the clinically used photosensitizer, 5‐aminolevulinicacid (5‐ALA, PI>30) against HeLa cancer cells. The observed necro‐apoptotic anticancer activity of Ir2 was due to the Ir2 triggered photo‐induced intracellular redox imbalance (by NAD(P)H oxidation and ROS generation) and change in the mitochondrial membrane potential. Remarkably, Ir2 showed in vivo photo‐induced catalytic anticancer activity in mouse models.