Highly Efficient Ir(III)‐Coumarin Photo‐Redox Catalyst for Synergetic Multi‐Mode Cancer Photo‐Therapy

Abstract

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.

Os(ii) complexes for catalytic anticancer therapy: recent update

“…Aside from the conventional chemotherapeutic drugs, redox-active drug molecules which can effectively disturb the redox balance in cancer cells by elevating the intracellular ROS level have drawn attention due to their selective cytotoxicity at the desired tumor site. 10,11,18,69 Many transition metal-based prodrugs have been reported to produce ROS in cancer cells, misbalancing the intracellular redox state through reduction of either the ligand or metal. 11,69,70 In this regard, Sadler et al synthesized the Os( ii ) arene half-sandwich complexes viz.…”

“…Metal-based cancer treatments have evolved into photodynamic therapy, photo-activated chemotherapy, sonodynamic therapy, combination therapy, etc. 7,9–16 Metal complexes have various applications for different purposes. Many metal complexes have been reported for in-cell catalytic reactive oxygen species (ROS) generation.…”

“…Many metal complexes have been reported for in-cell catalytic reactive oxygen species (ROS) generation. 9–12,17–22 The generated ROS are found to kill cancer cells by oxidative stress. Besides their anticancer activity, metal complexes also have significant catalytic applications in various industrial syntheses.…”

Cyanine-Functionalized 2,2′-Bipyridine Compounds for Photocatalytic Cancer Therapy

“…3 A recent advancement in the area of cancer phototherapy is the development of the concept of photocatalytic drug. 4,5 Photocatalytic drugs have various advantages, such as (i) low drug concentration required for treatment, (ii) control over the drug action, and more. 6 Recently, several photoactive metal complexes have shown great potential in photocatalytic anticancer therapy, a new methodology to obtain an anticancer effect with an unrevealed mechanism of action.…”

“…In cancer therapy, photoactivation of a prodrug provides spatiotemporal control over the drug action to eliminate unwanted off-target toxicity. , This strategy can overcome the drug side effect issue of first-generation cancer drugs . A recent advancement in the area of cancer phototherapy is the development of the concept of photocatalytic drug. , Photocatalytic drugs have various advantages, such as (i) low drug concentration required for treatment, (ii) control over the drug action, and more . Recently, several photoactive metal complexes have shown great potential in photocatalytic anticancer therapy, a new methodology to obtain an anticancer effect with an unrevealed mechanism of action. , Reduced nicotinamide adenine dinucleotide (NADH), the essential coenzyme in living cells, maintains intracellular redox and metabolic balance. , Ir­(III) photocatalysts are reported to induce significant NADH photo-oxidation via a single electron transfer mechanism. , As a result, cellular redox and metabolic balance were significantly perturbed, leading to cancer cell death. , So far, in photocatalytic cancer drug development, NADH photo-oxidation has been performed mainly by metal complexes .…”