In-Cell NAD(P)H Photocatalysis with a Metal Complex for Photocatalytic Anticancer Therapy

Photodynamic therapy (PDT), which uses a photosensitizer (PS) to produce reactive oxygen species (ROS), has attracted great attention for cancer therapy. However, the hypoxic microenvironment within solid tumors strongly inhibits the PDT efficiency. Therefore, developing novel phototherapeutic strategies is urgently needed. In living cells, the reduced form of nicotinamide adenine dinucleotide (NADH) and its phosphorylated counterpart NADPH are essential reducing coenzymes (E = -0.32 V) for more than 400 metabolic processes, including redox balance, hypoxia modulation, respiration, and biosynthesis. In this regard, in-cell NADH/NADPH depletion represents a promising mechanism of action (MoA) for cancer treatment. Under hypoxia, cancer cells use NADH to release the ROS signal via the mitochondrial electron transport chain, thereby activating hypoxia-inducible factor-1α to support cell survival. Based on this, we constructed mitochondria-targeting Ir(III) complex Ir8, which exhibited a high excited-state redox potential (+1.22 V). Under 463 nm light irradiation, Ir8 induced in-cell NADH photocatalysis via a photoinduced single electron transfer mechanism with a high NADH turnover frequency (TOF = 100 h^-1). Though Ir8 exhibited similar photocatalytic anticancer activity under normoxia and hypoxia, it suffered from a low visible light absorption ability. Thus, we extended the conjugation system of the ligand and designed homodinuclear Ir(III) complex Ir10, which extended the light absorption and increased the NADH photocatalysis activity (TOF = 449 h^-1). Moreover, to improve the visible light molar extinction coefficient of Ir(III) complexes, we enhanced the electron-pushing effect of the ligand and tuned the ³ES reactivity of Ir16-Ir20. As a result, Ir18 showed a strong 465 nm light absorption efficiency with the NADH TOF reaching 1357 h^-1, with strong photocytotoxicity toward A431 cells (IC₅₀ = 3 nM). Moreover, we also designed heterodinuclear complex Ir-Pt for synergistic therapy by covalently linking Ir21 with a photoactivated Pt(IV) complex. Upon light irradiation, Ir-Pt exhibited photocatalytic therapy and photoactivated chemotherapeutic activity. Furthermore, to address the short light absorption wavelength issue of Ir(III) complexes, we designed a series of Ru(II) complexes (Ru1-Ru8). Through activation of the ligand-centered charge transfer process, Ru4 demonstrated 635 nm red-light-triggered NADPH photocatalysis and strong anticancer activity against cisplatin-, 5-fluorouracil-, and paclitaxel-resistant cancer cell lines. Recently, we introduced electron donor-acceptor-donor (D-A-D) motifs to promote the electron transfer process and synthesized a series of homodinuclear Ru(II) complexes. Ru6 exhibited a strong near-infrared (NIR) light absorption property (ε_700 nm = 61063 M^-1·cm^-1) and 700 nm NIR-light-triggered photocatalytic anticancer activity. Based on the above findings, we demonstrated that in-cell NADH/NADPH photocatalysis has the potential to address the hypoxia and drug resistance limitations of conventional therapy. We hope that this Account will inspire the design of innovative agents for efficient anticancer phototherapy.