Catalytic Frontiers in Cancer Therapy: Ruthenium, Rhenium, and Iridium Complexes as Redox-Active Chemodynamic Agents
Platinum-based drugs like cisplatin have long dominated chemotherapy but are limited by severe toxicity and resistance. In contrast, redox-active metal complexes—particularly those of Ruthenium (Ru), Rhenium (Re), and Iridium (Ir)—have emerged as next-generation candidates for chemodynamic therapy (CDT), a strategy that exploits the unique redox environment of tumour cells to catalytically generate reactive oxygen species (ROS) and induce programmed cell death. Unlike conventional drugs, these metallodrugs act selectively in tumour microenvironments characterised by elevated hydrogen peroxide (H₂O₂), acidic pH, and glutathione (GSH) imbalance, converting intracellular substrates into cytotoxic ROS that trigger apoptosis or necroptosis.
Ruthenium complexes, with flexible oxidation states (+2, +3, and +4) and rich coordination chemistry, exhibit excellent biocompatibility and tumour selectivity. Ru(III) prodrugs are reduced to active Ru(II) species under hypoxic conditions, catalysing Fenton-like reactions that decompose H₂O₂ into hydroxyl radicals while disrupting mitochondrial respiration and DNA synthesis.
Rhenium(I) tricarbonyl complexes, notable for their photophysical and redox versatility, act as both therapeutic and diagnostic agents. Their stability and luminescence enable ROS generation through catalytic or photoinduced processes, integrating CDT with photodynamic (PDT) or sonodynamic therapy (SDT). Their lipophilic nature favors mitochondrial localization, enhancing redox-induced apoptosis.
Iridium(III) complexes, featuring strong spin–orbit coupling and photoredox reactivity, efficiently catalyze ROS formation and oxidative damage via the Ir(III)/Ir(IV) redox cycle. Ligand tuning further allows incorporation of photophysical properties, leading to synergistic photochemodynamic effects.
Together, Ru-, Re-, and Ir-based complexes represent a new class of intelligent metallodrugs that merge catalysis, photochemistry, and molecular targeting. Their tumor-specific redox activation and ROS-driven cytotoxicity offer a precise, less toxic alternative to platinum therapy, paving the way for advanced, personalized redox-based cancer treatments.
Mechanistic Insights into Mitochondria-Targeting Ir(III)/Re(I) Multinuclear Complexes as Photo-Theranostic Agents in Cancer Therapy
Mitochondria-targeting Iridium(III) and Rhenium(I) multinuclear complexes represent a new frontier in photo-theranostic metallodrug design, integrating diagnosis and therapy within a single molecular system. These complexes exploit the redox sensitivity of cancer cell mitochondria, functioning as light-activated catalysts that induce oxidative stress while enabling real-time imaging. Their multinuclear architecture, featuring π-conjugated or polypyridyl linkers, enhances charge and energy transfer, extending triplet-state lifetimes and amplifying reactive oxygen species (ROS) generation under photoexcitation.
Ir(III) complexes, especially those bearing cyclometalated ligands like phenylpyridine, display strong spin–orbit coupling and high triplet energy, ideal for photoredox catalysis. Conjugation with mitochondria-targeting cations (e.g., triphenylphosphonium) enables selective mitochondrial accumulation driven by membrane potential. Upon visible or near-infrared irradiation, photoexcited Ir(III)* species transfer energy to oxygen, forming singlet oxygen and superoxide radicals that trigger mitochondrial depolarization, cytochrome-c release, and caspase-mediated apoptosis. Their Ir³⁺/Ir⁴⁺ redox cycling supports continuous ROS production even under hypoxia, overcoming a major limitation of conventional photodynamic therapy (PDT).
Rhenium(I) tricarbonyl complexes, with their d⁶ low-spin configuration and strong MLCT character, exhibit exceptional photostability and phosphorescence. Their fac-[Re(CO)₃(N^N)L]⁺ core can be functionalized to create multinuclear assemblies capable of dual photo- and redox-induced ROS generation. These complexes catalyse H₂O₂ decomposition to •OH and generate ¹O₂ upon irradiation, enabling photo-chemodynamic therapy (PCDT). Their intrinsic luminescence allows real-time imaging of mitochondrial localisation and ROS-mediated damage.
The multinuclear framework enhances light absorption, redox cycling, and mitochondrial affinity through increased cationic charge and lipophilicity. Collectively, Ir(III)/Re(I) complexes unify photochemistry, redox catalysis, and organelle-specific targeting, offering precision-guided, multimodal cancer therapy. By merging catalytic ROS generation with mitochondrial apoptosis signalling, these photo-theranostic systems redefine intelligent, redox-driven strategies in next-generation cancer treatment.
Mechanistic Advancements in Targeted Drug Delivery for Cancer Therapy
The convergence of organometallic chemistry and nanotechnology has given rise to nano-organometallic systems—hybrid therapeutic platforms that combine the catalytic and redox versatility of metal complexes with the precision and biocompatibility of nanocarriers. These systems address major challenges in oncology, such as non-specific toxicity, poor solubility, and drug resistance, by enabling targeted, stimuli-responsive, and sustained delivery of anticancer agents directly to tumors.
Organometallic complexes of ruthenium (Ru), iridium (Ir), rhenium (Re), and gold (Au) possess potent redox and photochemical activity capable of generating reactive oxygen species (ROS) and triggering apoptosis. However, their clinical use is often limited by instability and off-target effects. Encapsulation within nanocarriers—such as liposomes, micelles, dendrimers, mesoporous silica, or metal–organic frameworks (MOFs)—protects these complexes from premature deactivation, extends circulation time, and ensures tumor-specific accumulation via the enhanced permeability and retention (EPR) effect or receptor-mediated targeting.
Once internalized by cancer cells, intracellular stimuli (acidic pH, high glutathione, or enzyme activity) activate the complexes. For instance, Ru(III)→Ru(II) reduction in the tumor microenvironment generates hydroxyl radicals (•OH) through Fenton-like reactions, inducing oxidative stress, mitochondrial dysfunction, and apoptosis. Similarly, Ir(III) and Re(I) nano-conjugates produce singlet oxygen (¹O₂) under light irradiation, enabling photo-chemodynamic therapy with imaging capability.
Nano-organometallic platforms also function as multimodal carriers, co-delivering drugs, genes, or immunomodulators for synergistic therapy. Surface modification with targeting ligands such as folic acid or RGD peptides enhances tumor specificity, while metal-based luminescence or magnetism allows real-time imaging. Mechanistically, these systems operate via selective tumor accumulation, stimuli-triggered release, ROS generation, mitochondrial depolarization, and immunogenic cell death—overcoming multidrug resistance and amplifying therapeutic efficacy.
By uniting chemical reactivity with nanoscale targeting, nano-organometallics embody next-generation, mechanism-driven cancer nanomedicine, integrating therapy, imaging, and precision delivery into a single intelligent platform.
