Gloria Vigueras

Cyclometalated Ir( iii ) and Ru( ii ) complexes harness Type I photoreactivity to overcome oxygen limitations in photodynamic therapy.

Metal–coumarin photosensitizers enhance ROS generation and phototoxicity, offering promising solutions for cancer phototherapy.

Despite the potential of photodynamic therapy (PDT), this oxygen-dependent oncological treatment is greatly restricted in the clinic by the well-known hypoxic feature of solid tumors. Here we provide new insights on the development of PDT agents based on conjugates between COUPY fluorophores and cyclometalated iridium(III) complexes with the aim of overcoming this limitation. The structural modifications carried out within the metal core of Ir(III)-COUPY conjugates, based on the incorporation of trifluorobenzyl groups at the cyclometalating ligands, allowed efficient explotation of Type I PDT mechanisms while retaining operativity at long-wavelength visible light, which facilitates deeper tissue penetration compared with short wavelengths. Photobiological evaluation revealed that Ir(III)‑COUPY conjugate 3c achieved potent photocytotoxicity towards cisplatin-resistant ovarian (A2780cis) and mammary (EO771) cancer cell lines, efficiently photogenerated Type I and Type II ROS and photoinduced apoptotic cell death using red light irradiation (620 nm). Importantly, this Ir(III)-COUPY conjugate retained such potent photoactivity under low-oxygen environment conditions (2% O2), delivering equipotent photocytotoxicity towards normoxic and hypoxic adherent cancer cells. Compound 3c was found highly phototoxic against EO771 multicellular tumor spheroids and showed no signs of toxicity or adverse effects in mice, which could facilitate in vivo phototherapeutic applications. Taken together, this study demonstrated that the conjugation between COUPY dyes and rationally-designed Ir(III) complexes represents a frontier strategy for the development of new red light‑activated photosensitizers capable of operating under hypoxia, holding promise to achieve satisfactory anticancer PDT effects.

Activating photosensitizers with long-wavelength excitation is an important parameter for effective photodynamic therapy due to the minimal toxicity of this light, its superior tissue penetration, and excellent spatial resolution. Unfortunately, most Ir(III) complexes suffer from limited absorption within the phototherapeutic window, rendering them ineffective against deep-seated and/or large tumors, which poses a significant barrier to their clinical application. To address this issue, several efforts have been recently made to shift the absorption of Ir(III) photosensitizers to the deep-red/near-infrared region by using different strategies: functionalization with organic fluorophores, including porphyrinoid compounds, and ligand design via π-extension and donor–acceptor interactions. In this Frontier, we highlight such new developments and the ongoing challenges in this field.

Half-sandwich arene osmium(ii) complex 2 can inhibit the amyloid-β aggregation in vitro and in vivo using a Caenorhabditis elegans animal model of Alzheimer's disease.

Despite the potential of photodynamic therapy (PDT) in cancer treatment, the development of efficient and photostable photosensitizing molecules that operate at long wavelengths of light has become a major hurdle. Here, we report for the first time an Ir(III)-phthalocyanine conjugate (Ir-ZnPc) as a novel photosensitizer for high-efficiency synergistic PDT treatment that takes advantage of the long-wavelength excitation and near infrared (NIR) emission of the phthalocyanine scaffold and the known photostability and high phototoxicity of cyclometalated Ir(III) complexes. In order to increase water solubility and cell membrane permeability, the conjugate and parent zinc phthalocyanine (ZnPc) were encapsulated in amphoteric redox-responsive polyurethane-polyurea hybrid nanocapsules (Ir-ZnPc-NCs and ZnPc-NCs, respectively). Photobiological evaluations revealed that the encapsulated Ir-ZnPc conjugate achieved high photocytotoxicity in both normoxic and hypoxic conditions under 630 nm light irradiation, which can be attributed to dual Type I and Type II reactive oxygen species (ROS) photogeneration. Interestingly, PDT treatments with Ir-ZnPc-NCs and ZnPc-NCs significantly inhibited the growth of three-dimensional (3D) multicellular tumor spheroids. Overall, the nanoencapsulation of Zn phthalocyanines conjugated to cyclometalated Ir(III) complexes provides a new strategy for obtaining photostable and biocompatible red-light-activated nano-PDT agents with efficient performance under challenging hypoxic environments, thus offering new therapeutic opportunities for cancer treatment.

The valproic acid conjugation to Ir(iii) and Rh(iii) half-sandwich complexes seems to switch on their antibacterial activity towards Enterococcus faecium and Staphylococcus aureus Gram-positive bacteria.

Oncosis (from Greek ónkos, meaning “swelling”) is a non-apoptotic cell death process related to energy depletion. In contrast to apoptosis, which is the main form of cell death induced by anticancer drugs, oncosis has been relatively less explored but holds potential to overcome drug resistance phenomena. In this study, we report a novel rationally designed mitochondria-targeted iridium(III) complex (OncoIr3) with advantageous properties as a bioimaging agent. OncoIr3 exhibited potent anticancer activity in vitro against cancer cells and displayed low toxicity to normal dividing cells. Flow cytometry and fluorescence-based assays confirmed an apoptosis-independent mechanism involving energy depletion, mitochondrial dysfunction and cellular swelling that matched with the oncotic process. Furthermore, a Caenorhabditis elegans tumoral model was developed to test this compound in vivo, which allowed us to prove a strong oncosis-derived antitumor activity in animals (with a 41% reduction of tumor area). Indeed, OncoIr3 was non-toxic to the nematodes and extended their mean lifespan by 18%. Altogether, these findings might shed new light on the development of anticancer metallodrugs with non-conventional modes of action such as oncosis, which could be of particular interest for the treatment of apoptosis-resistant cancers. Graphical abstract

The antimicrobial activity of a new series of heteroleptic iridium(III) complexes of the type [Ir(C^N)₂(N^N)][PF₆] (C^N = deprotonated 2-phenylbenzimidazole-κN, κC; N^N = phen (Ir1), dpq (Ir2), dppz (Ir3), dppn (Ir4), and dppz-idzo (Ir5)) was studied towards two Gram positive (vancomycin-resistant Enterococcus faecium and a methicillin-resistant Staphylococcus aureus) and two Gram negative (Acinetobacter baumanii and Pseudomonas aeruginosa) multidrug-resistant bacterial strains of clinical interest. Although the complexes were inactive towards Gram negative bacteria, their effectiveness against Gram positive strains was remarkable, especially for Ir1 and Ir2, the most bactericidal complexes that were even more active (10 times) than the fluoroquinolone antibiotic norfloxacin and displayed no toxicity in human kidney cells (HEK293). Mechanistic studies revealed that the cell wall and membrane of MRSA S. aureus remained intact on treatment with these compounds and that DNA was not their main target. It is important to note that the complexes were able to induce ROS generation, this being the feature key to their antimicrobial activity.