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The fast-moving field of photodynamic therapy (PDT) has provided fresh opportunities to expand the potential of metallodrugs to combat cancers in a light-controlled manner. As such, in the present study, a series of cyclometalated Ir(III) complexes modified with a tetrazine functional group (namely, Ir-ppy-Tz, Ir-pbt-Tz, and Ir-dfppy-Tz) are developed as potential two-photon photodynamic anticancer agents. These complexes target mitochondria but exhibit low toxicity towards HLF primary lung fibroblast normal cells in the dark. When receiving a low-dose one- or two-photon PDT, they become highly potent towards A549 lung cancer cells (with IC50 values ranging from 24.0 nM to 96.0 nM) through the generation of reactive oxygen species (ROS) to induce mitochondrial damage and subsequent apoptosis. Our results indicated that the incorporation of tetrazine with cyclometalated Ir(III) matrices would increase the singlet oxygen (1O2) quantum yield (ΦΔ) and, meanwhile, enable a type I PDT mechanism. Ir-pbt-Tz, with the largest two-photon absorption (TPA) cross-section (σ2 = 102 GM), shows great promise in serving as a two-photon PDT agent for phototherapy. [ABSTRACT FROM AUTHOR]

Photodynamic therapy (PDT) provides an alternative option to root out localized triple-negative breast cancer (TNBC) and has been experiencing a surge of research interest over recent years. In this study, we put forward a paradigm of designing novel transition metal-based PSs with the following characteristics: favorable cell-permeability, significant light-harvesting ability and prominent ROS yield. A novel BODIPY-Ir(III) conjugate has been designed as a photoinduced ROS (1O2, ˙OH and ˙O2−) generator. BODIPY-Ir is highly photoactive in subduing cancer cells in the PDT regimen with PI values ranging from 172 to 519 and EC50 in the nanomolar regime. Among various cancerous cell lines, TNBC was especially sensitive to BODIPY-Ir-mediated PDT, with a stunning EC50 value of 4.32 nM (PI = 519) under a moderate flux of visible-light irradiation (500 nm, 10.5 mW cm−2). BODIPY-Ir mainly accumulates in mitochondria and induces cell apoptosis under irradiation. Furthermore, the nanomolar antiproliferative activity of BODIPY-Ir is retained under hypoxia (2.5% O2). This work sheds light on instilling the O2-independent type I mechanism and conferring a red-shift absorption to metal-based PSs which fundamentally facilitate the clinical translation of PSs. [ABSTRACT FROM AUTHOR]

Photodynamic therapy (PDT), a therapeutic mode involving light triggering, has been recognized as an attractive oncotherapy treatment. However, nonnegligible challenges remain for its further clinical use, including finite tumor suppression, poor tumor targeting, and limited therapeutic depth. The photosensitizer (PS), being the most important element of PDT, plays a decisive role in PDT treatment. This review summarizes recent progress made in the development of PSs for overcoming the above challenges. This progress has included PSs developed to display enhanced tolerance of the tumor microenvironment, improved tumor-specific selectivity, and feasibility of use in deep tissue. Based on their molecular photophysical properties and design directions, the PSs are classified by parent structures, which are discussed in detail from the molecular design to application. Finally, a brief summary of current strategies for designing PSs and future perspectives are also presented. We expect the information provided in this review to spur the further design of PSs and the clinical development of PDT-mediated cancer treatments. [ABSTRACT FROM AUTHOR]

A Ru(II)–BODIPY conjugate has been rationally designed and exhibits an intense absorption in the NIR region to boost lysosome-targeted PDT in vitro and in vivo. The advantages of Ru(II) and BODIPY were successfully instilled into the conjugate to yield highly effective PDT efficacy against malignant melanoma A375 cells (PI = 3448) and A375 mice xenografts. [ABSTRACT FROM AUTHOR]

An RGD-peptide conjugated ruthenium(II) complex has been developed, which functions as a two-photon absorption (TPA) photodynamic therapy (PDT) agent for ablating tumours by selectively targeting the mitochondria of integrin αvβ3-rich tumour cells. This approach offers a new and effective design and application for tumour-targeting metallo-anticancer drugs via two-photon PDT. [ABSTRACT FROM AUTHOR]

Herein, we present a series of dual-targeted ruthenium–glucose conjugates that can function as two-photon absorption (TPA) PDT agents to effectively destroy tumors by preferentially targeting both tumor cells and mitochondria. The in vivo experiments revealed an excellent tumor inhibitory efficiency of the dual-targeted TPA PSs. [ABSTRACT FROM AUTHOR]

A mitochondria-targeting hetero-binuclear Ir(III)–Ru(II) complex was developed as a photoactivated chemotherapy (PACT) and photodynamic therapy (PDT) bifunctional agent to achieve a synergistic effective therapeutic outcome for the therapy of cisplatin-resistant tumour cells. [ABSTRACT FROM AUTHOR]

The endoplasmic reticulum (ER) is an indispensable organelle that undertakes the synthesis and export of proteins and membrane lipids. Subtle interferences of the ER redox signaling pathway are very likely to cause ER-stress induced apoptosis. In view of this, we herein present a series of ER-targeted Ir(iii) complexes (Ir1–Ir3) as photodynamic therapy (PDT) photosensitizers with a gradually extended conjugation area in the main ligand, and study the correlation between the conjugation area and PDT performance. The results showed that all of these complexes can accumulate in the ER and effectively induce cell apoptosis after PDT therapeutics (405 nm, 6 J cm−2) by an ER stress mechanism, and both their singlet oxygen quantum yields and cytotoxicities increase as the conjugation area extends. All complexes showed PDT efficacy towards different cancer cell lines. Among them, Ir2 exhibited the highest PI value (94.3) against A549 cells with an IC50 down to 0.65 μM. In addition, the post PDT ER-stress induced apoptosis along with the efflux of Ca2+ from the ER system in A549 cells in a short period of time (45–90 min) with the pretreatment of Ir2 was demonstrated. All of these results indicate the promising potential of Ir2 as an effective PDT photosensitizer. [ABSTRACT FROM AUTHOR]

Despite their past triumphs, platinum-based therapeutics remain limited by chemo-resistance and severe side effects. As an alternative therapeutic modality which bypasses these issues, photodynamic therapy (PDT) holds great promise. The first FDA approved PDT agent, Photofrin, stimulated an outpouring of porphyrin-motif studies, while metallodrugs have long been underappreciated in this area. Due to their unique and versatile properties, ruthenium complexes are receiving increasing attention in the field of PDT. Herein, we introduce the recent advances in Ru(II)-based PDT agents ranging from single molecules to delicate nanomaterials, how these agents are unique suited to PDT and the merits provided by their various forms. [ABSTRACT FROM AUTHOR]

Herein a series of mitochondria-targeted AIE (aggregation-induced emission)-active Ir(iii) complexes were designed to selectively exert one-/two-photon photodynamic activities in mitochondria to address the issues which current PDT are confronted with (i.e., shallow penetration depth of routinely used irradiation; systematic toxicity associated with effective drug concentration; concentration-quenched photodynamic activity at the target, etc.). [ABSTRACT FROM AUTHOR]

Clinical acceptance of photodynamic therapy is currently hindered by poor depth efficacy and inefficient activation of the cell death machinery in cancer cells during treatment. To address these issues, photoactivation using two-photon absorption (TPA) is currently being examined. Mitochondria-targeted therapy represents a promising approach to target tumors selectively and may overcome the resistance in current anticancer therapies. Herein, four ruthenium(II) polypyridyl complexes ( RuL1 – RuL4) have been designed and developed to act as mitochondria-targeted two-photon photodynamic anticancer agents. These complexes exhibit very high singlet oxygen quantum yields in methanol (0.74–0.81), significant TPA cross sections (124–198 GM), remarkable mitochondrial accumulation, and deep penetration depth. Thus, RuL1 – RuL4 were utilized as one-photon and two-photon absorbing photosensitizers in both monolayer cells and 3D multicellular spheroids (MCSs). These Ru(II) complexes were almost nontoxic towards cells and 3D MCSs in the dark and generate sufficient singlet oxygen under one- and two-photon irradiation to trigger cell death. Remarkably, RuL4 exhibited an IC 50 value as low as 9.6 μM in one-photon PDT ( λ irr = 450 nm, 12 J cm −2 ) and 1.9 μM in two-photon PDT ( λ irr = 830 nm, 800 J cm −2 ) of 3D MCSs; moreover, RuL4 is an order of magnitude more toxic than cisplatin in the latter test system. The combination of mitochondria-targeting and two-photon activation provides a valuable paradigm to develop ruthenium(II) complexes for PDT applications. [ABSTRACT FROM AUTHOR]

The photodynamic therapy (PDT) of cancer is limited by tumor hypoxia as PDT efficiency depends on O 2 concentration. A novel oxygen self-sufficient photosensitizer (Ru-g-C 3 N 4) was therefore designed and synthesized via a facile one-pot method in order to overcome tumor hypoxia-induced PDT resistance. The photosensitizer is based on [Ru(bpy) 2 ]2+ coordinated to g-C 3 N 4 nanosheets by Ru–N bonding. Compared to pure g-C 3 N 4 , the resulting nanosheets exhibit increased water solubility, stronger visible light absorption, and enhanced biocompatibility. Once Ru-g-C 3 N 4 is taken up by hypoxic tumor cells and exposed to visible light, the nanosheets not only catalyze the decomposition of H 2 O 2 and H 2 O to generate O 2 , but also catalyze H 2 O 2 and O 2 concurrently to produce multiple ROS (•OH, •O 2 −, and 1O 2). In addition, Ru-g-C 3 N 4 affords luminescence imaging, while continuously generating O 2 to alleviate hypoxia greatly improving PDT efficacy. To the best of our knowledge, this oxygen self-sufficient photosensitizer produced via grafting a metal complex onto g-C 3 N 4 is the first of its type to be reported. A novel oxygen self-sufficient photosensitizer (Ru-g-C 3 N 4) was constructed from cis -Ru 2 (bpy) 2 Cl 2 and g-C 3 N 4 by Ru–N coordination to achieve enhanced PDT in hypoxia. Ru-g-C 3 N 4 not only catalyze the decomposition of H 2 O 2 and H 2 O to generate O 2 , but also catalyze H 2 O 2 and O 2 concurrently to produce multiple ROS (•OH, •O 2 −, and 1O 2) for the treatment of cancer both in vitro and in vivo. Moreover, Ru-g-C 3 N 4 can be used for in vivo luminescence imaging to allow highly precise treatment. [Display omitted] [ABSTRACT FROM AUTHOR]