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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]

A hetero-bimetallic Ru(II)–Ir(III) photosensitizer was developed. Upon light exposure, contrary to the homogeneous Ru(II)–Ru(II) and Ir(III)–Ir(III) complexes that can only produce singlet oxygen, Ru(II)–Ir(III) can generate multiple reactive oxygen species and kill hypoxic tumors. This study presents the first example of a hetero-bimetallic type-I and type-II dual photosensitizer. [ABSTRACT FROM AUTHOR]

Metal complexes have shown promise as photosensitizers for cancer diagnosis and therapeutics. However, the vast majority of metal photosensitizers are not ideal and associated with several limitations including pharmacokinetic limitations, off-target toxicity, fast systemic clearance, poor membrane permeability, and hypoxic tumour microenvironments. Metal complex functionalized nanomaterials have the potential to construct multifunctional systems, which not only overcome the above defects of metal complexes but are also conducive to modulating the tumour microenvironment (TME) and employing combination therapies to boost photodynamic therapy (PDT) efficacy. In this review, we first introduce the current challenges of photodynamic therapy and summarize the recent research strategies (such as metal coordination bonds, self-assembly, π–π stacking, physisorption, and so on) used for preparing metal complexes functionalized nanomaterials in the application of PDT. [ABSTRACT FROM AUTHOR]

Chiral rhodium(III)–azobenzene complexes that are able to intercalate into DNA were developed. Upon light exposure, the azobenzene moiety of the metal complexes can photoisomerize from the trans-form to the cis-form, and strongly stabilize the DNA double-helix and modulate DNA transcription. This study presents the first example of metal-based photoswitchable DNA molecular locks. [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]

Herein, we developed the first metal-based mitochondrial topoisomerase inhibitors to achieve an effective therapeutic outcome for the therapy of cisplatin-resistant tumour cells. [ABSTRACT FROM AUTHOR]

Herein, we developed the first Ru(II) complex-based bioorthogonal two-photon photosensitizers. Through bioorthogonal labelling, they realize effective tumour-specific photodynamic therapy against triple-negative breast cancer cells. [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]

The drug-resistance of cancer cells has become a major obstacle to the development of clinical drugs for chemotherapy. In order to overcome cisplatin-resistance, seven cyclometalated ruthenium(II) complexes were synthesized with a varying degree of fluorine substitution, for use as anticancer agents. A cytotoxicity assay testified that the complexes possessed a more cytotoxic effect than cisplatin towards the cisplatin-resistant cell line A549R. The number of fluorine atoms regulated the lipophilicity of the complexes, but the relationship was not linear. Ru1 containing one fluorine atom had the highest lipophilicity and the best therapeutic effect. The complexes enter cells through an energy-dependent pathway and then localize in the nuclei and mitochondria. The complexes induced nuclear dysfunction by the inhibition of DNA replication as well as mitochondrial dysfunction by the loss of membrane potential. The damage to these vital organelles leads to cell apoptosis via the caspase 3/7 pathway. Our results indicated that the modulation of the number of fluorine atoms in therapeutic agents can have a profound effect and Ru1 is a complex with a high potential as a drug for the treatment of cisplatin-resistant cancer. [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]

Nucleus-targeting NPs based on RuO2 (RuO2NPs) were developed by controlling the size and the surface charge of nanoparticles (NPs). This study not only demonstrates a facile approach for the fabrication of ultrasmall CS-RuO2NPs with good biocompatibility and excellent photothermal properties but also their unique potential for the nucleus-targeted low-temperature PTT. [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]

Ru(II) polypyridyl complexes, containing a morpholine moiety, and possessing two-photon absorption properties and pH dependent singlet oxygen production were used for stepwise lysosomes-to-mitochondria photodamage of cancer cells. [ABSTRACT FROM AUTHOR]

Platinum-resistant cancer cells are sensitive to changes in the levels of reactive oxidative species (ROS). Herein, we design a biotin-modified Ru(II) complex as a photosensitizer (denoted as Ru-Biotin). Ru-Biotin can selectively target cancer cells and produce vast amounts of singlet oxygen under two-photon excitation at 820 nm leading to cell apoptosis. Ru-Biotin is therefore an excellent candidate to overcome platinum resistance via two-photon photodynamic therapy. [ABSTRACT FROM AUTHOR]

Ir(III) complex modified gold nanorods, Ir@AuNRs, were developed as mitochondria-targeted theranostic nanoagents. Their hypoxia imaging and photothermal therapeutic properties were demonstrated in vitro and in vivo. [ABSTRACT FROM AUTHOR]

Cu2−xSe nanoparticles (Cu2−xSeNPs) were camouflaged with a red blood cell membrane (RBC) to create nanoparticles with improved biocompatibility, longer blood retention times, excellent absorption properties, superior photothermal conversion efficiency (67.2%) and singlet oxygen production capabilities for the synergistic photothermal and photodynamic therapy of cancer in the second near-infrared (NIR-II) window. [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]

Multidrug resistance mediated by the overexpression of ABC transporters is a major challenge in cancer chemotherapy. Here, we report the synthesis of an organoruthenium complex, RuF, that was designed to surmount multidrug resistance by combining ABCG2 inhibition and cancer cell cytotoxicity, yielding synergistic efficacy. [ABSTRACT FROM AUTHOR]

In this paper, the DNA interaction properties of four Ru(ii) polypyridyl complexes, [Ru(bpy)2(pip)]2+ (1), bpy = 2,2′-bipyridine, pip = 2-phenyl-imidazo[4,5-f][1,10]phenanthroline, [Ru(bpy)2(nip)]2+ (2), nip = 2-naphthyl-imidazo[4,5-f][1,10]phenanthroline, [Ru(bpy)2(aip)]2+ (3), aip = 2-(9-anthryl)-imidazo[4,5-f][1,10]phenanthroline and [Ru(bpy)2(pyip)]2+ (4), pyip = 2-(1-pyrenyl)-imidazo[4,5-f][1,10]phenanthroline, were investigated by spectral titration. The intensity increases in the MLCT band of the complexes and the decrease in absorption due to the DNA secondary structure was attributed to DNA condensation by these complexes. The DNA condensing behavior of these complexes was investigated in more detail by gel electrophoresis (GAR), dynamic light scattering (DLS), zeta potential, atomic force microscopy (AFM), and transmission electron microscopy (TEM). The results suggest that the concentration of the complex plays a critical role in its DNA intercalating and DNA condensing behavior. Meanwhile, the aryl units in the ligands of complex 1–4 also have a large effect on their interactions with DNA. [ABSTRACT FROM AUTHOR]

Abnormal levels of biological viscosity are closely associated with some diseases and malfunction (e.g. cancer, diabetes). Sensitive viscosity probes are of significant importance in disease diagnosis and remain an unmet need. In this research, we present a novel viscosity-sensitive dinuclear Ir(iii) complex (1), which freely rotates and shows weak phosphorescence in a low-viscosity environment, while in viscous media, both the phosphorescence intensity and lifetime are enhanced significantly. 1 can further be applied for phosphorescence lifetime imaging (PLIM) and measure lysosomal microviscosity with high accuracy and reliability. Interestingly, this PLIM property can distinguish between tumorous and nontumorous cells. Importantly, the probe shows much stronger phosphorescence in the fresh blood of diabetic mice than that of normal mice. This work offers a potential efficient probe for diagnosing viscosity related diseases. [ABSTRACT FROM AUTHOR]

Iridium complexes were used as a mitochondria-targeting agent to modify the surface of a photothermogenic nanozyme Fe3O4 nanoparticles (Ir@Fe3O4 NPs). Upon NIR irradiation, Ir@Fe3O4 NPs increase the localized temperature to 42 °C which accelerates the catalysis of ṖOH production from H2O2 resulting in excellent mild photothermal therapy. [ABSTRACT FROM AUTHOR]

Mitochondria are the control centers of apoptosis. To study mitochondrial dynamics during apoptosis, four phosphorescent fluorinated iridium(iii) complexes (Ir1–Ir4) were designed and synthesized. The complexes' emission maxima, phosphorescent quantum yields, and phosphorescent lifetimes are tuned by the degree of fluorination of the ligand. The complexes exhibit excellent photostability and low (photo)cytotoxicity in HeLa cells. As the complexes are cationic and lipophilic, they localize in mitochondria and enter cells through an energy-independent pathway. In comparison with commercially available mitochondrial trackers (e.g., MTR), Ir1–Ir4 exhibit high specificity to mitochondria even in fixed cells. Due to these outstanding properties, the complexes were successfully used to track mitochondrial dynamics during apoptosis. [ABSTRACT FROM AUTHOR]

A hetero-binuclear Ir(iii)–Pt(ii) complex was developed as an antitumor agent. In vitro cytotoxicity results indicated that this complex was effective against cisplatin-resistant tumor cells. Mechanism experiments showed that it can overcome cisplatin resistance by increasing cellular uptake, targeting mitochondria, and inducing cell necrosis. [ABSTRACT FROM AUTHOR]

Two iridium(iii) complexes with ligands containing morpholine groups were used to track mitochondrial pH fluctuation during cell apoptosis as their emissive intensities linearly increased with increase in pH values. [ABSTRACT FROM AUTHOR]

A novel near infrared (NIR) phosphorescent osmium complex (Os1) was developed for lysosome tracking and photodynamic therapy. Owing to its NIR photophysical properties, cellular imaging ability and phototoxicity, it has advantages over its ruthenium analogue (Ru1). [ABSTRACT FROM AUTHOR]

In this article, we report on the development of new metal-based anticancer agents with imaging, chemotherapeutic and photosensitizing properties. Hence, a new heterobimetallic complex (Pt-LQ-Re) was prepared by connecting a non-conventional trans-chlorido Pt(ii) complex to a photoactive Re tricarbonyl unit (LQ-Re), which can be replaced by 99mTc to allow for in vivo imaging. We describe the photophysical and biological properties of the new complexes, in the dark and upon light irradiation (DNA interaction, cellular localization and uptake, and cytotoxicity). Furthermore, planar scintigraphic images of mice injected with Pt-LQ-Tc clearly showed that the radioactive compound is taken up by the excretory system organs, namely liver and kidneys, without significant retention in other tissues. All in all, the strategy of conjugating a chemotherapeutic compound with a PDT photosensitizer endows the resulting complexes with an intrinsic cytotoxic activity in the dark, driven by the non-classical platinum core, and a selective activity upon light irradiation. Most importantly, the possibility of integrating a SPECT imaging radiometal (99mTc) in the structure of these new heterobimetallic complexes might allow for in vivo non-invasive visualization of their tumoral accumulation, a crucial issue to predict therapeutic outcomes. [ABSTRACT FROM AUTHOR]

Cancer is rapidly becoming the top killer in the world. Most of the FDA approved anticancer drugs are organic molecules, while metallodrugs are very scarce. The advent of the first metal based therapeutic agent, cisplatin, launched a new era in the application of transition metal complexes for therapeutic design. Due to their unique and versatile biochemical properties, ruthenium-based compounds have emerged as promising anti-cancer agents that serve as alternatives to cisplatin and its derivertives. Ruthenium(iii) complexes have successfully been used in clinical research and their mechanisms of anticancer action have been reported in large volumes over the past few decades. Ruthenium(ii) complexes have also attracted significant attention as anticancer candidates; however, only a few of them have been reported comprehensively. In this review, we discuss the development of ruthenium(ii) complexes as anticancer candidates and biocatalysts, including arene ruthenium complexes, polypyridyl ruthenium complexes, and ruthenium nanomaterial complexes. This review focuses on the likely mechanisms of action of ruthenium(ii)-based anticancer drugs and the relationship between their chemical structures and biological properties. This review also highlights the catalytic activity and the photoinduced activation of ruthenium(ii) complexes, their targeted delivery, and their activity in nanomaterial systems. [ABSTRACT FROM AUTHOR]

A series of NIR-emitting iridium(iii) complexes were developed for multimodal phosphorescence imaging (NIR imaging, phosphorescence lifetime imaging and time-gated imaging) of mitochondria in living cells, 3D multicellular spheroids (MTCCs) and hippocampus slice under two-photon excitation. [ABSTRACT FROM AUTHOR]

Herein we present a series of DCA-Ir(iii) co-drug complexes that preferentially accumulate in mitochondria and selectively cause cancer cell metabolic alterations and were found to act in synergy by sensitizing cancer cells for PDT to achieve cancer-specific enhanced two-photon PDT in the hypoxic environment of multicellular tumor spheroids. [ABSTRACT FROM AUTHOR]

The DNA photoswitch [Ru(bpy)2dppz]2+ (bpy = 2,2′-bipyridine, dppz = dipyrido[3,2-a:2′,3′-c]phenazine) has attracted much attention and become a powerful tool for studying the interaction of metal polypyridyl complexes with DNA. A large number of Ru-dppz complexes have been designed for a wide range of uses in many fields. In this perspective, we first introduce the latest results of Ru-dppz complexes that bind with DNA. The mechanisms of the light-switch effect and the structural modifications of Ru-dppz systems are also briefly introduced. We also review the recent advances in biological applications of the Ru-dppz system in DNA binders, cellular imaging, anticancer drugs, protein aggregation detection and chemosensors. [ABSTRACT FROM AUTHOR]

By integrating targeting, imaging and treatment, organelle-targeted photodynamic therapy (PDT) has been reported to be an effective strategy for cancer therapy. However, targeting leads to the accumulation of photosensitizers (PSs) in the targeted organelles, which leads to a reduction in 1O2 generation and fluorescence quenching, especially for the lipophilic mitochondria-targeted PSs. Moreover, because PSs always need exposure to light for a specific period, photobleaching is difficult to avoid. To address these issues, two iridium(iii) complexes with aggregation-induced two-photon emission (AITPE) characteristics were developed. With lipophilicity, the complexes aggregated in water and targeted mitochondria. Owing to their impressive 1O2 production quantum yields and excellent two-photon properties in the aggregate states, the complexes were successfully used for mitochondria-targeted two-photon PDT in monolayer cells and multicellular spheroids. Our results highlighted that the use of a PS with aggregation enhanced 1O2 generation and fluorescence is an effective solution for aggregation in organelle-targeted PDT. [ABSTRACT FROM AUTHOR]

Six cyclometalated iridium(iii) complexes bearing different numbers of fluorine atoms were synthesized. These complexes demonstrated much better anti-proliferation activities towards five tumour cell lines than the widely used clinical chemotherapeutic agent cisplatin. Moreover, the anti-proliferation activities were correlated to the number of substituted fluorine atoms. Colocalization and inductively coupled plasma-mass spectrometry (ICP-MS) indicated that this series of complexes could penetrate cell membranes rapidly and preferentially target mitochondria. Manifesting high selectivity between tumour cells and normal cells and remarkable sensitivity to a cisplatin-resistant cell line (A549R), complex Ir6 was successfully developed as a novel anticancer agent (with IC50 values of 0.5 ± 0.1 μM for HeLa, 1.1 ± 0.2 μM for HepG2, 1.5 ± 0.3 μM for BEL-7402, 0.8 ± 0.1 μM for A549, and 0.7 ± 0.2 μM for A549R cell lines). Further mechanism studies including mitochondrial membrane potential depolarization and caspase 3/7 activation revealed that Ir6 induced apoptosis via mitochondrial pathways. These results demonstrated that complex Ir6 might be a promising candidate as a mitochondria-targeted theranostic anticancer agent. [ABSTRACT FROM AUTHOR]

Biocompatible transition metal complexes dyes emitting in the near-infrared (NIR) region, are highly desirable in fluorescence imaging techniques. However, a high-performance mitochondria-specific labeling NIR probe with high photostability is still lacking. Herein we reported two NIR-emitting cationic iridium(iii) complexes [Ir(pbq-g)2(N^N)]+Cl− (pbq-g = phenylbenzo[g]-quinoline; N^N = 2-(1-benzyl-1H-pyrazol-3-yl) pyridine (Ir1) and 2-(1-(naphthalen-1-ylmethyl)-1H-pyrazol-3-yl) pyridine (Ir2)). These two novel Ir(iii) complexes with different N^N ligands exhibited similar NIR emission with λmax at 751 nm for Ir1 and 750 nm for Ir2 in PBS solution, with luminescence quantum yields of around 0.62 for Ir1 and 0.85 for Ir2. These two complexes showed high mitochondrial specificity, superior photostability, high resistance to the loss of the mitochondrial membrane potential and appreciable tolerance to environmental changes, allowing NIR imaging of mitochondrial morphological changes over long periods of time. These excellent photophysical and imaging properties made them promising NIR luminescent tags for applications in bioimaging. [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]

A glutathione (GSH)-activatable ruthenium(ii)-azo photosensitizer was prepared. The complex had low toxicity towards cells under dark conditions. It exhibited excellent phototoxicity under two-photon excitation (810 nm) and thus was developed as a two-photon photodynamic anticancer agent for cancer therapy. [ABSTRACT FROM AUTHOR]

Gold nanorods (AuNRs) and nanostars (AuNTs) were widely applied in photothermal cancer therapy recently. However, due to the photothermal effect, naked AuNRs and AuNTs easily melt into gold spheres. This drawback results in loss of the characteristic near-infrared (NIR) surface plasmon resonance (SPR) and limits their therapeutic applications. In this paper, we reported that ruthenium(ii) complex-functionalized AuNRs (AuNRs@Ru) and AuNTs (AuNTs@Ru) exhibit higher photothermal stability and photothermal efficiency than naked AuNRs and AuNTs. AuNRs@Ru and AuNTs@Ru maintain the morphology and NIR SPR absorption of gold nanoparticles upon 0.25 W cm−2 laser irradiation, which is lower than the maximal permissible exposure of skin as per ANSI regulation (0.33 W cm−2 at 808 nm). Further photothermal therapy studies on three-dimensional (3D) HeLa spheroids and an in vivo tumor model show that AuNRs@Ru and AuNTs@Ru are more effective for the photothermal destruction of tumors than AuNRs and AuNTs. [ABSTRACT FROM AUTHOR]