Ruthenium(II) complexes coordinated to graphitic carbon nitride: Oxygen self-sufficient photosensitizers which produce multiple ROS for photodynamic therapy in hypoxia.

The photodynamic therapy (PDT) of cancer is limited by tumor hypoxia as PDT efficiency depends on O2 concentration. A novel oxygen self-sufficient photosensitizer (Ru-g-C3N4) 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-C3N4 nanosheets by Ru-N bonding. Compared to pure g-C3N4, the resulting nanosheets exhibit increased water solubility, stronger visible light absorption, and enhanced biocompatibility. Once Ru-g-C3N4 is taken up by hypoxic tumor cells and exposed to visible light, the nanosheets not only catalyze the decomposition of H2O2 and H2O to generate O2, but also catalyze H2O2 and O2 concurrently to produce multiple ROS (•OH, •O2-, and 1O2). In addition, Ru-g-C3N4 affords luminescence imaging, while continuously generating O2 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-C3N4 is the first of its type to be reported.

Nano-assembly of ruthenium(II) photosensitizers for endogenous glutathione depletion and enhanced two-photon photodynamic therapy.

Photodynamic therapy (PDT) is a promising noninvasive cancer treatment. PDT in the clinic faces several hurdles due to the unique tumor environment, a feature of which is high levels of glutathione (GSH). An excess amount of GSH consumes reactive oxygen species (ROS) generated by photosensitizers (PSs), reducing PDT efficiency. Herein, nano-photosensitizers (RuS1 NPs and RuS2 NPs) are reported. These consist of ruthenium complexes joined by disulfide bonds forming GSH sensitive polymer nanoparticles. The NPs achieve enhanced uptake compared to their constituent monomers. Inside cancer cells, high levels of GSH break the S-S bonds releasing PS molecules in the cell. The level of GSH is also then reduced leading to excellent PDT activity. Furthermore, RuS2 NPs functionalized with tumor targeting hyaluronic acid (HA@RuS2 NPs) assessed in vivo were highly effective with minimal side effects. To the best of our knowledge, RuS NPs are the first metal complex-based nano-assembled photosensitizers which exhibit enhanced specificity and consume endogenous GSH simultaneously, thus achieving excellent two-photon PDT efficiency in vitro and in vivo.

An ER-Targeting Iridium(III) Complex That Induces Immunogenic Cell Death in Non-Small-Cell Lung Cancer.

Immunogenic cell death (ICD) is a vital component of therapeutically induced anti-tumor immunity. An iridium(III) complex (Ir1), containing an N,N-bis(2-chloroethyl)-azane derivate, as an endoplasmic reticulum-localized ICD inducer for non-small cell lung cancer (NSCLC) is reported. The characteristic discharge of damage-associated molecular patterns (DAMPs), that is, cell surface exposure of calreticulin (CRT), extracellular exclusion of high mobility group box 1 (HMGB1), and ATP, were generated by Ir1 in A549 lung cancer cells, accompanied by an increase in endoplasmic reticulum stress and reactive oxygen species (ROS). The vaccination of immunocompetent mice with Ir1-treated dying cells elicited an antitumor CD8+ T cell response and Foxp3+ T cell depletion, which eventually resulted in long-acting anti-tumor immunity by the activation of ICD in lung cancer cells. Ir1 is the first Ir-based complex that is capable of developing an immunomodulatory response by immunogenic cell death.

Supramolecular Assembly of An Organoplatinum(II) Complex with Ratiometric Dual Emission for Two-Photon Bioimaging.

The organoplatinum(II) complex [Pt(C^N^N)(Cl)] (C^N^N=5,6-diphenyl-2,2'-bipyridine, Pt1) can assemble into nanoaggregates via π-π stacking and complementary hydrogen bonds, rather than Pt-Pt interactions. Pt1 exhibits ratiometric dual emission, including rare blue emission (λem =445 nm) and assembly-induced yellow emission (λem =573 nm), under one- and two-photon excitation. Pt1 displays blue emission in cells with an intact membrane due to its low cellular uptake. In cells where the membrane is disrupted, uptake of the complex is increased and at higher concentrations yellow emission is observed. The ratio of yellow to blue emission shows a linear relationship to the loss of cell membrane integrity. Pt1 is, to our knowledge, the first example of an assembly-induced two-photon ratiometric dual emission organoplatinum complex. The excellent and unique characteristics of the complex enabled its use for the tracking of cell apoptosis, necrosis, and the inflammation process in zebrafish.

A Mitochondrion-Localized Two-Photon Photosensitizer Generating Carbon Radicals Against Hypoxic Tumors.

The efficacy of photodynamic therapy is typically reliant on the local concentration and diffusion of oxygen. Due to the hypoxic microenvironment found in solid tumors, oxygen-independent photosensitizers are in great demand for cancer therapy. We herein report an iridium(III) anthraquinone complex as a mitochondrion-localized carbon-radical initiator. Its emission is turned on under hypoxic conditions after reduction by reductase. Furthermore, its two-photon excitation properties (λex =730 nm) are highly desirable for imaging. Upon irradiation, the reduced form of the complex generates carbon radicals, leading to a loss of mitochondrial membrane potential and cell death (IC50light =2.1 µm, IC50dark =58.2 µm, PI=27.7). The efficacy of the complex as a PDT agent was also demonstrated under hypoxic conditions in vivo. To the best of our knowledge, it is the first metal-complex-based theranostic agent which can generate carbon radicals for oxygen-independent two-photon photodynamic therapy.

Necroptosis Induced by Ruthenium(II) Complexes as Dual Catalytic Inhibitors of Topoisomerase I/II.

Inducing necroptosis in cancer cells is an effective approach to circumvent drug-resistance. Metal-based triggers have, however, rarely been reported. Ruthenium(II) complexes containing 1,1-(pyrazin-2-yl)pyreno[4,5-e][1,2,4]triazine were developed with a series of different ancillary ligands (Ru1-7). The combination of the main ligand with bipyridyl and phenylpyridyl ligands endows Ru7 with superior nucleus-targeting properties. As a rare dual catalytic inhibitor, Ru7 effectively inhibits the endogenous activities of topoisomerase (topo) I and II and kills cancer cells by necroptosis. The cell signaling pathway from topo inhibition to necroptosis was elucidated. Furthermore, Ru7 displays significant antitumor activity against drug-resistant cancer cells in vivo. To the best of our knowledge, Ru7 is the first Ru-based necroptosis-inducing chemotherapeutic agent.

Correction: Synthesis, characterization and anticancer mechanism studies of fluorinated cyclometalated ruthenium(ii) complexes.

Correction for 'Synthesis, characterization and anticancer mechanism studies of fluorinated cyclometalated ruthenium(ii) complexes' by Ya Wen et al., Dalton Trans., 2020, DOI: .

Synthesis, characterization and anticancer mechanism studies of fluorinated cyclometalated ruthenium(ii) complexes.

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.

A mitochondria-targeting magnetothermogenic nanozyme for magnet-induced synergistic cancer therapy.

Magnetic hyperthermia therapy (MHT) and chemodynamic therapy (CDT) are non-invasive in situ treatments without depth limitations and with minimum adverse effects on surrounding healthy tissue. We herein report a mitochondria-targeting magnetothermogenic nanozyme (Ir@MnFe2O4 NPs) for highly efficient cancer therapy. An iridium(III) complex (Ir) acts as a mitochondria-targeting agent on the surface of MnFe2O4 NPs. On exposure to an alternating magnetic field (AMF), the Ir@MnFe2O4 NPs induce a localized increase in temperature causing mitochondrial damage (MHT effect). Meanwhile glutathione (GSH) reduces Fe(III) to Fe(II) on the NPs surface, which in turn catalyzes the conversion of H2O2 to cytotoxic •OH (CDT effect). The depletion of GSH (a •OH scavenger) increases CDT efficacy, while the localized increase in temperature increases the rate of conversion of both Fe(III) to Fe(II) and H2O2 to •OH further enhancing the CDT effect. In addition, the disruption of cellular redox homeostasis due to CDT, leads to greater sensitivity of the cell towards MHT. This nanoplatform integrates these excellent therapeutic properties, with two-photon microscopy (TPM) (demonstrated in vitro) and magnetic resonance imaging (MRI) (demonstrated in vivo) to enable the precise and effective treatment of cancer.

Lysosome-Targeting Iridium(III) Probe with Near-Infrared Emission for the Visualization of NO/O2•- Crosstalk via In Vivo Peroxynitrite Imaging.

Nitric oxide (NO) and superoxide anions (O2•-) are two noteworthy reactive species implicated in various physiological and pathological processes, such as ROS-induced lysosomal cell death. The interaction ("crosstalk") between them may form a new mediator peroxynitrite (ONOO-) which has implications for cancer, diabetes, Alzheimer's disease, and liver-damage. It is therefore essential to investigate lysosomal NO/O2•- crosstalk in vivo through ONOO--responsive molecular tools in order to fully comprehend the physiological and pathological mechanisms involved. In this study, a lysosome-targeting iridium(III) complex, Ir-NIR, has been investigated as a near-infrared (NIR) phosphorescent probe for visualizing NO/O2•- crosstalk by the phosphorescent detection of endogenous ONOO- levels in vivo. Ir-NIR exhibits a rapid (within 200 s), highly sensitive, and approximately 100-fold enhanced response to ONOO- in phosphorescence intensity. Thus, these characteristics, coupled with good cell permeability and low cytotoxicity, enable the probe to be used to detect intracellular ONOO- living organisms both in vitro and in vivo.

Nucleus-targeting ultrasmall ruthenium(iv) oxide nanoparticles for photoacoustic imaging and low-temperature photothermal therapy in the NIR-II window.

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.

FerriIridium: A Lysosome-Targeting Iron(III)-Activated Iridium(III) Prodrug for Chemotherapy in Gastric Cancer Cells.

Reported is the FeIII -activated lysosome-targeting prodrug FerriIridium for gastric cancer theranostics. It contains a meta-imino catechol group that can selectively bond to, and be oxidized by, free FeIII inside the cell. Subsequent oxidative rearrangement releases FeII and hydrolyses the amine bond under acidic conditions, forming an aminobipyridyl Ir complex and 2-hydroxybenzoquinone. Thus, FeII catalyzes the Fenton reaction, transforming hydrogen peroxide into hydroxyl radicals, the benzoquinone compounds interfere with the respiratory chain, and conversion of the prodrug into the Ir complex leads to an increase in phosphorescence and toxicity. These properties, combined with the high FeIII content and acidity of cancer cells, make FerriIridium a selective and efficient theranostic agent (IC50 =9.22 µm for AGS cells vs. >200 µm for LO2 cells). FerriIridium is the first metal-based compound that has been developed for chemotherapy using FeIII to enhance both selectivity and potency.

A mitochondria-targeting dinuclear Ir-Ru complex as a synergistic photoactivated chemotherapy and photodynamic therapy agent against cisplatin-resistant tumour cells.

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.

A self-assembled Ru-Pt metallacage as a lysosome-targeting photosensitizer for 2-photon photodynamic therapy.

Photodynamic therapy (PDT) is a treatment procedure that relies on cytotoxic reactive oxygen species (ROS) generated by the light activation of a photosensitizer. The photophysical and biological properties of photosensitizers are vital for the therapeutic outcome of PDT. In this work a 2D rhomboidal metallacycle and a 3D octahedral metallacage were designed and synthesized via the coordination-driven self-assembly of a Ru(II)-based photosensitizer and complementary Pt(II)-based building blocks. The metallacage showed deep-red luminescence, a large 2-photon absorption cross-section, and highly efficient ROS generation. The metallacage was encapsulated into an amphiphilic block copolymer to form nanoparticles to encourage cell uptake and localization. Upon internalization into cells, the nanoparticles selectively accumulate in the lysosomes, a favorable location for PDT. The nanoparticles are almost nontoxic in the dark, and can efficiently destroy tumor cells via the generation of ROS in the lysosomes under 2-photon near-infrared light irradiation. The superb PDT efficacy of the metallacage-containing nanoparticles was further validated by studies on 3D multicellular spheroids (MCS) and in vivo studies on A549 tumor-bearing mice.

A biotinylated ruthenium(ii) photosensitizer for tumor-targeted two-photon photodynamic therapy.

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.

The stepwise photodamage of organelles by two-photon luminescent ruthenium(ii) photosensitizers.

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.

Mitochondria-targeted Ir@AuNRs as bifunctional therapeutic agents for hypoxia imaging and photothermal therapy.

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.

Bimodal Visualization of Endogenous Nitric Oxide in Lysosomes with a Two-Photon Iridium(III) Phosphorescent Probe.

Nitric oxide (NO) is a fundamental signaling molecule that shows complex effects on the catabolic autophagy process, which is closely linked with lysosomal function. In this study, a new lysosome-targeted, pH-independent, and two-photon phosphorescent iridium(III) complex, Ir-BPDA, has been investigated for endogenous NO detection and imaging. The rational design of the probe, as the addition of the morpholine moieties and the substitution of a benzyl group in the amino group in Ir-BPDA, facilitates its accumulation in lysosomes and makes the reaction product with NO, Ir-BPDA-NO, insusceptible in its phosphorescence intensity and lifetime against pH changes (pH 4-10), well suited for lysosomal NO detection (pH 4-6). Furthermore, Ir-BPDA exhibits a fast and 50-fold response to NO in phosphorescence intensity and a two-photon cross-section as high as 60 GM after the reaction, as well as a notably increased phosphorescence lifetime from 200.1 to 619.6 ns. Thus, accompanied by its photostability, Ir-BPDA enabled the detection of NO in the lipopolysaccharide-stimulated macrophages and zebrafish model, revealing the endogenous lysosomal NO distribution during inflammation in vivo by means of both TPM and PLIM imaging techniques.

Fabrication of red blood cell membrane-camouflaged Cu2-xSe nanoparticles for phototherapy in the second near-infrared window.

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.

DNA interaction of ruthenium(ii) complexes with imidazo[4,5-f][1,10]phenanthroline derivatives.

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.