👤 Li X.

Using photodynamic therapy (PDT) to trigger nonconventional cell death pathways has provided a new scheme for highly efficient and non-side effects to drug-resistant cancer therapies. Nonetheless, the unclear targets of available photosensitizers leave the manner of PDT-induced tumor cell death relatively unpredictable. Herein, we developed a novel Ru(II)-based photosensitizer, Ru-Poma. Possessing the E3 ubiquitin ligase CRBN-targeting moiety and high singlet oxygen yield of 0.96, Ru-Poma was demonstrated to specifically photodegrade endogenous CRBN, increase lipid peroxide, downregulate GPX4 and GAPDH expression, and consequently induce ferroptosis in cisplatin-resistant cancerous cells. Furthermore, with the deep penetration of two-photon excitation, Ru-Poma achieved drug-resistant circumvention in a 3D tumor cell model. Thus, we describe the first sample of the CRBN-targeting Ru(II) complex active in PDT. Show less

Title: Novel tris-bipyridine based Ru(II) complexes as type-I/-II photosensitizers for antitumor photodynamic therapy through ferroptosis and immunogenic cell death. Abstract: Ru(II) complexes have attracted attention as photosensitizers for their promising photodynamic properties. Herein, novel tris-bipyridine based Ru(II) complexes (6a-e) were synthesized by introducing saturated heterocycles to improve photodynamic properties and lipid-water partition coefficients. Among them, 6d demonstrated significant phototoxicity towards three cancer cells, with IC50 values of 5.66-7.17 μM, exceeding values in dark (IC50s > 100 μM). Under hypoxic conditions, 6d maintained excellent photodynamic activity in A549 cells, with PI values exceeding 24, highlighting its potential for highly effective type-I/-II photodynamic therapy by inducing ROS generation, oxidative stress, and mitochondrial damage. Additionally, it induced ferroptosis and immunogenic cell death of A549 cells by regulating the expression of relevant markers. Finally, 6d remarkably inhibited the growth of A549 transplanted tumor growth by 95.4 %. This Ru(II) complex shows great potential for cancer treatment with its potent photodynamic activity and diverse mechanisms of tumor cell death. Show less

Ruthenium polypyridyl complexes are promising anticancer candidates, while their cellular targets have rarely been identified, which limits their clinical application. Herein, we design a series of Ru(II) polypyridyl complexes containing bioactive β-carboline derivatives as ligands for anticancer evaluation, among which Ru5 shows suitable lipophilicity, high aqueous solubility, relatively high anticancer activity and cancer cell selectivity. The subsequent utilization of a photo-clickable probe, Ru5a, serves to validate the significance of ATP synthase as a crucial target for Ru5 through photoaffinity-based protein profiling. Ru5 accumulates in mitochondria, impairs mitochondrial functions and induces mitophagy and ferroptosis. Combined analysis of mitochondrial proteomics and RNA-sequencing shows that Ru5 significantly downregulates the expression of the chloride channel protein, and influences genes related to ferroptosis and epithelial-to-mesenchymal transition. Finally, we prove that Ru5 exhibits higher anticancer efficacy than cisplatin in vivo. We firstly identify the molecular targets of ruthenium polypyridyl complexes using a photo-click proteomic method coupled with a multiomics approach, which provides an innovative strategy to elucidate the anticancer mechanisms of metallo-anticancer candidates. Show less

Title: A Ru(II) complex-based COX-2 targeting type I photosensitizer evokes ferroptosis and apoptosis. Abstract: Photodynamic therapy (PDT) often faces challenges such as oxygen dependence and limited tumour specificity. We report a tumour-targeting photosensitizer (PS), RuCXB, which enhances uptake by cancer cells by targeting overexpressed cyclooxygenase-2 enzyme in tumours. RuCXB also reduces oxygen dependence via a type I PDT mechanism and achieves a strong therapeutic effect through the synergistic induction of ferroptosis and apoptosis. This work presents a reliable strategy for developing potent PSs with enhanced PDT efficacy, tumour selectivity, and diminished oxygen dependence. Show less

Half-sandwich iridium(III) (Ir^III) anticancer complexes, as promising alternatives to platinum-based drugs, especially for solving resistance to platinum drugs, have demonstrated excellent application prospect. The potency of these Ir^III complexes as anticancer agents could be significantly enhanced through the strategic modification of their peripheral ligands. In this study, four structurally varied triphenylamine (TPA)-modified half-sandwich Ir^III Schiff base complexes were designed and prepared. The incorporation of TPA unit has effectively endowed these complexes with suitable emission, which facilitates the evaluation of intracellular accumulation and cell morphology. These complexes demonstrated favorable in vitro anti-proliferative activity against A549 cell line (lung cancer cells, derived from alveolar basal epithelial cells), especially for pentamethylcyclopentadiene (Cp*)-based one (IrTS1 and IrTS3), and that is almost 2.5-fold more than cisplatin under the same conditions. Meanwhile, IrTS1 and IrTS3 possessed excellent activity against A549/DDP (cisplatin-resistant) cell line and the similar cytotoxicity to cisplatin against BEAS-2B cell line (derived from the bronchial epithelium of normal human lungs), then following a mitochondria apoptotic channel. Show less

Bladder cancer (BC) is one of the most common malignant tumors of the urinary system, and has a high recurrence rate and treatment resistance. Recent results indicate that mitochondrial metabolism influences the therapeutic outcomes of BC. Mitochondria-targeted photosensitizer (PS) is a promising anticancer therapeutic approach that may overcome the limitations of conventional BC treatments. Herein, two mitochondria-targeted iridium(III) PSs, Ir-Mito1 and Ir-Mito2, have been designed for BC treatment. Mechanically, Ir-Mito2 induced a decrease in mitochondrial membrane potential via white light activation, further triggering a reduction of the B-cell lymphoma 2 protein (Bcl-2)/Bcl-associated X protein (Bax) ratio and increment of cleaved caspase3. Meanwhile, the reduction of glutathione, deactivation of glutathione peroxidase 4 (GPX4), increase of acyl-CoA synthetase long chain family member 4 (ACSL4), and accumulation of lipid peroxide resulted in synergistically activating of ferroptosis and apoptosis. The results demonstrated that Ir-Mito2 exhibited excellent antitumor efficacy with superior biosafety in vivo. This work on light-activated and mitochondrial-targeted PS provides an innovative therapeutic platform for BC. Show less

In this study, the ligand EIPP (5-ethoxy-2-(1H-imidazo[4,5-f] [1,10] phenanthrolin-2-yl)phenol) and [Ir(ppy)₂(EIPP)](PF₆)] (5a, ppy = 2-phenylpyridine) and [Ir(piq)₂(EIPP)](PF₆)] (5b, piq = 1-phenylisoquinoline) were synthesized and they were entrapped into liposomes to produce 5alipo and 5blipo. 5a and 5b were characterized via HRMS, NMR, UV-vis and IR. The cytotoxicity of 5a, 5b, 5alipo and 5blipo on cancer and non-cancer cells was estimated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT). MTT assay demonstrated that 5a and 5b did not show any significant cellular activity but their liposome-encapsulated 5alipo and 5blipo had significant toxic effects. The mechanism of 5alipo, 5blipo-inducing apoptosis was explored by studying cellular uptake, mitochondrial localization, mitochondrial membrane potential, cytochrome C, glutathione (GSH), malondialdehyde (MDA) and protein immunoblotting. The results demonstrated that 5alipo and 5blipo caused a release of cytochrome C, downregulated the expression of Bcl-2, upregulated the expression of BAX, activated caspase 3, and downregulated PARP expression. It was shown that 5alipo and 5blipo could inhibit cancer cell proliferation in G2/M phase by regulating p53 and p21 proteins. Additionally, 5alipo and 5blipo induced autophagy through an adjustment from LC3-I to LC3-II and caused ferroptosis. The in vivo antitumor activity of 5alipo was examined in detail. Show less

Title: Design and anticancer behaviour of cationic/neutral half-sandwich iridium(III) imidazole-phenanthroline/phenanthrene complexes. Abstract: Considerable attention has been devoted to the exploration of organometallic iridium(III) (IrIII) complexes for their potential as metallic anticancer drugs. In this study, twelve half-sandwich IrIII imidazole-phenanthroline/phenanthrene complexes were prepared and characterized. Complexes exhibited promising in-vitro anti-proliferative activity, and some are obviously superior to cisplatin towards A549 cells. These complexes possessed suitable fluorescence, and a non-energy-dependent uptake pathway was identified, subsequently leading to their accumulation in the lysosome and the lysosomal damage. Additionally, complexes could inhibit the cell cycle (G1-phase) and catalyze intracellular NADH oxidation, thus substantiating the elevation of intracellular reactive oxygen species (ROS) level, which confirming the oxidative mechanism. Western blotting further confirmed that complexes could induce A549 cell apoptosis through the lysosomal-mitochondrial anticancer pathway, which was inconsistent with cisplatin. In summary, these complexes offer fresh concepts for the development of organometallic non‑platinum anticancer drugs. Show less

Title: White light increases anticancer effectiveness of iridium(III) complexes toward lung cancer A549 cells. Abstract: Anticancer activity has been extensively studies. In this article, three ligands 2-(6-bromobenzo[d][1,3]dioxol-5-yl)-1H-imidazo[4,5-f][1,10]phenanthroline (BDIP), 2-(7-methoxybenzo[d][1,3]dioxol-5-yl)-1H-imidazo[4,5-f][1,10]phenanthroline (MDIP), 2-(6-nitrobenzo[d][1,3]dioxol-5-yl)-1H-imidazo[4,5-f][1,10]phenanthroline (NDIP) and their iridium(III) complexes: [Ir(ppy)2(BDIP)](PF6) (ppy = deprotonated 2-phenylpyridine, 3a), [Ir(ppy)2(MDIP)](PF6) (3b) and [Ir(ppy)2(NDIP)](PF6) (3c) were synthesized. The cytotoxicity of 3a, 3b, 3c against Huh7, A549, BEL-7402, HepG2, HeLa, and non-cancer NIH3T3 was tested using 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) method. The results obtained from the MTT test stated clearly that these complexes demonstrated moderate or non-cytotoxicity toward Huh7, BEL-7402, HepG2 and HeLa except A549 cells. To improve the anticancer efficacy, we used white light to irradiate the mixture of cells and complexes for 30 min, the anticancer activity of the complexes was greatly enhanced. Particularly, 3a and 3b exhibited heightened capability to inhibit A549 cells proliferation with IC50 (half maximal inhibitory concentration) values of 0.7 ± 0.3 μM and 1.8 ± 0.1 μM, respectively. Cellular uptake has shown that 3a and 3b can be accumulated in the cytoplasm. Wound healing and colony forming showed that 3a and 3b significantly hinder the cell migration and growth in the S phase. The complexes open mitochondrial permeability transition pore (MPTP) channel and cause the decrease of membrane potential, release of cytochrome C, activation of caspase 3, and finally lead to apoptosis. In addition, 3a and 3b cause autophagy, increase the lipid peroxidation and lead to ferroptosis. Also, 3a and 3b increase the expression of calreticulin (CRT), high mobility group box 1 (HMGB1), heat shock protein 70 (HSP70), thereby inducing immunogenic cell death. Show less

Title: Lysosome-targeted cyclometalated Ir(III) complexes as photosensitizers/photoredox catalysts for cancer therapy. Abstract: A novel lysosome-targeted photosensitizer/photoredox catalyst based on cyclometalated Ir(III) complex IrL has been designed and synthesized, which exhibited excellent phosphorescence properties and the ability to generate single oxygen (1O2) and photocatalytically oxidize 1,4-dihydronicotinamide adenine dinucleotide (NADH) under light irradiation. Most importantly, the aforementioned activities are significantly enhanced due to protonation under acidic conditions, which makes them highly attractive in light-activated tumor therapy, especially for acidic lysosomes and tumor microenvironments. The photocytotoxicity of IrL and the mechanism of cell death have been investigated. Additionally, the tumor-killing ability of IrL under light irradiation was evaluated using a 4T1 tumor-bearing mouse model. This work provides a strategy for the development of lysosome-targeted photosensitizers/photoredox catalysts to overcome hypoxic tumors. Show less

Title: Anticancer activity and mechanism studies of photoactivated iridium(III) complexes toward lung cancer A549 cells. Abstract: Cyclometalated iridium(III) compounds have been widely explored due to their outstanding photo-physical properties and multiple anticancer activities. In this paper, three cyclometalated iridium(III) compounds [Ir(ppy)2(DBDIP)]PF6 (5a), [Ir(bzq)2(DBDIP)]PF6 (5b), and [Ir(piq)2(DBDIP)]PF6 (5c) (ppy: 2-phenylpyridine; bzq: benzo[h]quinoline; piq: 1-phenylisoquinoline, and DBDIP: 2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1H-imidazo[4,5-f][1,10]phenanthroline) were synthesized and the mechanism of antitumor activity was investigated. Compounds photoactivated by visible light show strong cytotoxicity against tumor cells, especially toward A549 cells. Biological experiments such as migration, cellular localization, mitochondrial membrane potential and permeability, reactive oxygen species (ROS) and calcium ion level detection were performed, and they demonstrated that the compounds induced the apoptosis of A549 cells through a mitochondrial pathway. At the same time, oxidative stress caused by ROS production increases the release of damage-related molecules and the expression of porogen gasdermin D (GSDMD), and the content of LDH released from damaged cell membranes also increased. Besides, the content of the lipid peroxidation product, malondialdehyde (MDA), increased and the expression of GPX4 decreased. These indicate that the compounds promote cell death by combining ferroptosis and pyroptosis. The results reveal that cyclometalated iridium(III) compounds 5a-5c may be a potential chemotherapeutic agent for photodynamic therapy of cancers. Show less

Title: Mitochondrial-targeted cyclometalated Ir(III)-5,7-dibromo/dichloro-2-methyl-8-hydroxyquinoline complexes and their anticancer efficacy evaluation in Hep-G2 cells. Abstract: Both 8-hydroxyquinoline compounds and iridium (Ir) complexes have emerged as potential novel agents for tumor therapy. In this study, we synthesized and characterized two new Ir(III) complexes, [Ir(L1)(bppy)2] (Br-Ir) and [Ir(L2)(bppy)2] (Cl-Ir), with 5,7-dibromo-2-methyl-8-hydroxyquinoline (HL-1) or 5,7-dichloro-2-methyl-8-hydroxyquinoline as the primary ligand. Complexes Br-Ir and Cl-Ir successfully inhibited antitumor activity in Hep-G2 cells. In addition, complexes Br-Ir and Cl-Ir were localized in the mitochondrial membrane and caused mitochondrial damage, autophagy, and cellular immunity in Hep-G2 cells. We tested the proteins related to mitochondrial and mitophagy by western blot analysis, which showed that they triggered mitophagy-mediated apoptotic cell death. Remarkably, complex Br-Ir showed high in vivo antitumor activity, and the tumor growth inhibition rate was 63.0% (P < 0.05). In summary, our study on complex Br-Ir revealed promising results in in vitro and in vivo antitumor activity assays. Show less

Screening new drug-target interactions (DTIs) by traditional experimental methods is costly and time-consuming. Recent advances in knowledge graphs, chemical linear notations, and genomic data enable researchers to develop computational-based-DTI models, which play a pivotal role in drug repurposing and discovery. However, there still needs to develop a multimodal fusion DTI model that integrates available heterogeneous data into a unified framework. Show less

The Keap1-Nrf2 signaling pathway plays a crucial role in cellular defense against oxidative stress-induced damage. Its activation entails the expression and transcriptional regulation of several proteins involved in detoxification and antioxidation processes within the organism. Keap1, serving as a pivotal transcriptional regulator within this pathway, exerts control over the activity of Nrf2. Various post-translational modifications (PTMs) of Keap1, such as alkylation, glycosylation, glutathiylation, S-sulfhydration, and other modifications, impact the binding affinity between Keap1 and Nrf2. Consequently, this leads to the accumulation of Nrf2 and its translocation to the nucleus, and subsequent activation of downstream antioxidant genes. Given the association between the Keap1-Nrf2 signaling pathway and various diseases such as cancer, neurodegenerative disorders, and diabetes, comprehending the post-translational modification of Keap1 not only deepens our understanding of Nrf2 signaling regulation but also contributes to the identification of novel drug targets and biomarkers. Consequently, this knowledge holds immense importance in the prevention and treatment of diseases induced by oxidative stress. Show less

Two new ruthenium(II) complexes [Ru(dip)₂(PPβC)]PF₆ (Ru1, dip = 4,7-diphenyl-1,10-phenanthroline, PPβC = N-(1,10-phenanthrolin-5-yl)-1-phenyl-9H-pyrido[3,4-b]indole-3-carboxamide) and [Ru(phen)₂(PPβC)]PF₆ (Ru2, phen = 1, 10-phenanthroline) with β-carboline derivative PPβC as the primary ligand, were designed and synthesized. Ru1 and Ru2 displayed higher antiproliferative activity than cisplatin against the test cancer cells, with IC₅₀ values ranging from 0.5 to 3.6 μM. Moreover, Ru1 and Ru2 preferentially accumulated in mitochondria and caused a series of changes in mitochondrial events, including the depolarization of mitochondrial membrane potential, the damage of mitochondrial DNA, the depletion of cellular ATP, and the elevation of intracellular reactive oxygen species levels. Then, it induced caspase-3/7-mediated A549 cell apoptosis. More importantly, both complexes could act as topoisomerase I catalytic inhibitors to inhibit mitochondrial DNA synthesis. Accordingly, the developed Ru(II) complexes hold great potential to be developed as novel therapeutics for cancer treatment. Show less

Title: Potent Half-Sandwich 16-/18-Electron Iridium(III) and Ruthenium(II) Anticancer Complexes with Readily Available Amine-Imine Ligands. Abstract: The synthesis and biological evaluation of stable 16-electron half-sandwich complexes have remained scarce. We herein present the different coordination modes (16-electron or 18-electron) between half-sandwich iridium(III) complexes and ruthenium(II) complexes derived from the same amine-imine ligands chelating hybrid sp3-N/sp2-N donors. The 16-electron iridium(III) and 18-electron ruthenium(II) complexes with different counteranions were obtained and identified by various techniques. The promising cytotoxicity of these complexes against A549 lung cancer cells, cisplatin-resistant A549/DPP cells, cervical carcinoma HeLa cells, and human hepatocellular liver carcinoma HepG2 cells was observed with IC50 values ranging from 5.4 to 16.3 μM. Moreover, these complexes showed a certain selectivity (selectivity index: 2.1-3.7) toward A549 cells and BEAS-2B normal cells. The variation of metal center, counteranion, 16/18-electron coordination mode, and ligand substituents showed little influence on the cytotoxicity and selectivity of these complexes. The mechanism of action study showed that these complexes could target mitochondria, induce the depolarization of the mitochondrial membrane, and promote the generation of intracellular reactive oxygen species (ROS). Further, the induction of cell apoptosis and the perturbation of the cell cycle in the G0/G1 phase were also observed for these complexes. Overall, it seems that the redox mechanism dominated the anticancer efficacy of these complexes. Show less

Combination of novel immunomodulation and traditional chemotherapy has become a new tendency in cancer treatment. Increasing evidence suggests that blocking the "don't eat me" signal transmitted by the CD47 can promote the phagocytic ability of macrophages to cancer cells, which might be promising for improved cancer chemoimmunotherapy. In this work, we conjugated CPI-alkyne modified by Devimistat (CPI-613) with ruthenium-arene azide precursor Ru-N₃ by copper-catalyzed azide-alkyne cycloaddition (CuAAC) reaction to construct Ru complex CPI-Ru. CPI-Ru exhibited satisfactory cytotoxicity towards the K562 cells while nearly non-toxic towards the normal HLF cells. CPI-Ru has been demonstrated to cause severe damage to mitochondria and DNA, ultimately inducing cancer cell death through the autophagic pathway. Moreover, CPI-Ru could significantly downregulate the expression of CD47 on the surface of K562 accompanied by the enhanced immune response by targeting the blockade of CD47. This work provides a new strategy for utilizing metal-based anticancer agents to block CD47 signal to achieve chemoimmunotherapy in chronic myeloid leukemia treatment. Show less

Ruthenium complexes are one of the most promising anticancer drugs triggered extensive research. Here, the synthesis and characterization of two ruthenium(II) polypyridine complexes containing 8-hydroxylquinoline as ligand, [Ru(dip)₂(8HQ)]PF₆ (Ru1), [Ru(dpq)₂(8HQ)]PF₆ (Ru2) (8HQ = 8-hydroxylquinoline; dip = 4,7-diphenyl-1,10-phenanthroline; dpq = pyrazino[2,3-f][1,10]phenanthroline) were reported. On the basis of cytotoxicity tests, Ru1 (IC₅₀ = 1.98 ± 0.02 μM) and Ru2 (IC₅₀ = 10.02 ± 0.19 μM) both showed good anticancer activity in a panel of cell lines, especially in HeLa cells. Researches on mechanism indicated that Ru1 and Ru2 acted on mitochondria and nuclei and induced reactive oxygen species (ROS) accumulation, while the morphology of nuclei and cell cycle had no significant change. Western blot assay further proved that GPX4 and Ferritin were down-regulated, which eventually triggered ferroptosis in HeLa cells. In addition, the toxicity test of zebrafish embryos showed that the concentrations of Ru1 and Ru2 below 120 μM and 60 μM were safe and did not have obvious effect on the normal development of zebrafish embryos. Show less

The biological efficacy of half-sandwich platinum group organometallic complexes of the formula [(η⁵-Cp^x)/(η⁶-arene)M(XY)Cl]^0/+ (XY = bidentate ligands; Cp^x = functionalized cyclopentadienyl; M = Ir, Rh, Ru, Os) has received considerable attention due to the significance of the metal center, chelating ligand, and Cp^x/arene moieties in defining their anticancer potency and selectivity. With a facile access to the BIAN-derived imine-amine ligands using alkylaluminum as the reductant, we herein described the preparation and characterization of 16 half-sandwich Ir(III), Rh(III), and Ru(II) complexes chelating the hybrid sp²-N/sp³-N donor ligand. A nonplanar five-member metallacycle was confirmed by X-ray single-crystal structures of Ir1-Ir3, Ir7, Rh1, Ru1, and Ru4. The attempt to prepare imine-amido complexes using a base as the deprotonating agent led to the mixture of imine-amine complexes, within which the leaving group Cl^- was displaced, and 16-electron imine-amido complexes without Cl^-. The half-sandwich imine-amine complexes in this system underwent rapid hydrolysis in aqueous solution, exhibited weak photoluminescence, and showed the ability of binding to CT-DNA and BSA. The cytotoxicity of all imine-amine complexes against A549 lung cancer cell lines, HeLa cervical cancer cell lines, and 4T1 mouse breast cancer cells was determined by an MTT assay. The IC₅₀ values of these complexes were in a range of 5.71-67.28 μM. Notably, most of these complexes displayed improved selectivity toward A549 cancer cells versus noncancerous BEAS-2B cells in comparison with the corresponding α-diimine complexes chelating the sp²-N/sp²-N donor ligand, which have been shown no selectivity in our previous report. The anticancer selectivity of these complexes appeared to be related to the redox-based mechanism including the catalytic oxidation of NADH to NAD⁺, reactive oxygen species (ROS) generation, and depolarization of the mitochondrial membrane. Further, inducing apoptosis of these complexes in A549 cancer cells and BEAS-2B normal cells also correlated with their anticancer selectivity, indicating the apoptosis mode of cell death in this system. In addition, these complexes could enter A549 cells via energy-dependent pathway and were able to impede the in vitro migration of A549 cells. Show less

The main challenge of cancer chemotherapy is the resistance of tumor cells to oxidative damage. Herein, we proposed a novel antitumor strategy: cyclic metal‑ruthenium (Ru) complexes mediate reductive damage to kill tumor cells. We designed and synthesized Ru(II) complexes with β-carboline as ligands: [Ru (phen)₂(NO₂-Ph-βC)](PF₆) (RuβC-7) and [Ru(phen)₂(1-Ph-βC)](PF₆) (RuβC-8). In vitro experimental results showed that RuβC-7 and RuβC-8 can inhibit cell proliferation, promote mitochondrial abnormalities, and induce DNA damage. Interestingly, RuβC-7 with SOD activity could reduce intracellular reactive oxygen species (ROS) levels, while RuβC-8 has the opposite effect. Accordingly, this study identified the reductive damage mechanism of tumor apoptosis, and may provide a new ideas for the design of novel metal complexes. Show less

A novel Ru(II) cyclometalated photosensitizer (PS), Ru-NH₂ , for photodynamic therapy (PDT) of formula [Ru(appy)(bphen)₂ ]PF₆ (where appy=4-amino-2-phenylpyridine and bphen=bathophenanthroline) and its cetuximab (CTX) bioconjugates, Ru-Mal-CTX and Ru-BAA-CTX (where Mal=maleimide and BAA=benzoylacrylic acid) were synthesised and characterised. The photophysical properties of Ru-NH₂ revealed absorption maxima around 580 nm with an absorption up to 725 nm. The generation of singlet oxygen (¹ O₂ ) upon light irradiation was confirmed with a ¹ O₂ quantum yield of 0.19 in acetonitrile. Preliminary in vitro experiments revealed the Ru-NH₂ was nontoxic in the dark in CT-26 and SQ20B cell lines but showed outstanding phototoxicity when irradiated, reaching interesting phototoxicity indexes (PI) >370 at 670 nm, and >150 at 740 nm for CT-26 cells and >50 with NIR light in SQ20B cells. The antibody CTX was successfully attached to the complexes in view of the selective delivery of the PS to cancer cells. Up to four ruthenium fragments were anchored to the antibody (Ab), as confirmed by MALDI-TOF mass spectrometry. Nonetheless, the bioconjugates were not as photoactive as the Ru-NH₂ complex. Show less

In this work, four naphthalene diimide (NDI)-functionalized half-sandwich Ru(II) complexes Ru1-Ru4 bearing the general formula [(η⁶-arene)Ru^II(N^N)Cl]PF₆, where arene = benzene (bn), p-cymene (p-cym), 1,3,5-trimethylbenzene (tmb), and hexamethylbenzene (hmb), have been synthesized and characterized. By introducing the NDI unit into the N,N-chelating ligand of these half-sandwich complexes, the poor luminescent half-sandwich complexes are endowed with excellent emission performance. Besides, modification on the arene ligand of arene-Ru(II) complexes can influence the electron density of the metal center, resulting in great changes in the kinetic properties, catalytic activities in the oxidative conversion of NADH to NAD⁺, and biological activities of these compounds. Particularly, Ru4 exhibits the highest reactivity and the strongest inhibitory activity against the growth of three tested cancer cell lines. Further study revealed that Ru4 can enter cells quickly in an energy-dependent manner and preferentially accumulate in the mitochondria of MDA-MB-231 cells, inducing cell apoptosis via reactive oxygen species overproduction and mitochondrial dysfunction. Significantly, Ru4 can effectively inhibit the cell migration and invasion. Overall, the complexation with NDI and modification on the arene ligand endowed the half-sandwich Ru(II) complexes with improved spectroscopic properties and anticancer activities, highlighting their potential applications for cancer treatment. Show less

Title: Comparative studies on Abstract: On the basis of our previous comparative studies on the DNA binding of a pair of ruthenium(II) complex enantiomers, Δ-[Ru(bpy)2PBIP]2+ and Λ-[Ru(bpy)2PBIP]2+ {bpy = 2,2'-bipyridine, PBIP = 2-(4-bromophenyl)imidazo[4,5-f]1,10-phenanthroline}, in this study, their antitumor activities and mechanisms were further investigated comparatively. The cytotoxicity assay demonstrated that both the enantiomers exerted selective antiproliferative effects on cancer cell lines A2780 and PC3. Fluorescence localization experiments suggested that both the enantiomers effectively permeated the nucleus of HeLa cells and co-localized with DNA, resulting in their DNA damage and apoptosis. Flow cytometry experiments showed that the apoptosis was enhanced by increasing the concentration of each enantiomer. Western blotting analyses indicated that both extrinsic and intrinsic apoptosis pathways were activated by the two enantiomers. miRNA microarray analyses displayed that both the enantiomers up- and downregulated multiple miRNAs, some of which were predicted to be associated with carcinogenesis. The above experimental results also showed that the Δ-enantiomer exerted a more potent antitumor activity, a higher efficiency of entering cancer cells and a stronger apoptosis-inducing effect compared with the Λ-enantiomer. Combined with the previously published research results, experimental results from this study implied that the antitumor activity of a metal complex might have originated from the conformation change of DNA in tumor cells caused by the intercalation of the complex, that the antitumor mechanism of a metal complex could be related to its DNA-binding mode, and that the antitumor efficiency of a metal complex could result from its DNA-binding strength. Show less

Three ruthenium arene complexes, namely {[(η⁶-p-cymene)Ru(Cl)]₂(dpb)}(PF₆)₂ (1), [(η⁶-p-cymene)Ru(dpb)Cl](PF₆) (2) and [(η⁶-p-cymene) Ru(dpb)py](PF₆) (3) (dpb = 2,3-bis(2-pyridyl)benzo-quinoxaline, py = pyridine), were synthesized and their antitumor properties were introduced. Complexes 1-3 were characterized by ¹H NMR, MS, and elemental analysis. As a binuclear ruthenium structure, the absorption of metal ligand electron transfer (MLCT) of 1 extended to 700 nm. Complex 1 was significantly hydrolyzed under dark conditions. The cytotoxicity in vitro study showed that complexes 1 and 2 are more toxic to human lung cancer cells (A549) and human cervial cancer cells (Hela) than cisplatin. Moreover, there was almost no cross-resistance between complex 1-2 and cisplatin. Under the irradiation at 478 nm, complexes 1-3 all produced singlet oxygen (¹O₂), and the ¹O₂ quantum yield of complex 1 in PBS is the highest among complexes 1-3. Complex 1 also produced ¹O₂ under 600 nm light irradiation. DNA gel electrophoresis showed that 1 caused the photocleavage of plasmid DNA. The hydrolysis rate of complex 1 was accelerated under light (λ > 600 nm). And the phototoxicity of complex 1 to Hela cells under light (λ > 600 nm) was much greater than its dark toxicity, which may be due to its generation of ¹O₂ and the promotion of its hydrolysis under long-wave light irradiation. Show less

The potential use of Ru(II) complexes as photosensitizers (PSs) in photodynamic therapy (PDT) has gained significant attention. In comparison with fluorophores with aggregation-caused quenching (ACQ), fluorophores with aggregation-induced emission (AIE) characteristics exhibit sustained fluorescence and dispersibility in aqueous solutions. PSs with AIE characteristics have received much attention in recent years. Herein, we reported two novel biotin-conjugated Ru(II) polypyridyl complexes (Ru1 and Ru2) with AIE characteristics. When exposed to 460 nm (10 mW cm^-2) light, Ru1 and Ru2 exhibited outstanding photostability and photocatalytic activity. Ru1 and Ru2 could efficiently generate singlet oxygen and induce pUC19 DNA photolysis when exposed to 460 nm light. Interestingly, both Ru1 and Ru2 also functioned as catalysts for NADH oxidation when exposed to 460 nm light. The presence of biotin fragments in Ru1 and Ru2 enhanced the specific uptake of these complexes by tumor cells. Both complexes showed minimal toxicity to selected cells in the dark. Nevertheless, the phototoxicity of both complexes significantly increased upon 460 nm light irradiation for 15 min. Further experiments revealed that Ru2 primarily accumulated in mitochondria and might bind to mitochondrial DNA. Under 460 nm light irradiation, Ru2 induced the generation of reactive oxygen species (ROS) and NADH depletion disrupting intracellular redox homeostasis in A549 cells, activating the mitochondrial apoptosis pathway resulting in up-regulation of apoptotic marker caspase-3, effectively damaged A549 cell DNA and arrested A549 cell cycle in the S phase. In vivo anti-tumor experiments were conducted to assess the effects of Ru2 on tumor growth in A549 tumor-bearing mice. The results showed that Ru2 effectively inhibited tumor growth under 460 nm light irradiation conditions. These findings indicate that Ru2 has great potential as a targeted photosensitizer for mitochondrial targeting imaging and photodynamic therapy of tumors. Show less

To develop next-generation metal drugs with high efficiency and low toxicity for targeting inhibition of gastric tumor growth and metastasis, we not only optimized a series of ruthenium (Ru, III) 2-hydroxy-1-naphthaldehyde thiosemicarbazone complexes to obtain a Ru(III) complex (4b) with remarkable cytotoxicity in vitro but also constructed a 4b-decitabine (DCT)/liposome (Lip) delivery system (4b-DCT-Lip). The in vivo results showed that 4b-DCT-Lip not only had a stronger capacity to inhibit gastric tumor growth and metastasis than 4b-DCT but also addressed the co-delivery problems of 4b-DCT and improved their targeting ability. Furthermore, we confirmed the mechanism of 4b-DCT/4b-DCT-Lip inhibiting the growth and metastasis of a gastric tumor. DCT-upregulated gasdermin E (GSDME) was cleaved by 4b-activated caspase-3 to afford GSDME-N terminal and then was aggregated to form nonselective pores on the cell membrane of a gastric tumor, thereby inducing pyroptosis and a pyroptosis-induced immune response. Show less

Title: Selectively attacking tumor cells of Ru/Ir-arene complexes based on meclofenamic acid Abstract: Breast cancer (BC) is one of the most common malignant tumors and often accompanied by inflammatory processes. Inflammation is an essential component of the tumor microenvironment, which might influence tumor proliferation and metastasis. Herein, three metal-arene complexes MA-bip-Ru, MA-bpy-Ir, and MA-bpy-Ru were prepared by tethering the non-steroidal anti-inflammatory drug meclofenamic acid (MA). Among them, MA-bip-Ru and MA-bpy-Ir showed lower cytotoxicity towards cancer cells, but MA-bpy-Ru showed significantly high selectivity and cytotoxicity towards MCF-7 cells through the autophagic pathway and exhibited no toxicity against normal HLF cells, showing potential for selective treatment of tumor cells. MA-bpy-Ru could also effectively destroy the 3D multicellular tumor spheroids, demonstrating its potential for clinical application. Besides, MA-bip-Ru, MA-bpy-Ir, and MA-bpy-Ru exhibited anti-inflammatory properties superior to MA, notably downregulating the expression of cyclooxygenase-2 (COX-2) and inhibiting the secretion of prostaglandin E2 in vitro. These findings demonstrated that MA-bpy-Ru was capable of intervening in inflammatory processes and showed the potential of MA-bpy-Ru to act as a selective anticancer agent, thus presenting a new mechanism of action for metal-arene complexes. Show less

Abstract: A series of half-sandwich ruthenium complexes containing quinoline derivative ligands was synthesized, which had excellent antitumor toxicity toward a variety of cell lines and could localize lysosomes. The damage of lysosomes promotes the release of cathepsin B and initiates downstream apoptotic cascade signals. The increase in reactive oxygen species (ROS) caused by the decrease in mitochondrial membrane potential (ΔΨm) synergistically amplified the damage degree of lysosomes. In addition, the complex could inhibit cell transfer and clone formation. In vivo results showed that the complex had excellent biological effects in tested mouse samples as the body weight of mice did not change much during the treatment, and the mean tumor volume was significantly lower than the control group. Show less

We have designed and synthesized two Ir(III) complexes (Ir1 and Ir2) coordinated with an 8-sulfonamidoquinoline derivative ligand as photosensitizers, which exhibit strong red phosphorescence emission and a long phosphorescence lifetime. The Ir(III) complexes exhibit a high population of triplet states, which enable red phosphorescence and efficient singlet oxygen generation. Ir1 and Ir2 rapidly enter the cancer cells and accumulate in lysosomes, producing large amounts of intracellular singlet oxygen when exposed to light irradiation, eventually leading to cancer cell death, and the phototoxic indexes of complexes Ir1 and Ir2 against cancer cells are in the range of 76-228. Overall, our studies indicate that the synthesized Ir(III) complexes with quinoline ligands exhibit photosensitizing properties, effectively inducing cancer cell death when exposed to light. These promising results suggest their potential application in photodynamic therapy. Show less

Boronic acid (or ester) is a well-known temporary masking group for developing anticancer prodrugs responsive to tumoral reactive oxygen species (ROS), but their clinic application is largely hampered by the low activation efficiency. Herein, we report a robust photoactivation approach that can spatiotemporally convert boronic acid-caged iridium(III) complex IrBA into bioactive IrNH₂ under hypoxic tumor microenvironments. Mechanistic studies show that the phenyl boronic acid moiety in IrBA is in equilibrium with phenyl boronate anion that can be photo-oxidized to generate phenyl radical, a highly reactive species that is capable of rapidly capturing O₂ at extremely low concentrations (down to 0.02%). As a result, while IrBA could hardly be activated by intrinsic ROS in cancer cells, upon light irradiation, the prodrug is efficiently converted into IrNH₂ even in limited O₂ supply, along with direct damage to mitochondrial DNA and potent antitumor activities in hypoxic 2D monolayer cells, 3D tumor spheroids, and mice bearing tumor xenografts. Of note, the photoactivation approach could be extended to intermolecular photocatalytic activation by external photosensitizers with red absorption and to activate prodrugs of clinic compounds, thus offering a general approach for activation of anticancer organoboron prodrugs. Show less