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Ferroptosis is a unique cell death mode that relies on iron and lipid peroxidation (LPO) and is extensively utilized to treat drug-resistant tumor. However, like the other antitumor model, requirement of oxygen limited its application in treating the malignant tumors in anaerobic environments, just as photodynamic therapy, a very promising anticancer therapy. Here, we show that an iridium(III) complex (Ir-dF), which was often used in proton-coupled electron transport (PCET) process, can induce efficient cell death upon photo irradiation, which can be effectively protected by the typical ferroptosis inhibitor Fer-1 but not by the classic iron chelating agents and ROS scavengers. Surprisingly, LPO was further demonstrated to be directly induced by Ir-dF/light activation via PCET, by utilizing a model polyunsaturated fatty acid. Ir-dF was found to be accumulated preferentially in mitochondria and the endoplasmic reticulum (ER), leading to mitochondrial swelling and ER stress accompanied by obvious LPO accumulation and downregulation of the characteristic ferroptosis protein GPX4. More interestingly, Ir-dF was also found to induce photocytotoxicity under hypoxia, and an in vivo experiment further confirmed that Ir-dF can effectively inhibit the growth of tumor under two-photon laser irradiation. Taken together, for the first time, this article introduces a new mechanism of inducing the LPO through a photoactivated PCET process, leading to a ferroptosis-like cell death which is independent of the iron and oxygen. This innovative mechanism holds great potential as a future treatment option for hypoxic malignant tumors and drug-resistant tumors. Show less

Title: New cyclometalated iridium(III) complexes bearing substituted 2-(1H-benzimidazol-2-yl)quinoline: Synthesis, characterization, electrochemical and anticancer studies. Abstract: New iridium(III) compounds (C1-C3) bearing 2-(1H-benzimidazol-2-yl)quinoline ligands with different side groups (benzyl, 2,3,4,5,6-pentamethylbenzyl and 2,3,4,5,6-pentafluorobenzyl) were synthesized and characterized by using spectroscopic analyses. The effects of different side groups of iridium compounds on the photophysical and electrochemical properties have been investigated. The cytotoxicity and apoptosis of the compounds have been evaluated on breast cancer cell lines using various methods including MTT assay, flow cytometry, qRT-PCR, and colony formation. The cytotoxicity of C1, expressed as IC50 values, was found to be 11.76 μM for MDA-MB-231 and 5.35 μM for MCF-7 cells. For C3, the IC50 value was 16.22 μM for MDA-MB-231 and 8.85 μM for MCF-7 cells. In both cell lines, increased levels of Bax and caspase 3, along with downregulation of BCL-2 and positive annexin V staining, were observed, confirming apoptosis. Moreover, the colony-forming abilities in both cell lines decreased after C1 and C3 complex treatment. All these results suggest that the compounds C1 and C3 may have potential in the treatment of breast cancer, though further research is needed to confirm their efficacy. Show less

The design and synthesis of a series of metal complexes formed by non-steroidal anti-inflammatory drugs (NSAIDs) ibuprofen (IBP) and iridium(III), with the molecular formula [Ir(C^N)₂bpy(4-CH₂OIBP-4'-CH₂OIBP)](PF₆) (Ir-IBP-1, Ir-IBP-2) (C^N = 2-phenylpyridine (ppy, Ir-IBP-1), 2-(2-thienyl)pyridine (thpy, Ir-IBP-2)) was introduced in this article. Firstly, it was found that the anti-proliferative activity of these complexes was more effective than that of cisplatin. Further research showed that Ir-IBP-1 and Ir-IBP-2 can accumulate in intracellular mitochondria, thereby disrupting mitochondrial membrane potential (MMP), increasing intracellular reactive oxygen species (ROS), blocking the G2/M phase of the cell cycle, and inducing cell apoptosis. In terms of protein expression, the expression of COX-2, MMP-9, NLRP3 and Caspase-1 proteins can be downregulated, indicating their ability to anti-inflammatory and overcome immune evasion. Furthermore, Ir-IBP-1 and Ir-IBP-2 can induce immunogenic cell death (ICD) by triggering the release of cell surface calreticulin (CRT), high mobility group box 1 (HMGB1) and adenosine triphosphate (ATP). Overall, iridium(III)-IBP conjugates exhibit various anti-tumor mechanisms, including mitochondrial damage, cell cycle arrest, inflammatory suppression, and induction of ICD. Show less

Title: Mitochondria Localized Anticancer Iridium(III) Prodrugs for Targeted Delivery of Myeloid Cell Leukemia-1 (Mcl-1) Inhibitors and Cytotoxic Iridium(III) Complex. Abstract: Myeloid cell leukemia-1 (Mcl-1) is an antiapoptotic oncoprotein overexpressed in several malignancies and acts as one of the promising therapeutic targets for cancer. Even though there are several small molecule based Mcl-1 inhibitors reported, the delivery of Mcl-1 inhibitor at the target site is quite challenging. In this regard, we developed a series of mitochondria targeting luminescent cyclometalated iridium(III) prodrugs bearing Mcl-1 inhibitors via ester linkage due to the presence of Mcl-1 protein in the outer mitochondrial membrane. Among the synthesized prodrugs, IrThpy@L2 was found to exhibit the potent cytotoxicity (IC50 = 30.93 nM) against HCT116 cell line when compared with bare Mcl-1 inhibitors (IC50 > 100 μM). Mechanistic studies further revealed that IrThpy@L2 quickly gets internalized inside the mitochondria of HCT116 cells and undergoes activation in the presence of overexpressed esterase which leads to the release of two cytotoxic species i.e. Mcl-1 inhibitors (I-2) and cytotoxic iridium(III) complex (IrThpy@OH). The improved cytotoxicity of IrThpy@L2 is due to the mitochondria targeting ability of iridium(III) prodrug, subsequent esterase activated release of I-2 to inhibit Mcl-1 protein and IrThpy@OH to generate reactive oxygen species (ROS). After prodrug activation, the released cytotoxic species cause mitochondrial membrane depolarization, activate a cascade of mitochondria-mediated cell death events, and arrest the cell cycle in S-phase which leads to apoptosis. The potent anticancer activity of IrThpy@L2 was further evident from the drastic morphological changes, size reduction in the solid tumor mimicking 3D multicellular tumor spheroids (MCTS) of HCT116. 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

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

Autophagy is a crucial quality control mechanism that degrades damaged cellular components through lysosomal fusion with autophagosomes. However, elevated autophagy levels can promote drug resistance in cancer cells, enhancing their survival. Downregulation of autophagy through oxidative stress is a clinically promising strategy to counteract drug resistance, yet precise control of oxidative stress in autophagic proteins remains challenging. Here, a molecular design strategy of biocompatible neutral Ir(III) photosensitizers is demonstrated, B2 and B4, for precise reactive oxygen species (ROS) control at lysosomes to inhibit autophagy. The underlying molecular mechanisms for the biocompatibility and lysosome selectivity of Ir(III) complexes are explored by comparing B2 with the cationic or the non-lysosome-targeting analogs. Also, the biological mechanisms for autophagy inhibition via lysosomal oxidation are explored. Proteome analyses reveal significant oxidation of proteins essential for autophagy, including lysosomal and fusion-mediator proteins. These findings are verified in vitro, using mass spectrometry, live cell imaging, and a model SNARE complex. The anti-tumor efficacy of the precise lysosomal oxidation strategy is further validated in vivo with B4, engineered for red light absorbance. This study is expected to inspire the therapeutic use of spatiotemporal ROS control for sophisticated modulation of autophagy. Show less

Title: Radiosensitization effect of iridium (III) complex on lung cancer cells via mitochondria apoptosis pathway. Abstract: BACKGROUND: Lung cancer is the leading cause of cancer-related death in the worldwide. Although cisplatin and other platinum-based drugs are widely used as radiosensitizers in radiotherapy and considered the first-line treatment for advanced lung cancer, their clinical utility is often limited by drug resistance and severe cytotoxic side effects. In recent years, iridium-based complexes and other transition metal cation complexes with similar structural properties have garnered increasing research interest due to their potential anticancer properties. METHODS: Recently, we synthesized a novel iridium (III) complex (Ir-1) and evaluated its safety and stability. The present study aimed to identify Ir-1 with potent anticancer activity by assessing its cytotoxic effects on lung cancer cells in vitro. Additionally, it investigated Ir-1's radiosensitizing efficacy and the underlying mechanisms. RESULTS: The results demonstrated that Ir-1 exhibited significant radiosensitizing effects on lung cancer cells. Ir-1 effectively reduced cell viability and colony formation, arrested the cell cycle at the G2/M phase, inhibited cell migration and invasion, decreased mitochondrial membrane potential, and increased reactive oxygen species (ROS) generation in lung cancer cells. Importantly, these cytotoxic effects were selective, with minimal impact on normal cells. Mechanistic studies showed that Ir-1 enhanced radiation-induced cancer cell death by disrupting mitochondrial function and activating the mitochondrial apoptotic pathway. This was evidenced by upregulated expression levels of Bax, Cytochrome c (Cyt-C), and Caspase9 proteins, along with reduced level of Bcl-2 protein. Notably, the addition of a Cyt-C inhibitor significantly reduced the expression of Cyt-C and Caspase9 proteins. Similarly, treatment with the Caspase9 inhibitor Z-LEHD-FMK also reduced Caspase9 protein level. CONCLUSION: This study provides robust evidence that Ir-1 is a promising and safe radiosensitizer for lung cancer therapy. Its ability to enhance radiation-induced cytotoxicity through mitochondrial dysfunction and activation of apoptotic pathways highlights its potential for clinical application. Show less

Hepatic ischemia-reperfusion injury (HIRI) is one of the main causes of liver insufficiency and failure after liver surgery. However, the effectiveness of current methods of treating HIRI is generally limited. Previous studies have shown that hydrogen sulfide (H₂S) has a beneficial effect on HIRI, and an appropriate concentration of H₂S can significantly reduce HIRI by protecting the mitochondria. Therefore, establishing an accurate imaging platform for monitoring variations in mitochondrial H₂S is an effective strategy for anti-HIRI drug discovery and efficacy evaluation. To this end, a cyclometalated iridium(III) complex-based probe, Cym-Ir-EDB, was developed for detecting mitochondrial H₂S in HIRI. Cym-Ir-EDB possesses good sensitivity, high selectivity, negligible cytotoxicity, and excellent mitochondrial-targeting ability, rendering it a promising imaging tool for analyzing variations in mitochondrial H₂S in HIRI cells. Using Cym-Ir-EDB as a probe, anti-HIRI drugs were screened from isothiocyanates by monitoring variations in mitochondrial H₂S in HIRI cells, for the first time. Moreover, the dynamics of mitochondrial H₂S in HIRI cells were visualized and the response of HIRI to treatment with the screened erucin was monitored. The findings indicate that Cym-Ir-EDB can serve as a useful imaging platform for the precise imaging of mitochondrial H₂S in HIRI, thereby contributing to anti-HIRI drug discovery and efficacy evaluation. Show less

S: Mercury ions (Hg²⁺) are highly toxic and prone to bioaccumulation, showing a strong attraction to proteins and enzymes that contain sulfur. Even minute quantities of Hg²⁺ can lead to severe health issues. Given that mitochondria are a primary target organelle of Hg²⁺, it is essential to create a probe that can accurately detect Hg²⁺ within intracellular mitochondria. In this study, we developed two innovative Ir(III) complex probes that emit near-infrared light. The crystal structure of Ir2 was determined using X-ray techniques, which reveals that Ir2 contains a pyridine group capable of recognizing Hg²⁺ and targeting mitochondria, allowing for the precise identification of Hg²⁺ both in vitro and within the mitochondria of living cells. Additionally, these two novel near-infrared phosphorescent Ir(III) complexes demonstrate significant capabilities in producing ROS including singlet oxygen, ·O₂^- and ·OH, which renders them effective photosensitizers under visible light exposure for photodynamic therapy (PDT). This research offers a promising approach for detecting Hg²⁺ in vitro and in the mitochondrial microenvironment of living cells, which have some implications for the future development of pertinent transition metal complexes for mitochondria-targeted photodynamic therapy in cancer cells. Show less

Intracellular imaging of anticancer metallodrugs often relies on prelabeling with organic fluorophores, which significantly affects their physicochemical properties and intracellular distribution. On the other hand, the reported postlabeling strategies based on click-chemistry reactions require cell fixation and permeabilization. Here, this study presents a postlabeling approach based on the catalyst-free, inverse electron-demand Diels-Alder reaction (iEDDA) between a strained fluorescein-tagged bicyclononyne derivative (BCN-FAM) and half-sandwich Ir(III) complexes containing bidentate ligands comprising a tetrazine (Tz-R,R') entity. Five half-sandwich Ir(III) complexes with formula [Cp*Ir(Tz-R,R')Cl]^0/+ have been synthesized and fully characterized, including the X-ray crystal structures of three of the five derivatives. Investigations of their stability and their reactivity in aqueous solution and in a model iEDDA reaction reveal the strong influence of the tetrazine ligand structure on the chemical properties of the corresponding complexes. A highly cytotoxic metallodrug candidate (Ir-C,N_Ph,Me) is identified from biological studies, and chemical reactivity studies disclose an unusual preference for binding of methionine over cysteine. Postlabeling of Ir-C,N_Ph,Me in live HeLa cells highlights its preferential accumulation within the nucleus, suggesting its retention through covalent modifications of nuclear proteins in good agreement with other half-sandwich iridium(III) complexes. Show less

Three phosphorescent iridium(III) complexes consisting bis-diphosphine ligands were prepared and characterized by single-crystal XRD, CHN analysis, spectroscopic techniques, cyclic voltammetry, and DFT. The synthesized complexes were the three monomeric [Ir(ppy)₂(L₁)Cl] (1), [Ir(ppy)₂(L₂)]Cl (2) and [Ir(ppy)₂(L₃)]Cl (3) where L₁ = bis-(diphenylphosphino)methane (dppm), L₂ = bis-(diphenylphosphino)propane (dppp) and L₃ = bis-(diphenylphosphino)benzene (dppbe). Complexes 1-3 gave an absorption band between 240 to 380 nm in both CH₂Cl₂ and DMSO, which is assigned as a charge transfer transition based on theoretical calculation. They showed a blue-green emission at 460-520 nm in DMSO with an absolute quantum efficiency of 0.013-0.046 at room temperature. The selective photo-induced electron transfer (PET) by Fe³⁺ in DMSO, was studied to obey the Rehm-Weller principle. The 1:1 binding soichiometry between 1-3 and Fe³⁺ was established by Job's plot. The binding constants (K_a) were determined using the Benesi-Hildebrand plot. All the complexes are extremely more potent than cisplatin for in vitro antiproliferative activity towards the human breast cancer cells, HCC1937, MCF-7, and MDA-MB-231. The values of IC₅₀ were in the range of 0.077-0.485 μM, and 1 exhibited the most effective IC₅₀ against MDA-MB-231 cell line, the triple-negative breast cancer cell. Their lipophilicities (log P) were also examined to explain the penetration ability of the studied complexes towards cell barriers, and transport to the molecular target. Show less

Title: A Bioactive Benzimidazole-Cyclometalated Iridium(III) Complex as an Epigenetic Regulator through Effectively Interrupting the EED-EZH2 Interaction. Abstract: Epigenetic regulation plays a fundamental role in controlling gene expression and maintaining cellular identity. Among epigenetic processes, the translocation of methyltransferases is critical for the modification of chromatin structure and transcriptional activity. The regulation of these translocation events and the mechanisms involved are complex, yet critical for understanding and manipulating epigenetic states. Therefore, novel strategies are required for detecting and visualizing the movement and interaction of methyltransferases within cells. Using enhancer of zeste homolog 2 (EZH2) methyltransferase as an example, a bifunctional compound capable of both monitoring and disrupting its translocation process is developed by targeting the protein-protein interaction (PPI) between embryonic ectoderm development (EED) and EZH2. The Ir(III) complex 1 bound enthalpically to EED and effectively inhibited the methyltransferase activity of EZH2. Moreover, disruption of the EED-EZH2 PPI led to increased transcriptional activity of P21 and P27, resulting in the suppression of triple-negative breast cancer (TNBC) cell proliferation. Excitingly, 1 suppressed tumor metastasis in a TNBC mouse model in vivo. To our knowledge, complex 1 is the first metal-based bifunctional therapeutic agent designed to probe and inhibit the EED-EZH2 PPI, highlighting the feasibility and significance of using metal complexes to monitor and influence methyltransferase translocations for therapeutic applications. Show less

Title: Iridium(III)-Based Infrared Two-Photon Photosensitizers: Systematic Regulation of Their Photodynamic Therapy Efficacy. Abstract: Cyclometalated iridium(III) complexes are of significant importance in the field of antitumor photodynamic therapy (PDT), whether they exist as single molecules or are incorporated into nanomaterials. Nevertheless, a comprehensive examination of the relationship between their molecular structure and PDT effectiveness remains awaited. The influencing factors of two-photon excited PDT can be anticipated to be further multiplied, particularly in relation to intricate nonlinear optical properties. At present, a comprehensive body of research on this topic is lacking, and few discernible patterns have been identified. In this study, through systematic structure regulation, the nitro-substituted styryl group and 1-phenylisoquinoline ligand containing YQ2 was found to be the most potent infrared two-photon excitable photosensitizer in a 4 × 3 combination library of cyclometalated Ir(III) complexes. YQ2 could enter cells via an energy-dependent and caveolae-mediated pathway, bind specifically to mitochondria, produce 1O2 in response to 808 nm LPL irradiation, activate caspases, and induce apoptosis. In vitro, YQ2 displayed a remarkable phototherapy index for both malignant melanoma (>885) and non-small-cell lung cancer (>1234) based on these functions and was minimally deleterious to human normal liver and kidney cells. In in vivo antitumor phototherapy, YQ2 inhibited tumor growth by an impressive 85% and could be eliminated from the bodies of mice with a half-life as short as 43 h. This study has the potential to contribute significantly to the development of phototherapeutic drugs that are extremely effective in treating large, profoundly located solid tumors as well as the understanding of the structure-activity relationship of Ir(III)-based PSs in PDT. Show less

Photodynamic therapy holds great promise as a non-invasive anticancer tool against drug-resistant cancers. However, highly effective, non-toxic, and reliable photosensitizers with operability under hypoxic conditions remain to be developed. Herein, we took the advantageous properties of COUPY fluorophores and cyclometalated Ir(III) complexes to develop novel PDT agents based on Ir(III)-COUPY conjugates with the aim of exploring structure-activity relationships. The structural modifications carried out within the coumarin scaffold had a strong impact on the photophysical properties and cellular uptake of the conjugates. All Ir(III)-COUPY conjugates exhibited high phototoxicity under green light irradiation, which was attributed to the photogeneration of ROS, while remaining non-toxic in the dark. Among them, two hit conjugates showed excellent phototherapeutic indexes in cisplatin-resistant A2780cis cancer cells, both in normoxia and in hypoxia, suggesting that photoactive therapy approaches based on the conjugation of far-red/NIR-emitting COUPY dyes and transition metal complexes could effectively tackle in vitro acquired resistance to cisplatin. Show less

The clinical application of photodynamic therapy is hindered by the high glutathione concentration, poor cancer-targeting properties, poor drug loading into delivery systems, and an inefficient activation of the cell death machinery in cancer cells. To overcome these limitations, herein, the formulation of a promising Ir^III complex into a biodegradable coordination polymer (IrS NPs) is presented. The nanoparticles were found to remain stable under physiological conditions but deplete glutathione and disintegrate into the monomeric metal complexes in the tumor microenvironment, causing an enhanced therapeutic effect. The nanoparticles were found to selectively accumulate in the mitochondria where these trigger cell death by hybrid apoptosis and ferroptosis pathways through the photoinduced production of singlet oxygen and superoxide anion radicals. This study presents the first example of a coordination polymer that can efficiently cause cancer cell death by apoptosis and ferroptosis upon irradiation, providing an innovative approach for cancer therapy. Show less

Title: Photoinduction of Ferroptosis and cGAS-STING Activation by a H Abstract: Triggering ferroptosis represents a promising anticancer therapeutic strategy, but the development of a selective ferroptosis inducer for cancer-specific therapy remains a great challenge. Herein, a H2S-responsive iridium(III) complex NA-Ir has been well-designed as a ferroptosis inducer. NA-Ir could selectively light up H2S-rich cancer cells, primarily localize in mitochondria, intercalate into mitochondrial DNA (mtDNA), and induce mtDNA damage, exhibiting higher anticancer activity under light irradiation. Mechanistic studies showed that NA-Ir-mediated PDT triggered lipid peroxidation and glutathione peroxidase 4 downregulation through ROS production and GSH depletion, resulting in ferroptosis through multiple pathways. Moreover, the intense mtDNA damage can activate the cyclic GMP-AMP synthase-stimulator of the interferon gene (cGAS-STING) pathway, leading to ferritinophagy and further ferroptosis. RNA-sequencing analysis showed that NA-Ir-mediated PDT mainly affects the expression of genes related to ferroptosis, autophagy, and cancer immunity. This study demonstrates the first cancer-specific example with ferroptosis and cGAS-STING activation, which provides a new strategy for multimodal synergistic therapy. Show less

Title: Modulatory Role of Pantropic Cell Signaling Pathways in the Antimigratory and Antiproliferative Action of Triazole Chelated Iridium(III) Complexes in Cervical Cancer Cells. Abstract: In the current study, the antimigratory and antiproliferative effect of three substituted triazole-chelated iridium(III) complexes Ir-TRN, Ir-TRH, and Ir-TRF were studied with special emphasis on modulation of P53 activity, a cell cycle regulator. ERK2/MAPK, another crucial cell signaling pathway protein, was also shown to play a crucial role in cell migration and proliferation. The complexes increase the ROS generation within the cell, further supporting apoptotic induction by exerting cellular oxidative stress. These metal complexes also affect ER stress by altering ERp29, an ER-resident chaperone, further inducing the process of apoptosis. The iridium(III) complexes restrict cervical cancer cell migration and proliferation by exerting pronounced effects as P53 activators and downregulation of ERK2/MAPK activity in cervical cancer cells. The underpinning mechanism of P53 and ERK2/MAPK activity in cervical cancer cells in the presence of iridium(III) complexes was studied in detail in this study, which paves the way for developing promising avenues for cancer therapeutics. Show less

In this paper, three new iridium(III) complexes: [Ir(piq)₂(DFIPP)]PF₆ (piq = deprotonated 1-phenylisoquinoline, DFIPP = 3,4-difluoro-2-(1H-imidazo[4,5-f][1,10]phenenthrolin-2-yl)phenol, 3a), [Ir(bzq)₂(DFIPP)]PF₆ (bzq = deprotonated benzo[h]quinoline, 3b), and [Ir(ppy)₂(DFIPP)]PF₆ (ppy = deprotonated 1-phenylpyridine, 3c), were synthesized and characterized. The complexes were found to be nontoxic to tumor cells via 3-(4,5-dimethylthiazole-2-yl)-diphenyltetrazolium bromide (MTT) assay. Surprisingly, its liposome-entrapped complexes 3alip, 3blip, and 3clip on B16 cells showed strong cytotoxicity (IC₅₀ = 13.6 ± 2.8, 9.6 ± 1.1, and 18.9 ± 2.1 μM). Entry of 3alip, 3blip, and 3clip into B16 cells decreases mitochondrial membrane potential, regulates Bcl-2 family proteins, releases cytochrome c, triggers caspase family cascade reaction, and induces apoptosis. In addition, we also found that 3alip, 3blip, and 3clip triggered ferroptosis and autophagy. In vivo studies demonstrated that 3blip inhibited melanoma growth in C57 mice with a high inhibitory rate of 83.95%, and no organic damage was found in C57 mice. Show less

Given the extensive role of lipids in cancer development, there is substantial clinical interest in developing therapies that target lipid metabolism. In this study, we identified one cyclometalated iridium complex (Ir2) that exhibits potent antiproliferation activity in MIA PaCa-2 cells by regulating fatty acid metabolism and sphingolipid metabolism simultaneously. Ir2 also efficiently overcomes cisplatin resistance in vitro. Satisfyingly, the generated Ir2@F127 carriers, as a temperature-sensitive in situ gelling system of Ir2, showed effective cancer treatment with minimal side effects in an in vivo xenograft study. To the best of our knowledge, Ir2 is the first reported cyclometalated iridium complex that exerts anticancer activity in MIA PaCa-2 cells by intervening in lipid metabolism, which provides an alternative pathway for the anticancer mechanism of cyclometalated iridium complexes. Show less

To develop a potential theranostic metal agent to reverse the resistance of cancer cells to cisplatin and effectively inhibit tumor growth and metastasis, we proposed to design a cyclometalated iridium (Ir) complex based on the properties of the tumor environment (TME). To the end, we designed and synthesized a series of Ir(III) 2-hydroxy-1-naphthaldehyde thiosemicarbazone complexes by modifying the hydrogen atom(s) of the N-3 position of 2-hydroxy-1-naphthaldehyde thiosemicarbazone compounds and the structure of cyclometalated Ir(III) dimers and then investigated their structure-activity and structure-fluorescence relationships to obtain an Ir(III) complex (Ir5) with remarkable fluorescence and cytotoxicity to cancer cells. Ir5 not only possesses mitochondria-targeted properties but also overcomes cisplatin resistance and effectively inhibits tumor growth and metastasis in vivo. Besides, we confirmed the anticancer mechanisms of Ir5 acting on different components in the TME: directly killing liver cancer cells by inducing necroptosis and activating the necroptosis-related immune response. Show less

A second-generation series of biscyclometalated 2-(5-aryl-thienyl)-benzimidazole and -benzothiazole Ir(III) dppz complexes [Ir(C^N)₂(dppz)]⁺, Ir1-Ir4, were rationally designed and synthesized, where the aryl group attached to the thienyl ring was p-CF₃C₆H₄ or p-Me₂NC₆H₄. These new Ir(III) complexes were assessed as photosensitizers to explore the structure-activity correlations for their potential use in biocompatible anticancer photodynamic therapy. When irradiated with blue light, the complexes exhibited high selective potency across several cancer cell lines predisposed to photodynamic therapy; the benzothiazole derivatives (Ir1 and Ir2) were the best performers, Ir2 being also activatable with green or red light. Notably, when irradiated, the complexes induced leakage of lysosomal content into the cytoplasm of HeLa cancer cells and induced oncosis-like cell death. The capability of the new Ir complexes to photoinduce cell death in 3D HeLa spheroids has also been demonstrated. The investigated Ir complexes can also catalytically photo-oxidate NADH and photogenerate ¹O₂ and/or ^•OH in cell-free media. Show less

In this article, we report IriPlatins 1-3, a new class of heterobimetallic Ir(III)-Pt(IV) conjugates as multifunctional potent anticancer theranostic agents. In the designed construction, the octahedral Pt(IV) prodrug is tethered to the cancer cell targeting biotin ligand through one of the axial sites and the other axial site of Pt(IV) center is attached to multifunctional Ir(III) complexes that possess organelle-targeting capabilities with excellent anticancer and imaging properties. The conjugates preferentially accumulate within the mitochondria of cancer cells, and subsequently, Pt(IV) is reduced to Pt(II) species that concomitantly releases both the Ir(III) complex and biotin from its axial sites. The IriPlatin conjugates demonstrate potent anticancer activity in various 2D monolayer cancer cells, including the cisplatin-resistant cells in the nanomolar concentrations and 3D multicellular tumor spheroids. The mechanistic investigation of conjugates suggests that the loss of MMP, generation of ROS, and caspase-3-mediated apoptosis are responsible for cell death. Show less