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Title: Mitochondrial-targeted iridium(III) complexes suppress tumor growth through inducting immunogenic cell death to activate immune response. Abstract: A new ligand, 2-(2-hydroxyl-4-methyl)phenyl-1H-imidazo[4,5-f][1,10]phenanthroline (IPMP), and [Ir(ppy)2(IPMP)]PF6 (7a), [Ir(bzq)2(IPMP)]PF6 (7b), and [Ir(piq)2(IPMP)]PF6 (7c) have been prepared and characterized by HRMS, NMR spectra. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays revealed that 7b exhibited excellent activity (IC50 = 4.5 ± 0.4 μM), while 7a and 7c showed good cytotoxicity (IC50 = 8.5 ± 0.9 μM and 8.9 ± 2.2 μM) against non-small cell lung cancer A549 cells. The experiments of cellular uptake and mitochondrial localization demonstrate that these new iridium(III) complexes are readily taken up by A549 cells and accumulate in the mitochondria and damage the structure of the mitochondria, which results in the loss of mitochondrial membrane potential (MMP), elevated lipid peroxidation, as well as DNA damage, the inhibition of microtubule polymerization, hindrance of the cell cycle in the G0/G1 phase, and release of cytochrome c, collectively leading to apoptosis. Furthermore, upregulation of Beclin-1, overexpression of NF-κB and downregulation of GPX4 protein were observed, which resulted in the activation of autophagy, pyroptosis and ferroptosis, respectively. In the C57BL/6 mouse model, the 7b demonstrated promising in vivo antitumor efficacy, with a tumor inhibitory rate of 66.9 %. Additionally, the complexes induce an immunogenic cell death to activate immune response, further enhance CD8+ T cells and efficiently inhibit tumor growth. Collectively, we consider that the complexes may be utilized as potential candidate agents for the treatment of A549 cancer. Show less

Title: Synthesis and mitochondria-localized iridium (III) complexes induce cell death through pyroptosis and ferroptosis pathways. Abstract: This paper introduces a new ligand, 4,6-dichloro-5-(1H-imidazo [4,5-f]phenanthroline-2-yl)pyrimidin-2-amine (DPPA), and its corresponding new iridium(III) complexes: [Ir(ppy)2(DPPA)](PF6) (2a) (where ppy represents deprotonated 2-phenylpyridine), [Ir(bzq)2(DPPA)](PF6) (2b) (with bzq indicating deprotonated benzo[h]quinoline), and [Ir(piq)2(DPPA)](PF6) (2c) (piq denoting deprotonated 1-phenylisoquinoline). The cytotoxic effects of both DPPA and 2a, 2b, and 2c were evaluated against human lung carcinoma A549, melanoma B16, colorectal cancer HCT116, human hepatocellular carcinoma HepG2 cancer cell lines, as well as the non-cancerous LO2 cell line using the 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method. While DPPA exhibited moderate anticancer activity toward A549, B16, HCT116 and HepG2 cells, complexes 2a, 2b, and 2c displayed remarkable efficacy against A549, B16, and HCT116 cells. The cell colonies and wound healing were investigated. Moreover, various aspects of the anticancer mechanisms were explored. The cell cycle analyses revealed that the complexes block cell proliferation of A549 cells during the S phase. Complex 2c induce an early apoptosis, while 2a and 2b cause a late apoptosis. The interaction of 2a, 2b and 2c with endoplasmic reticulum and mitochondria was identified, leading to elevated ROS and Ca2+ amounts. This resulted in a reduced mitochondrial membrane potential, mitochondrial permeability transition pore opening, and an increase of cytochrome c. Also, ferroptosis was investigated through measurements of intracellular glutathione (GSH), malondialdehyde (MDA), and recombinant glutathione peroxidase (GPX4) protein expression. The pyroptosis was explored via cell morphology, release of lactate dehydrogenase (LDH) and expression of pyroptosis-related proteins. RNA sequencing was applied to examine the signaling pathways. Western blot analyses illuminated that the complexes regulate the expression of Bcl-2 family proteins. Additionally, an in vivo antitumor study demonstrated that complex 2c exhibited a remarkable inhibitory rate of 58.58% in restraining tumor growth. In summary, the findings collectively suggest that the iridium(III) complexes induce cell death via ferroptosis, apoptosis by a ROS-mediated mitochondrial dysfunction pathway and GSDMD-mediated pyroptosis. Show less

Title: Mitochondria-targeted iridium(III) complexes encapsulated in liposome induce cell death through ferroptosis and gasdermin-mediated pyroptosis. Abstract: This paper unveils a novel perspective on synthesis and characterization of the ligand 5-bromo-2-amino-2'-(phenyl-1H-imidazo[4,5-f][1,10]phenanthroline) (BAPIP), and its iridium(III) complexes [Ir(PPY-)2(BAPIP)](PF6) (1a, with PPY- as deprotonated 2-phenylpyridine), [Ir(PIQ-)2(BAPIP)](PF6) (1b, piq- denoting deprotonated 1-phenylisoquinoline), and [Ir(BZQ-)2(BAPIP)](PF6) (1c, bzq- signifying deprotonated benzo[h]quinoline). Systematic evaluation of the cytotoxicity of 1a, 1b, and 1c across diverse cell lines encompassing B16, HCT116, HepG2, A549, HeLa, and LO2 using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method. Unexpectedly, compounds 1b and 1c demonstrated no cytotoxicity against the above cell lines. Motivated by the pursuit of heightened anti-proliferative potential, a strategic encapsulation approach yielded liposomes 1alip, 1blip, and 1clip. As expectation, 1alip, 1blip, and 1clip displayed remarkable anti-proliferative efficacy, particularly noteworthy in A549 cells, exhibiting IC50 values of 4.9 ± 1.0, 5.9 ± 0.1, and 7.6 ± 0.2 μM, respectively. Moreover, our investigation illuminated the mitochondrial accumulation of these liposomal entities, 1alip, 1blip, and 1clip, evoking apoptosis through the mitochondrial dysfunction mediated by reactive oxygen species (ROS). The ferroptosis was confirmed by decrease in glutathione (GSH) concentrations, the downregulation of glutathione peroxidase 4 (GPX4), increase of high mobility group protein 1 (HMGB1), and lipid peroxidation. Simultaneously, pyroptosis as another mode of cell death was undertaken. RNA-sequencing was employed to investigate intricate signalling pathways. In vivo examination provided tangible evidence of 1alip in effectively curbing tumor growth. Collectively, this study provides a multifaceted mode of cellular demise orchestrated by 1a, 1alip, 1blip, and 1clip, involving pathways encompassing apoptosis, ferroptosis, and pyroptosis. Show less

Title: Endoplasmic reticulum-targeted iridium(III) photosensitizer induces pyroptosis for augmented tumor immunotherapy. Abstract: An ideal tumor treatment strategy involves therapeutic approaches that can enhance the immunogenicity of the tumor microenvironment while simultaneously eliminating the primary tumor. A cholic acid-modified iridium(III) (Ir3) photosensitizer, targeted to the endoplasmic reticulum (ER), has been reported to exhibit potent type I and type II photodynamic therapeutic effects against triple-negative breast cancer (MDA-MB-231). This photosensitizer induces pyroptotic cell death mediated by gasdermin E (GSDME) through photodynamic means and enhances tumor immunotherapy. Mechanistic studies have revealed that complex Ir3 induces characteristics of damage-related molecular patterns (DAMPs) in MDA-MB-231 breast cancer cells under light conditions. These include cell-surface calreticulin (CRT) eversion, extracellular high mobility group box 1 (HMGB1) and ATP release, accompanied by ER stress and increased reactive oxygen species (ROS). Consequently, complex Ir3 promotes dendritic cell maturation and antigen presentation under light conditions, fully activates T cell-dependent immune response in vivo, and ultimately eliminates distant tumors while destroying primary tumors. In conclusion, immune regulation and targeted intervention mediated by metal complexes represent a new and promising approach to tumor therapy. This provides an effective strategy for the development of combined targeted therapy and immunotherapy. 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

A series of rhenium(I) complexes of the type fac-[Re(CO)₃(N^N)L]^0/+, Re1-Re9, was synthesized, where N^N = benzimidazole-derived bidentate ligand with an ester functionality and L = chloride or pyridine-type ligand. The new compounds demonstrated potent activity toward ovarian A2780 cancer cells. The most active complexes, Re7-Re9, incorporating 4-NMe₂py, exhibited remarkable activity in 3D HeLa spheroids. The emission in the red region of Re9, which contains an electron-deficient benzothiazole moiety, allowed its operability as a bioimaging tool for in vitro and in vivo visualization. Re9 effectivity was tested in two different C. elegans tumoral strains, JK1466 and MT2124, to broaden the oncogenic pathways studied. The results showed that Re9 was able to reduce the tumor growth in both strains by increasing the ROS production inside the cells. Moreover, the selectivity of the compound toward cancerous cells was remarkable as it did not affect neither the development nor the progeny of the nematodes. Show less

Title: Ru(II)-modified TiO Abstract: The alternations in the hypoxic and immune microenvironment are closely related to the therapeutic effect and prognosis of oral squamous cell carcinoma (OSCC). Herein, a new nanocomposite, TiO2@Ru@siRNA is constructed from a ruthenium-based photosensitizer (Ru) modified-TiO2 nanoparticles (NPs) loaded with siRNA of hypoxia-inducible factor-1α (HIF-1α). Under visible light irradiation, TiO2@Ru@siRNA can elicit both Type I and Type II photodynamic effects, which causes lysosomal damage, HIF-1α gene silencing, and OSCC cell elimination efficiently. As a consequence of hypoxia relief and pyroptosis induction, TiO2@Ru@siRNA reshapes the immune microenvironment by downregulation of key immunosuppressive factors, upregulation of immune cytokines, and activation of CD4+ and CD8+ T lymphocytes. Furthermore, patient-derived xenograft (PDX) and rat oral experimental carcinogenesis models prove that TiO2@Ru@siRNA-mediated photodynamic therapy significantly inhibits the tumor growth and progression, and markedly enhances cancer immunity. In all, this study presents an effective hypoxia-adaptive photo-immunotherapeutic nanosystem with great potential for OSCC prevention and treatment. Show less