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Herein, we synthesized and characterized two novel iridium (III) complexes: [Ir(bzq) 2 (PPD)](PF 6 ) (4a, with bzq = deprotonated benzo[h]quinoline and PPD = pteridino[6,7-f][1,10]phenanthroline-11,13-diamine) and [Ir(piq) 2 (PPD)](PF 6 ) (4b, with piq = deprotonated 1-phenylisoquinoline). The anticancer efficacy of these complexes, 4a and 4b, was investigated using 3-(4,5-dimethylthiazole)-2,5-diphenltetraazolium bromide (MTT). Complex 4a exhibited no cytotoxic activity, while 4b demonstrated moderate efficacy against SGC-7901, A549, and HepG2 cancer cells. To enhance their anticancer potential, we explored two strategies: (I) light irradiation and (II) encapsulation of the complexes in liposomes, resulting in the formation of 4alip and 4blip. Both strategies significantly increased the ability of 4a, 4b to kill cancer cells. The cellular studies indicated that both the free complexes 4a, 4b and their liposomal forms 4alip and 4blip effectively inhibited cell proliferation. The cell cycle arrest analysis uncovered 4alip and 4blip arresting cell growth in the S period. Additionally, we investigated apoptosis and ferroptosis pathways, observing an increase in malondialdehyde (MDA) levels, a reduction of glutathione (GSH), a down-regulation of GPX4 (glutathione peroxidase) expression, and lipid peroxidation. The effects on mitochondrial membrane potential and intracellular Ca 2+ concentrations were also examined, revealing that both light-activated and liposomal forms of 4alip and 4blip caused a decline in mitochondrial membrane potential and an enhancement in intracellular Ca 2+ levels. In conclusion, these complexes and them encapsulated liposomes induce cell death through apoptosis and ferroptosis., Competing Interests: Declaration of competing interest The authors declare no competing interest exists., (Copyright © 2023. Published by Elsevier Inc.)

In this report, a new ligand TFBIP (TFBIP = 2-(4'-trifluoromethyl)-[1,1'-biphenyl]-4-yl)-1H-imidazo[4,5-f][1,10]phenanthroline) and its three iridium (III) complexes [Ir(ppy) 2 (TFBIP)](PF 6 ) (Ir1, ppy = 2-phenylpyridine), [Ir(bzq) 2 (TFBIP)](PF 6 ) (Ir2, bzq = benzo[h]quinolone) and [Ir(piq) 2 (TFBIP)](PF 6 ) (Ir3, piq = 1-phenylisoquinoline) were synthesized and characterized. The cytotoxicity in vitro of the complexes toward several cancer cells was evaluated by 3-(4,5-dimethylthiazole-2-yl)-2,5-biphenyl tetrazolium bromide (MTT) methods. The complexes show no cytotoxicity (IC 50  > 100 μM) against these cancer cells. To enhance anticancer activity, these complexes were trapped in liposomes to form Ir1Lipo, Ir2Lipo and Ir3Lipo. The liposomes Ir1Lipo, Ir2Lipo and Ir3Lipo exhibit high or moderate cytotoxic activity. In particular, Ir1Lipo can effectively inhibit the cell growth with a low IC 50 value (< 10 μM) toward A549, HepG2, BEL-7402, B16, HeLa and SGC-7901 cells. Surprisingly, Ir1Lipo has no cytotoxic activity against the normal cell LO2 (IC 50  > 100 μM). The apoptosis and pyroptosis were investigated. Ir3Lipo induces apoptosis with a high early apoptotic number of 37%. The reactive oxygen species (ROS) levels, mitochondrial permeability transition pore open and mitochondrial membrane potential were detected. The intracellular Ca 2+ concentration and release of cytochrome c were investigated. The expression of Bcl-2 (B-cell lymphoma-2) family proteins was explored by western blot. The antitumor activity in vivo of Ir1Lipo was evaluated with an inhibitory rate of 53%., (Copyright © 2022 Elsevier Inc. All rights reserved.)

The studies of iridium (III) complexes as potent anticancer reagents have attracted great attention. Here, a new iridium (III) complex [Ir(bzq) 2 (PYIP)](PF 6 ) (Ir1, bzq = benzo[h]quinoline, PYIP = 2-(pyren-1-yl)-1H-imidazo[4,5-f][1,10]phenanthroline) was synthesized and its liposomes (Ir1Lipo) was prepared. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method was used to detect the cytotoxic activity of Ir1 and Ir1Lipo on HepG2, SGC-7901, BEL-7402, HeLa, B16, A549 and normal NIH3T3 cells. The complex Ir1 displays no obvious inhibitory effect on the growth of BEL-7402 cells, while the Ir1Lipo shows significant cytotoxic activity on BEL-7402 cells (IC 50  = 2.6 ± 0.03 μM). In further studies, Ir1Lipo induced apoptosis by the mitochondrial pathways, such as increasing intracellular reactive oxygen species (ROS) content and intracellular Ca 2+ level, decreasing the mitochondrial membrane potential (MMP). In addition, after incubation with Ir1Lipo, the colony formation of BEL-7402 cells was significantly inhibited. Moreover, flow cytometry was used to detect the impact of Ir1Lipo on cell cycle distribution, and western blot was used to detect the expression of caspases and Bcl-2 (B-cell lymphoma-2) family proteins. Furthermore, Ir1Lipo exhibited significant antitumor activity in vivo with an inhibitory rate of 65.8%. These results indicated that Ir1Lipo induces apoptosis in BEL-7402 cells through intrinsic mitochondrial pathway., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Iridium(III) complexes have gained great attention in cancer treatment in recent years. In this paper, we designed and synthesized a new iridium(III) complex [Ir(piq) 2 (DQTT)](PF 6 ) Ir1 (piq = 1-phenylisoquinoline, DQTT = 12-(1,4-dihydroquinoxalin-6-yl)-4,5,9,14-tetraazabenzo[b]triphenylene). The Ir1-loaded PEGylated liposomes (Lipo-Ir1) were prepared using the ethanol injection method. The anticancer activity of the complex and Lipo-Ir1 against SGC-7901 (human gastric adenocarcinoma), A549 (human lung carcinoma), HeLa (human cervical carcinoma), HepG2 (human hepatocellular carcinoma), BEL-7402 (human hepatocellular carcinoma), and normal NIH3T3 (mouse embryonic fibroblasts) was tested by the MTT method. The complex Ir1 shows moderate or low cytotoxicity against the selected cancer cells, whereas the Lipo-Ir1 exhibits high anticancer activity toward the same cancer cells. The apoptosis induced by Lipo-Ir1 was assayed by flow cytometry and Lipo-Ir1 induced apoptosis through increasing intracellular reactive-oxygen species levels, decreasing mitochondrial membrane potential, further promoting cytochrome c release and causing the increase of level of intracellular Ca 2+ . Western blot was used to detect the changes in Bcl-2 family protein and PI3K/AKT pathway proteins. The cloning experiments demonstrated that the Lipo-Ir1 can effectively inhibit cell proliferation. In vivo experiments, Lipo-Ir1 inhibited tumor growth in xenograft nude mice, and the percentage of tumor growth inhibition in vivo was 75.70%. Overall, the liposomes Lipo-Ir1 exhibits higher anticancer activity than Ir1 under the same conditions. These results indicated that Lipo-Ir1 may be a valuable resource for cancer therapy.

Herein an Ir(III) complex [Ir(Hppy)2(HMNPIP)](PF6) (Ir1, Hppy = 2-phenylpyridine, HMNPIP = 2-(1H-imidazo[4,5-f][1, 10]phenanthroline-3-yl)-6-methoxy-4-nitrophenol) was prepared and characterized. Due to the low anticancer activity of Ir1 when administered free drug, we prepared a liposome Ir1Lipo encapsulated form of Ir1 to improve the antitumor effect, furthermore, we explored the antitumor mechanism of both forms in vitro experiments on HepG2 cells. We investigated the inhibitory efficiency of Ir1 and Ir1Lipo on cell viability and proliferation using MTT (MTT = 3-(4,5-dimethylthiazole)-2,5-diphenltetraazolium bromide) and colony-forming assay. Intracellular accumulation of reactive oxygen species (ROS) was examined using a fluorescence microscope (High Content Screening System, ImageXpress Micro XLS System, Molecular Devices LLC, Sunnyvale, CA), programmed cell death cells stained with acridine orange/ethidium bromide (AO/EB) using flow cytometry detection and western blot have been performed. An in vivo study where HepG2 cells were transplanted into nude nice as xenografts. Tumour volume and body weight were monitored during the 10 days of administration. After encapsulation in liposomes Ir1Lipo displayed high potency against a variety of tumour cells in vitro, especially against HepG2 (IC50 = 4.6 ± 0.5 μM). Mechanism studies indicated that Ir1Lipo initiated apoptosis by generating intracellular ROS that regulate lysosomal-mitochondrial dysfunction, followed by microtubule disruption that subsequently leads to a G0/G1 phase of cell cycle arrest. Additionally, Ir1Lipo significantly curbed tumour growth in nude mice. The tumour inhibitory rate was 51.2% (5.6 mg/kg). Therefore, liposome as a drug delivery system greatly enhances anticancer activity of Ir1 by a factor of relatively minor side effects. [ABSTRACT FROM AUTHOR]

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)](PF 6) (1a, with PPY− as deprotonated 2-phenylpyridine), [Ir(PIQ−) 2 (BAPIP)](PF 6) (1b, piq− denoting deprotonated 1-phenylisoquinoline), and [Ir(BZQ−) 2 (BAPIP)](PF 6) (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 IC 50 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. Three new iridium(III) complexes were synthesized and characterized. The anticancer activity of the complexes toward A549 cells were explored, the liposomes entrapped complexes exhibit high antitumor efficacy in vivo. [Display omitted] • Three new iridium(III) complexes and their liposomes were synthesized and characterized. • The cytotoxicity in vitro and in vivo of the complexes and their liposomes was investigated. • Apoptosis, reactive oxygen species and cell cycle arrest were examined. • The RNA-sequence were carried out. • The antitumor efficacy in vivo was studied. [ABSTRACT FROM AUTHOR]

In this study, ligands 2-phenyl-1H-imidazo[4,5-f][1,10]phenanthroline (PIP), 2-(2-nitrophenyl)-1H-imidazo[4,5-f][1,10]phenanthroline (NPIP), 2-(2-nitronaphthalen-1-yl)-1H-imidazo[4,5-f][1,10]phenanthroline (NNIP) and their iridium(III) metal compounds [Ir(ppy) 2 (PIP)](PF 6) (ppy = 2-phenylpyridine, 1a), [Ir(ppy) 2 (NPIP)](PF 6) (1b), [Ir(ppy) 2 (NNIP)](PF 6) (1c) were designed and synthesized. The anti-cancer activities of 1a, 1b and 1c on BEL-7402, HepG2, SK-Hep1 and non-cancer LO2 were detected using MTT method. 1a shows moderate, 1b and 1c display low or no anti-cancer activities. To elevate the anti-cancer effectiveness, encapsulating the compounds 1a, 1b and 1c into the ordinary or targeted liposomes to produce 1alip, 1blip, 1clip, or targeted 1aTlip, 1bTlip and 1cTlip. The IC 50 values of 1alip, 1blip, 1clip, 1aTlip, 1bTlip and 1cTlip against HepG2 cells are 7.9 ± 0.1, 8.6 ± 0.2, 16.9 ± 0.5, 5.9 ± 0.2, 7.3 ± 0.1 and 9.7 ± 0.7 μM, respectively. Specifically, the anti-tumor activity assays in vivo found that the inhibitory rates are 23.24 % for 1a, 61.27 % for 1alip, 76.06 % for 1aTlip. It is obvious that the targeted liposomes entrapped iridium(III) compound greatly enhance anti-cancer efficacy. Additionally, 1alip, 1blip and 1clip or targeted 1aTlip, 1bTlip and 1cTlip can effectively restrain the cell colony and proliferation in the G0/G1 period. 1alip, 1blip, 1clip, 1aTlip, 1bTlip and 1cTlip can increase reactive oxygen species (ROS) concentration, arouse a decline in the mitochondrial membrane potential and promote Ca2+ release. RNA-sequence was applied to examine the signaling pathways. Taken together, the liposomes or targeted liposomes encapsulated compounds trigger cell death by way of apoptosis, autophagy, ferroptosis, disruption of mitochondrial function and PI3K/AKT/mTOR signaling pathways. Three iridium(III) polypyridyl compounds 1a, 1b, 1c and compound-loaded ordinary 1alip, 1blip, 1clip and targeted liposomes 1aTlip, 1bTlip and 1cTlip were synthesized and characterized. The antiproliferative ability of 1a, 1b, 1c, 1alip, 1blip, 1clip, 1aTlip, 1bTlip and 1cTlip against BEL-7402, HepG2, SK-Hep1 and non-cancer LO2 cells was investigated. The inhibitory rate in vivo of 1a, 1alip and 1aTlip inhibiting HepG2 tumor growth attains 23.24, 61.27 and 76.06 %. [Display omitted] • Three new iridium(III) complexes, ordinary and targeted liposomes were synthesized and characterization. • The cytotoxicity in vitro and in vivo of the complexes and their liposomes was investigated. • Cell cycle arrest, apoptosis, ferroptosis, reactive oxygen species were examined. • The RNA-sequence was explored. • The antitumor efficacy in vivo was evaluated. [ABSTRACT FROM AUTHOR]

Two polypyridyl ruthenium(II) complexes [Ru(DIP) 2 (BIP)](PF 6) 2 (DIP = 4,7-diphenyl-1,10-phenanthrolie, BIP = 2-(1,1′-biphenyl-4-yl)-1 H -imidazo[4,5-f][1,10]phenanthroline, Ru1) and [Ru(DIP) 2 (CBIP)](PF 6) 2 (CBIP = 2-(4′-chloro-1,1′-biphenyl-4-yl)-1 H -imidazo[4,5-f][1,10]phenanthroline, Ru2) were synthesized. The cytotoxic activities in vitro of Ru1, Ru2 toward B16, A549, HepG2, SGC-7901, HeLa, BEL-7402, non-cancer LO2 were investigated using MTT method (3-(4,5-dimethylthiazole)-2,5-diphenltetraazolium bromide). Unexpectedly, Ru1, Ru2 can't prevent these cancer cells proliferation. To improve the anti-cancer effect, we used liposomes to entrap the complexes Ru1, Ru2 to form Ru1lipo, Ru2lipo. As expectation, Ru1lipo and Ru2lipo exhibit high anti-cancer efficacy, especially, Ru1lipo (IC 50 3.4 ± 0.1 μM), Ru2lipo (IC 50 3.5 ± 0.1 μM) display strong ability to block the cell proliferation in SGC-7901. The cell colony, wound healing, and cell cycle distribution show that the complexes can validly inhibit the cell growth at G2/M phase. Apoptotic studied with Annex V/PI doubling method showed that Ru1lipo and Ru2lipo can effectively induce apoptosis. Reactive oxygen species (ROS), malondialdehyde, glutathione and GPX4 demonstrate that Ru1lipo and Ru2lipo improve ROS and malondialdehyde levels, inhibit generation of glutathione, and finally result in a ferroptosis. Ru1lipo and Ru2lipo interact on the lysosomes and mitochondria and damage mitochondrial dysfunction. Additionally, Ru1lipo and Ru2lipo increase intracellular Ca2+ concentration and induce autophagy. The RNA-sequence and molecular docking were performed, the expression of Bcl-2 family was investigated by Western blot analysis. Antitumor in vivo experiments confirm that 1.23 mg/kg, 2.46 mg/kg of Ru1lipo possesses a high inhibitory rate of 53.53% and 72.90% to prevent tumor growth, hematoxylin-eosin (H&E) results show that Ru1lipo doesn't cause chronic organ damage and strongly promotes the necrosis of solid tumor. Taken together, we conclude that Ru1lipo and Ru2lipo cause cell death through the following pathways: autophagy, ferroptosis, ROS-regulated mitochondrial dysfunction, and blocking the PI3K/AKT/mTOR. Two new Ru(II) polypyridyl complexes [Ru(dip) 2 (BIP)](PF 6) 2 (dip = 4,7-diphenyl-1,10-phenanthrolie, BIP = 2-(1,1′-biphenyl-4-yl)-1 H -imidazo[4,5-f] [1,10]phenanthroline, Ru1) and [Ru(dip) 2 (CBIP)](PF 6) 2 (CBIP = 2-(4′-chloro-1,1′-biphenyl-4-yl)-1 H -imidazo[4,5-f] [1,10]phenanthroline, Ru2) and complexes-loaded liposomes Ru1lipo and Ru2lipo were synthesized and characterized. The cytotoxicity of the complexes Ru1, Ru2, Ru1lipo and Ru2lipo against B16, BEL-7402, A549, HepG2, SGC-7901 cancer cells and non-cancer cell LO2 was evaluated using 3-(4,5-dimethylthiazole-2-yl)-2,5-biphenyl tetrazolium bromide (MTT) method. The high inhibitory rate in vivo of Ru1lipo inhibiting SGC-7901 tumor growth reaches 72.90%. [Display omitted] • Two new Ru(II) polypyridyl complexes were synthesized and characterized. • The cytotoxicity in vitro and in vivo of the complexes and liposomes was investigated. • Apoptosis, reactive oxygen species and cell cycle arrest were performed. • RNA-sequence assay was investigated. • The antitumor activity in vivo was investigated. [ABSTRACT FROM AUTHOR]

In this study, two new iridium(III) polypyridyl complexes [Ir(bzq) 2 (DIPH)](PF 6) (bzq = deprotonated benzo[ h ]quinoline, DIPH = 4-(2,5-dibromo-4-(1 H -imidazo[4,5-f][1,10]phenanthrolim-2-yl)-4-hydroxybutan-2-one) (Ir1) and [Ir(piq) 2 (DIPH)](PF 6) (piq = deprotonated 1-phenylisoquinoline) (Ir2) were synthesized and characterized by elemental analysis, HRMS, 1H and 13C NMR. The cytotoxic activity of Ir1 , Ir2 , Ir1lipo and Ir2lipo against cancer cells SGC-7901, HepG2, A549, HeLa, B16 and normal NIH3T3 cells in vitro was evaluated using 3-(4,5-dimethylthiazole-2-yl)-2,5-biphenyl tetrazolium bromide (MTT) method. Ir1 and Ir2 showed no cytotoxic activity, but their liposome-entrapped Ir1 (Ir1lipo) and Ir2 (Ir2lipo) showed significant cellular activity, especially sensitive to SGC-7901 with IC 50 values of 4.7 ± 0.2 and 12.4 ± 0.5 μM, respectively. The cellular uptake, endoplasmic reticulum (ER) localization, autophagy, tubulin polymerization, glutathione (GSH), malondialdehyde (MDA) and release of cytochrome c were investigated to explore the mechanisms of apoptosis. The calreticulin (CRT), heat shock protein 70 (HSP70), high mobility group box 1 (HMGB1) were also explored. Western blotting showed that Ir1lipo and Ir2lipo inhibited PI3K (phosphoinositide-3 kinase), AKT (protein kinase B), p-AKT and activated Bcl-2 (B-cell lymphoma-2) protein and apoptosis-regulated factor caspase 3 (cysteinyl aspartate specific proteinase-3) and cleaving PARP (poly ADP-ribose polymerase). The results demonstrated that Ir1lipo and Ir2lipo induce cell apoptosis through targeting the endoplasmic reticulum (ER), cause oxidative stress damage, inhibiting PI3K/AKT signaling pathway, immunogenic cell death (ICD) and inhibit the cell growth at G2/M phase. Two new iridium(III) complexes were synthesized and characterized. The anticancer activity of the liposome-entrapped complexes against SGC-7901 cells were investigated, the liposome-entrapped complexes exhibit high anticancer activity toward SGC-7901 cells. [Display omitted] • Two iridium(III) complexes and liposomes was synthesized and characterized. • The cytotoxicity of the complexes and their liposomes was investigated. • Apoptosis, reactive oxygen species and cell cycle arrest were carried out. • The immunogenic cell death and molecular docking were performed. • The expression of B-cell lymphoma-2 family proteins was examined. [ABSTRACT FROM AUTHOR]

In this paper, two new iridium(III) complexes [Ir(ppy) 2 (CBIP)](PF 6) (ppy = 2-phenylpyridine, CBIP = 2-(4′-chloro-(1,1′-biphenyl))-1 H -imidazo[4,5-f][ 1 , 10 ]phenanthroline) (Ir1) and [Ir(piq) 2 (CBIP)](PF 6) (piq = 1-phenylisoquinoline) (Ir2) were synthesized and characterized. The anticancer activity of the complexes against cancer A549, HepG2, SGC-7901, BEL-7402, HeLa and LO2 cells was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method. Unexpectedly, the complexes exhibit no or low cytotoxic activity toward the selected cancer cells. To increase the anticancer activity, complexes Ir1 and Ir2 were encapsulated into the liposome to form Ir1lipo and Ir2lipo , while Ir1lipo and Ir2lipo show high cytotoxic efficacy against BEL-7402, SGC-7901 and HeLa cells and Ir2lipo displays moderate cytotoxic activity against A549 and HepG2. The anticancer mechanism was explored through wound healing, cell cycle arrest, apoptosis, the change of mitochondrial membrane potential and antitumor activity in vivo. The antitumor in vivo showed that Ir1Lipo (3.9 mg/kg) exhibited significant antitumor activity with an inhibitory rate of 62.16%. Additionally, the expression of B-cell lymphoma-2 family proteins was studies by western blotting analysis. The results demonstrate that Ir1lipo and Ir2lipo induce apoptosis in BEL-7402 cells via endoplasmic reticulum stress-mitochondrial pathway. [Ir(ppy) 2 (CBIP)](PF 6) (ppy = 2-phenylpyridine, Ir1), [Ir(piq) 2 (CBIP)](PF 6) (piq = 1-phenylisoquinoline, CBIP = 2-(4′-chloro-(1,1′-biphenyl))-1 H -imidazo[4,5-f] [1,10]phenanthroline, Ir2), complex-loaded liposomes Ir1lipo and Ir2lipo were synthesized. The anticancer activity in vitro and in vivo of the complexes and their liposomes were evaluated. [Display omitted] • Three iridium(III) complexes and complex-loaded liposomes were synthesized. • The cytotoxicity in vitro and in vivo of the complexes and liposomes was studied. • The apoptosis and cell cycle arrest were performed. • The location of the complexes at the endoplasm reticulum and mitochondria was explored. • The expression of B-cell lymphoma-2 family proteins was assayed. [ABSTRACT FROM AUTHOR]