Fabrication of Rhenium Disulfide/Mesoporous Silica Core-Shell Nanoparticles for a pH-Responsive Drug Release and Combined Chemo-Photothermal Therapy.

A stimuli-responsive drug delivery nanocarrier with a core-shell structure combining photothermal therapy and chemotherapy for killing cancer cells was constructed in this study. The multifunctional nanocarrier ReS2@mSiO2-RhB entails an ReS2 hierarchical nanosphere coated with a fluorescent mesoporous silica shell. The three-dimensional hierarchical ReS2 nanostructure is capable of effectively absorbing near-infrared (NIR) light and converting it into heat. These ReS2 nanospheres were generated by a hydrothermal synthesis process leading to the self-assembly of few-layered ReS2 nanosheets. The mesoporous silica shell was further coated on the surface of the ReS2 nanospheres through a surfactant-templating sol-gel approach to provide accessible mesopores for drug uploading. A fluorescent dye (Rhodamine B) was covalently attached to silica precursors and incorporated during synthesis in the mesoporous silica walls toward conferring imaging capability to the nanocarrier. Doxorubicin (DOX), a known cancer drug, was used in a proof-of-concept study to assess the material's ability to function as a drug delivery carrier. While the silica pores are not capped, the drug molecule loading and release take advantage of the pH-governed electrostatic interactions between the drug and silica wall. The ReS2@mSiO2-RhB enabled a drug loading content as high as 19.83 mg/g doxorubicin. The ReS2@mSiO2-RhB-DOX nanocarrier's cumulative drug release rate at pH values that simulate physiological conditions showed significant pH responsiveness, reaching 59.8% at pH 6.8 and 98.5% and pH 5.5. The in vitro testing using HeLa cervical cancer cells proved that ReS2@mSiO2-RhB-DOX has a strong cancer eradication ability upon irradiation with an NIR laser owing to the combined drug delivery and photothermal effect. The results highlight the potential of ReS2@mSiO2-RhB nanoparticles for combined cancer therapy in the future.

Neutral rhenium(I) tricarbonyl complexes with sulfur-donor ligands: anti-proliferative activity and cellular localization.

Rhenium(I) tricarbonyl complexes are widely studied for their cell imaging properties and anti-cancer and anti-microbial activities, but the complexes with S-donor ligands remain relatively unexplored. A series of six fac-[Re(NN)(CO)3(SR)] complexes, where (NN) is 2,2'-bipyridyl (bipy) or 1,10-phenanthroline (phen), and RSH is a series of thiocarboxylic acid methyl esters, have been synthesized and characterized. Cellular uptake and anti-proliferative activities of these complexes in human breast cancer cell lines (MDA-MB-231 and MCF-7) were generally lower than those of the previously described fac-[Re(NN)(CO)3(OH2)]+ complexes; however, one of the complexes, fac-[Re(CO)3(phen)(SC(Ph)CH2C(O)OMe)] (3b), was active (IC50 ∼ 10 µM at 72 h treatment) in thiol-depleted MDA-MB-231 cells. Moreover, unlike fac-[Re(CO)3(phen)(OH2)]+, this complex did not lose activity in the presence of extracellular glutathione. Taken together these properties show promise for further development of 3b and its analogues as potential anti-cancer drugs for co-treatment with thiol-depleting agents. Conversely, the stable and non-toxic complex, fac-[Re(bipy)(CO)3(SC(Me)C(O)OMe)] (1a), predominantly localized in the lysosomes of MDA-MB-231 cells, as shown by live cell confocal microscopy (λex = 405 nm, λem = 470-570 nm). It is strongly localized in a subset of lysosomes (25 µM Re, 4 h treatment), as shown by co-localization with a Lysotracker dye. Longer treatment times with 1a (25 µM Re for 48 h) resulted in partial migration of the probe into the mitochondria, as shown by co-localization with a Mitotracker dye. These properties make complex 1a an attractive target for further development as an organelle probe for multimodal imaging, including phosphorescence, carbonyl tag for vibrational spectroscopy, and Re tag for X-ray fluorescence microscopy.

Rhodium-Rhenium Alloy Nanozymes for Non-inflammatory Photothermal Therapy.

Analogous to thermal ablation techniques in clinical settings, cell necrosis induced during tumor photothermal therapy (PTT) can provoke an inflammatory response that is detrimental to the treatment of tumors. In this study, we employed a straightforward one-step liquid-phase reduction process to synthesize uniform RhRe nanozymes with an average hydrodynamic size of 41.7 nm for non-inflammatory photothermal therapy. The obtained RhRe nanozymes showed efficient near-infrared (NIR) light absorption for effective PTT, coupled with a remarkable capability to scavenge reactive oxygen species (ROS) for anti-inflammatory treatment. After laser irradiation, the 4T1 tumors were effectively ablated without obvious tumor recurrence within 14 days, along with no obvious increase in pro-inflammatory cytokine levels. Notably, these RhRe nanozymes demonstrated high biocompatibility with normal cells and tissues, both in vitro and in vivo, as evidenced by the lack of significant toxicity in female BALB/c mice treated with 10 mg/kg of RhRe nanozymes over a 14 day period. This research highlights RhRe alloy nanoparticles as bioactive nanozymes for non-inflammatory PTT in tumor therapy.

Comparative Study of Sonodynamic and Photoactivated Cancer Therapies with Re(I)-Tricarbonyl Complexes Comprising Phenanthroline Ligands.

Herein, we have compared the effectivity of light-based photoactivated cancer therapy and ultrasound-based sonodynamic therapy with Re(I)-tricarbonyl complexes (Re1-Re3) against cancer cells. The observed photophysical and TD-DFT calculations indicated the potential of Re1-Re3 to act as good anticancer agents under visible light/ultrasound exposure. Re1 did not display any dark- or light- or ultrasound-triggered anticancer activity. However, Re2 and Re3 displayed concentration-dependent anticancer activity upon light and ultrasound exposure. Interestingly, Re3 produced 1O2 and OH• on light/ultrasound exposure. Moreover, Re3 induced NADH photo-oxidation in PBS and produced H2O2. To the best of our knowledge, NADH photo-oxidation has been achieved here with the Re(I) complex for the first time in PBS. Additionally, Re3 released CO upon light/ultrasound exposure. The cell death mechanism revealed that Re3 produced an apoptotic cell death response in HeLa cells via ROS generation. Interestingly, Re3 showed slightly better anticancer activity under light exposure compared to ultrasound exposure.

Effectiveness of Rhenium(I)-diselenoether Low Doses in a Triple-negative Breast Cancer Chicken Embryo Model.

BACKGROUND/AIM: Rhenium(I)-diselenoether (Re-diSe) is a promising anticancer agent composed of one rhenium and two selenium atoms. Its effectiveness was established in inhibiting cancer cells while maintaining low toxicity toward normal cells at a 5 µM dose for 120 hours in MDA-MB-231 cells. In MDA-MB-231 breast tumor-bearing mice, anti-tumor and anti-metastatic effects were observed at a 10 mg/kg dose. However, contradictory results were observed in the 4T1 breast cancer model, where a dose of 60 mg/kg had a pro-tumor effect. To address these discrepancies, the efficacy of Re-diSe at the effective 10 mg/kg dose was validated in a transplanted MDA-MB-231 breast tumor model using the chicken chorioallantoic membrane assay. MATERIALS AND METHODS: MDA-MB-231 cancer cells were xenografted onto the chicken chorioallantoic membrane (CAM), and daily drug administration was carried out for nine days at doses of 0.1, 1, and 10 mg/kg. At the study's conclusion, a standard histological analysis was conducted. RESULTS: The low dose of 0.1 mg/kg showed a significant reduction in tumor weights compared to controls. The 1 mg/kg dose resulted in an increased inflammation score but did not induce a significant difference in tumor weights compared to the 0.1 mg/kg dose. Notably, at the 10 mg/kg dose, six out of 11 treated embryos displayed no visible signs of tumors. These tumors exhibited extensive tumor necrosis and significant infiltration by inflammatory cells. CONCLUSION: In this particular model, the anticancer efficacy of Re-diSe was achieved at the low dose of 0.1 mg/kg. The higher dose of 10 mg/kg, while eliminating visible tumors, might have immune-mediated effects, as indicated by substantial tumor necrosis and infiltration by inflammatory cells. Overall, this study successfully demonstrated the effectiveness of Re-diSe as an anticancer agent.

Necrosis-Inducing High-Valent Oxo-Rhenium(V) Complexes with Potent Antitumor Activity: Synthesis, Aquation Chemistry, Cisplatin Cross-Resistance Profile, and Mechanism of Action.

Chemotherapy with the cytotoxic platinum (Pt) drugs cisplatin, carboplatin, and oxaliplatin is the mainstay of anticancer therapy in the clinic. The antitumor activity of Pt drugs originates from their ability to induce apoptosis via covalent adduct formation with nuclear DNA. While the phenomenal clinical success is highly encouraging, resistance and adverse toxic side effects limit the wider applicability of Pt drugs. To circumvent these limitations, we embarked on an effort to explore the antitumor potential of a new class of oxo-rhenium(V) complexes of the type [(N∧N)(EG)Re(O)Cl] (where EG = ethylene glycolate and N∧N = bipyridine, Bpy (1); phenanthroline, Phen (2); 3,4,7,8-tetramethyl-phenanthroline, Me4Phen (3)). Investigation of speciation chemistry in aqueous media revealed the formation of [(N∧N)Re(O)(OH)3] as the biologically active species. Complex 3 was found to be the most potent among the three, with IC50 values ranging from 0.1 to 0.4 µM against a panel of cancer cells, which is 5-70-fold lower when compared with cisplatin. The higher potency of 3 is attributed to its higher lipophilicity, which enhanced cellular uptake. Importantly, complex 3 efficiently overcomes cisplatin resistance in ovarian, lung, and prostate cancer cells. In addition to reporting the aquation chemistry and identifying the active species in aqueous media, we performed in-depth in vitro mechanistic studies, which revealed that complex 3 preferentially accumulates in mitochondria, depletes mitochondrial membrane potential, and upregulates intracellular reactive oxygen species (ROS), leading to ER stress-mediated necrosis-mediated cancer cell death.

Remarkable Effects of a Rhenium(I)-diselenoether Drug on the Production of Cathepsins B and S by Macrophages and their Polarizations.

BACKGROUND/OBJECTIVE: Tumor-associated macrophages (TAMs) produce an excessive amount of cysteine proteases, and we aimed to study the effects of anticancer rhenium(I)-diselenoether (Re-diSe) on the production of cathepsins B and S by macrophages. We investigated the effect of Re-diSe on lipopolysaccharides (LPS) induced M1 macrophages, or by interleukin 6 (IL-6) induced M2 macrophages. METHODS: Non-stimulated or prestimulated murine Raw 264 or human THP-1 macrophages were exposed to increasing concentrations of the drug (5, 10, 20, 50 and 100 µM) and viability was assayed by the MTT assay. The amount of cysteine proteases was evaluated by ELISA tests, the number of M1 and M2 macrophages by the expression of CD80 or CD206 biomarkers. The binding of Re-diSe with GSH as a model thiol-containing protein was studied by mass spectrometry. RESULTS: A dose-dependent decrease in cathepsins B and S was observed in M1 macrophages. There was no effect in non-stimulated cells. The drug induced a dramatic dose-dependent increase in M1 expression in both cells, significantly decreased the M2 expression in Raw 264 and had no effect in non-stimulated macrophages. The binding of the Re atom with the thiols was clearly demonstrated. CONCLUSION: The increase in the number of M1 and a decrease in M2 macrophages treated by Re-diSe could be related to the decrease in cysteine proteases upon binding of their thiol residues with the Re atom.

Radio-immunotherapy by 188Re-antiCD20 and stable silencing of IGF-IR in Raji cells, new insight in treatment of lymphoma.

Hematologic malignancies such as Non-Hodgkin's lymphoma (NHL), remain a serious threat to human health due to their heterogeneity and complexity. The inherent genetic heterogeneity of NHL B-cells, as well as the instability of lymphoma cancer cells, results in drug resistance in lymphoma, posing a fundamental challenge to NHL treatment. Burkitt lymphoma (including Raji cell line) is a rare and highly aggressive form of B-cell NHL. Since overexpression of the insulin-like growth factor-1 receptor (IGF-1R) playing a prominent role in the development and transformation of different malignancies, especially lymphoma malignancies, we have explored the role of IGF-1R in the development and progression of Raji cells and the stable silencing of IGF-1R by lentivirus-mediated RNA interference (RNAi). We have shown that stable silencing of the IGF-1R gene in Raji cells using lentivirus-mediated-RNAi have resulted in a significant reduction in Raji cell proliferation. Moreover, the results of the cell viability assays indicatedhigh resistance of Raji cells to rituximab. However, coupling rituximab to 188Re potentially leads to specific targeting of Raji cells by 188Re, improving the therapeutic efficacy. We found that the synergistic effect of using a gene therapy-based system in combination with radioimmunotherapy could be a promising therapeutic strategy in the future. To the best of our knowledge, this is the first study that reports the knock down of IGF-1R via lentiviral-mediated shRNA in Raji cells.

Rhenium(I) Tricarbonyl Complexes of 1,10-Phenanthroline Derivatives with Unexpectedly High Cytotoxicity.

Eight rhenium(I) tricarbonyl aqua complexes with the general formula fac-[Re(CO)3(N,N'-bid)(H2O)][NO3] (1-8), where N,N'-bid is (2,6-dimethoxypyridyl)imidazo[4,5-f]1,10-phenanthroline (L1), (indole)imidazo[4,5-f]1,10-phenanthroline (L2), (5-methoxyindole)-imidazo[4,5-f]1,10-phenanthroline (L3), (biphenyl)imidazo[4,5-f]1,10-phenanthroline (L4), (fluorene)imidazo[4,5-f]1,10-phenanthroline (L5), (benzo[b]thiophene)imidazo[4,5-f]1,10-phenanthroline (L6), (5-bromothiazole)imidazo[4,5-f]1,10-phenanthroline (L7), and (4,5-dimethylthiophene)imidazo[4,5-f]1,10-phenanthroline (L8), were synthesized and characterized using 1H and 13C{1H} NMR, FT-IR, UV/Vis absorption spectroscopy, and ESI-mass spectrometry, and their purity was confirmed by elemental analysis. The stability of the complexes in aqueous buffer solution (pH 7.4) was confirmed by UV/Vis spectroscopy. The cytotoxicity of the complexes (1-8) was then evaluated on prostate cancer cells (PC3), showing a low nanomolar to low micromolar in vitro cytotoxicity. Worthy of note, three of the Re(I) tricarbonyl complexes showed very low (IC50 = 30-50 nM) cytotoxic activity against PC3 cells and up to 26-fold selectivity over normal human retinal pigment epithelial-1 (RPE-1) cells. The cytotoxicity of both complexes 3 and 6 was lowered under hypoxic conditions in PC3 cells. However, the compounds were still 10 times more active than cisplatin in these conditions. Additional biological experiments were then performed on the most selective complexes (complexes 3 and 6). Cell fractioning experiments followed by ICP-MS studies revealed that 3 and 6 accumulate mostly in the mitochondria and nucleus, respectively. Despite the respective mitochondrial and nuclear localization of 3 and 6, 3 did not trigger the apoptosis pathways for cell killing, whereas 6 can trigger apoptosis but not as a major pathway. Complex 3 induced a paraptosis pathway for cell killing while 6 did not induce any of our other tested pathways, namely, necrosis, paraptosis, and autophagy. Both complexes 3 and 6 were found to be involved in mitochondrial dysfunction and downregulated the ATP production of PC3 cells. To the best of our knowledge, this report presents some of the most cytotoxic Re(I) carbonyl complexes with exceptionally low nanomolar cytotoxic activity toward prostate cancer cells, demonstrating further the future viability of utilizing rhenium in the fight against cancer.

Infrared-Activated Bactericide: Rhenium Disulfide (ReS2)-Functionalized Mesoporous Silica Nanoparticles.

An attractive strategy for treating bacterial infection is the combination of antibiotic chemotherapy with photothermal therapy (PTT), which could be implemented using multifunctional nanomaterials. In this work, the intrinsic photothermal efficiency of two-dimensional (2D) rhenium disulfide (ReS2) nanosheets is enhanced by their coating on mesoporous silica nanoparticles (MSNs) to realize a highly efficient light-responsive nanoparticle endowed with controlled-release drug delivery capability, denoted as MSN-ReS2. The MSN component of the hybrid nanoparticle features augmented pore size toward facilitating increased loading of antibacterial drugs. The ReS2 synthesis is conducted in the presence of MSNs through an in situ hydrothermal reaction and leads to a uniform surface coating of the nanosphere. The MSN-ReS2 bactericide testing showed more than 99% bacterial killing efficiency in both Gram-negative bacteria (Escherichia coli) and Gram-positive bacteria (Staphylococcus aureus) upon laser irradiation. A cooperative effect that led to a 100% bactericide effect on Gram-negative bacteria (E. coli) was observed when tetracycline hydrochloride was loaded in the carrier. The results show the potential of MSN-ReS2 to be used as a wound-healing therapeutic with a synergistic bactericide role.

Biological Activity of fac-[Re(CO)3(phen)(aspirin)], fac-[Re(CO)3(phen)(indomethacin)] and Their Original Counterparts against Ishikawa and HEC-1A Endometrial Cancer Cells.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are inhibitors of cyclooxygenase enzyme (COX) and were found to have positive effects in reducing the risk of developing gynecological cancers. However, long-term administration of NSAIDs carries the risk of various side effects, including those in the digestive and circulatory systems. Therefore, there is a constant need to develop new NSAID derivatives. In this work, we investigated rhenium NSAIDs, comparing their effects on endometrial cancer cells with original NSAIDs, demonstrating the high activity of aspirin and indomethacin derivatives. The cytotoxic activity of rhenium derivatives against the Ishikawa and HEC-1A cancer cell lines was higher than that of the original NSAIDs. The IC50 after 24-h incubation of Ishikawa and HEC-1A were 188.06 µM and 394.06 µM for rhenium aspirin and 228.6 µM and 1459.3 µM for rhenium indomethacin, respectively. At the same time, IC50 of aspirin and indomethacin were 10,024.42 µM and 3295.3 µM for Ishikawa, and 27,255.8 µM and 5489.3 µM for HEC-1A, respectively. Moreover, these derivatives were found to inhibit the proliferation of both cell lines in a time- and state-dependent manner. The Ishikawa cell proliferation was strongly inhibited by rhenium aspirin and rhenium indomethacin after 72-h incubation (*** = p < 0.001), while the HEC-1A proliferation was inhibited by the same agents already after 24-h incubation (*** = p < 0.001). Furthermore, the ROS level in the mitochondria of the tested cells generated in the presence of rhenium derivatives was higher than the original NSAIDs. That was associated with rhenium indomethacin exclusively, which had a significant effect (*** = p < 0.001) on both Ishikawa and HEC-1A cancer cells. Rhenium aspirin had a significant effect (*** = p < 0.001) on the mitochondrial ROS level of Ishikawa cells only. Overall, the research revealed a high potential of the rhenium derivatives of aspirin and indomethacin against endometrial cancer cells compared with the original NSAIDs.

Synthesis and anti-microbial activity of a new series of bis(diphosphine) rhenium(V) dioxo complexes.

Rhenium-based metallodrugs have recently been highlighted as promising candidates for new antibiotics to combat multi-drug resistant (MDR) pathogens. A new class of rhenium(V) dioxo complexes were prepared from readily accessible diphosphine ligands, and have been shown to possess potent activity against Staphylococcus aureus (S. aureus) and Candida albicans (C. albicans) alongside low human cell toxicity.

Rhenium(I) derivatives of aminoquinoline and imidazolopiperidine-based ligands: Synthesis, in vitro and in silico biological evaluation against Plasmodium falciparum.

A small library of aminoquinoline and imidazolopiperidine (IMP)-based ligands, containing the 1,2,3-triazole moiety, and their corresponding tricarbonyl rhenium complexes were synthesised and their inhibitory activities evaluated against the chloroquine-sensitive (CQS) and multidrug-resistant (MDR) strains (NF54 and K1, respectively) of P. falciparum. The quinoline-based compounds (L1, L2, ReL1, and ReL2) were at least six-fold more potent than their IMP-based counterparts (L3, L4, ReL3, and ReL4) against both strains of P. falciparum, with the most promising compound (L1) displaying activity comparable to chloroquine diphosphate (CQDP) in the MDR strain. Additionally, all of the synthesised compounds have resistance indices less than CQDP. To gain insight into a possible mechanism of action, in silico hemozoin docking simulations were performed. These studies proposed that the tested compounds may act via hemozoin inhibition, as the new aminoquinoline-derivatives, with the exception of complex ReL2 (binding affinity: -12.62 kcal/mol), showed higher binding affinities than the reference drug chloroquine (CQ, -13.56 kcal/mol). Furthermore, the ligands exhibited superior binding affinity relative to their corresponding Re(I) complexes, which is reflected in their antiplasmodial activity.

Rhenium-guanidine complex as photosensitizer: trigger HeLa cell apoptosis through death receptor-mediated, mitochondria-mediated, and cell cycle arrest pathways.

The growing evidence over the past few decades has indicated that the photodynamic antitumor activity of transition metal complexes, and Re(I) compounds are potential candidates for photodynamic therapy. This study reports the synthesis, characterization, and anti-tumor activity of three new Re(I)-guadinium complexes. Cytotoxicity tests reveal that complex Re1 increased cytotoxicity by 145-fold from IC50 > 180 µM in the dark to 1.3 ± 0.7 µM following 10 min of light irradiation (425 nm) in HeLa cells. Further, the mechanism by which Re1 induces apoptosis in the presence or absence of light irradiation was investigated, and results indicate that cell death was caused through different pathways. Upon irradiation, Re1 first accumulates on the cell membrane and interacts with death receptors to activate the extrinsic death receptor-mediated signaling pathway, and then is transported into the cell cytoplasm. Most of the intracellular Re1 locates within mitochondria, improving the reactive oxygen species level, and decreasing mitochondrial membrane potential and ATP levels, and inducing the activation of caspase-9 and, thus, apoptosis. Subsequently, the residual Re1 can translocate into the cell nucleus, and activates the p53 pathway, causing cell cycle arrest and eventually cell death.

Rhenium Perrhenate (188ReO4) Induced Apoptosis and Reduced Cancerous Phenotype in Liver Cancer Cells.

Recurrence in hepatocellular carcinoma (HCC) after conventional treatments is a crucial challenge. Despite the promising progress in advanced targeted therapies, HCC is the fourth leading cause of cancer death worldwide. Radionuclide therapy can potentially be a practical targeted approach to address this concern. Rhenium-188 (188Re) is a ß-emitting radionuclide used in the clinic to induce apoptosis and inhibit cell proliferation. Although adherent cell cultures are efficient and reliable, appropriate cell-cell and cell-extracellular matrix (ECM) contact is still lacking. Thus, we herein aimed to assess 188Re as a potential therapeutic component for HCC in 2D and 3D models. The death rate in treated Huh7 and HepG2 lines was significantly higher than in untreated control groups using viability assay. After treatment with 188ReO4, Annexin/PI data indicated considerable apoptosis induction in HepG2 cells after 48 h but not Huh7 cells. Quantitative RT-PCR and western blotting data also showed increased apoptosis in response to 188ReO4 treatment. In Huh7 cells, exposure to an effective dose of 188ReO4 led to cell cycle arrest in the G2 phase. Moreover, colony formation assay confirmed post-exposure growth suppression in Huh7 and HepG2 cells. Then, the immunostaining displayed proliferation inhibition in the 188ReO4-treated cells on 3D scaffolds of liver ECM. The PI3-AKT signaling pathway was activated in 3D culture but not in 2D culture. In nude mice, Huh7 cells treated with an effective dose of 188ReO4 lost their tumor formation ability compared to the control group. These findings suggest that 188ReO4 can be a potential new therapeutic agent against HCC through induction of apoptosis and cell cycle arrest and inhibition of tumor formation. This approach can be effectively combined with antibodies and peptides for more selective and personalized therapy.

Anticancer and Antibiotic Rhenium Tri- and Dicarbonyl Complexes: Current Research and Future Perspectives.

Organometallic compounds are increasingly recognized as promising anticancer and antibiotic drug candidates. Among the transition metal ions investigated for these purposes, rhenium occupies a special role. Its tri- and dicarbonyl complexes, in particular, attract continuous attention due to their relative ease of preparation, stability and unique photophysical and luminescent properties that allow the combination of diagnostic and therapeutic purposes, thereby permitting, e.g., molecules to be tracked within cells. In this review, we discuss the anticancer and antibiotic properties of rhenium tri- and dicarbonyl complexes described in the last seven years, mainly in terms of their structural variations and in vitro efficacy. Given the abundant literature available, the focus is initially directed on tricarbonyl complexes of rhenium. Dicarbonyl species of the metal ion, which are slowly gaining momentum, are discussed in the second part in terms of future perspective for the possible developments in the field.

Relationship between the oxidative status and the tumor growth in transplanted triple-negative 4T1 breast tumor mice after oral administration of rhenium(I)-diselenoether.

BACKGROUND: Selective inhibitory effects of rhenium(I)-diselenoether (Re-diSe) were observed in cultured breast malignant cells. They were attributed to a decrease in Reactive Oxygen Species (ROS) production. A concomitant decrease in the production of Transforming Growth Factor-beta (TGFß1), Insulin Growth Factor 1 (IGF1), and Vascular Endothelial Growth Factor A (VEGFA) by the malignant cells was also observed. AIM: The study aimed to investigate the anti-tumor effects of Re-diSe on mice bearing 4T1 breast tumors, an experimental model of triple-negative breast cancer, and correlate them with several biomarkers. MATERIAL AND METHODS: 4T1 mammary breast cancer cells were orthotopically inoculated into syngenic BALB/c Jack mice. Different doses of Re-diSe (1, 10, and 60 mg/kg) were administered orally for 23 consecutive days to assess the efficacy and toxicity. The oxidative status was evaluated by assaying Advanced Oxidative Protein Products (AOPP), and by the dinitrophenylhydrazone (DNPH) test in plasma of healthy mice, non-treated tumor-bearing mice (controls), treated tumor-bearing mice, and tumors in all tumor-bearing mice. Tumor necrosis factor (TNFα), VEGFA, VEGFB, TGFß1, Interferon, and selenoprotein P (selenoP) were selected as biomarkers. RESULTS: Doses of 1 and 10 mg/kg did not affect the tumor weights. There was a significant increase in the tumor weights in mice treated with the maximum dose of 60 mg/kg, concomitantly with a significant decrease in AOPP, TNFα, and TGFß1 in the tumors. SelenoP concentrations increased in the plasma but not in the tumors. CONCLUSION: We did not confirm the anti-tumor activity of the Re-diSe compound in this experiment. However, the transplantation of the tumor cells did not induce an expected pro-oxidative status without any increase of the oxidative biomarkers in the plasma of controls compared to healthy mice. This condition could be essential to evaluate the effect of an antioxidant drug. The choice of the experimental model will be primordial to assess the effects of the Re-diSe compound in further studies.

A Carbonic Anhydrase IX (CAIX)-Anchored Rhenium(I) Photosensitizer Evokes Pyroptosis for Enhanced Anti-Tumor Immunity.

An ideal cancer treatment should not only destroy primary tumors but also improve the immunogenicity of the tumor microenvironment to achieve a satisfactory anti-tumor immune effect. We designed a carbonic anhydrase IX (CAIX)-anchored rhenium(I) photosensitizer, named CA-Re, that not only performs type-I and type-II photodynamic therapy (PDT) with high efficiency under hypoxia (nanomolar-level phototoxicity), but also evokes gasdermin D (GSDMD) mediated pyroptotic cell death to effectively stimulate tumor immunogenicity. CA-Re could disrupt and self-report the loss of membrane integrity simultaneously. This promoted the maturation and antigen-presenting ability of dendritic cells (DCs), and fully activated T cells dependent adaptive immune response in vivo, eventually eliminating distant tumors at the same time as destroying primary tumors. To the best of our knowledge, CA-Re is the first metal complex-based pyroptosis inducer.

ReI Tricarbonyl Complexes as Coordinate Covalent Inhibitors for the SARS-CoV-2 Main Cysteine Protease.

Since its outbreak, the severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) has impacted the quality of life and cost hundreds-of-thousands of lives worldwide. Based on its global spread and mortality, there is an urgent need for novel treatments which can combat this disease. To date, the 3-chymotrypsin-like protease (3CLpro ), which is also known as the main protease, is considered among the most important pharmacological targets. The vast majority of investigated 3CLpro inhibitors are organic, non-covalent binders. Herein, the use of inorganic, coordinate covalent binders is proposed that can attenuate the activity of the protease. ReI tricarbonyl complexes were identified that demonstrate coordinate covalent enzymatic inhibition of 3CLpro . Preliminary studies indicate the selective inhibition of 3CLpro over several human proteases. This study presents the first example of metal complexes as inhibitors for the 3CLpro cysteine protease.

Diversification of quinoline-triazole scaffolds with CORMs: Synthesis, in vitro and in silico biological evaluation against Plasmodium falciparum.

A discrete series of tricarbonyl manganese and rhenium complexes conjugated to a quinoline-triazole hybrid scaffold were synthesised and their inhibitory activities evaluated against Plasmodium falciparum. In general, the complexes show moderate activity with improved inhibitory activities for the photoactivatable manganese(I) tricarbonyl complexes in the malaria parasite. All complexes are active in the dark against the NF54 CQS (chloroquine-sensitive) and K1 MDR (multidrug-resistant) strains of Plasmodium falciparum, with IC50 values in the low micromolar range. Of significance, the complexes retain their activity in the MDR strain with resistance indices ranging between 1.1 and 2.1. The Mn(I) analogues display photodissociation of all three CO ligands upon irradiation at 365 nm. More importantly, the complexes show increased antimalarial activity in vitro upon photoactivation, something not observed by the clinically used reference drug, chloroquine. As a purported mechanism of action, the compounds were evaluated as ß-haematin inhibitors. To further understand the interactions of the complexes, in silico hemozoin docking simulations were performed, attesting to the fact that CO-release could be vital for blocking the hemozoin formation pathway. These results show that this strategy may be a valuable, novel route to design antimalarial agents with higher efficacy.