An Electron Donor–Acceptor Structured Rhenium(I) Complex Photo‐Sensitizer Evokes Mutually Reinforcing "Closed‐Loop" Ferroptosis and Immunotherapy

Advanced Healthcare Materials, Journal Year: 2024, Volume and Issue: 13(17)

Published: April 10, 2024

The hypoxic microenvironment of solid tumors severely lowers the efficacy oxygen-dependent photodynamic therapy (PDT). development hypoxia-tolerant photosensitizers for PDT is an urgent requirement. In this study, a novel rhenium complex (Re-TTPY) to develop "closed-loop" based on PDT-induced ferroptosis and immune reported. Due its electron donor-acceptor (D-A) structure, Re-TTPY undergoes energy transfer processes under 550 nm light irradiation displays type I/II combined capability, which can generate

Language: Английский

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Uridine-Modified Ruthenium(II) Complex as Lysosomal LIMP-2 Targeting Photodynamic Therapy Photosensitizer for the Treatment of Triple-Negative Breast Cancer

JACS Au, Journal Year: 2024, Volume and Issue: 4(3), P. 1081 - 1096

Published: Feb. 16, 2024

Lysosome-targeted photodynamic therapy, which enhances reactive oxygen species (ROS)-responsive tumor cell death, has emerged as a promising strategy for cancer treatment. Herein, uridine (dU)-modified Ru(II) complex (RdU) was synthesized by click chemistry. It found that RdU exhibits impressive photo-induced inhibition against the growth of triple-negative breast (TNBC) cells in normoxic and hypoxic microenvironments through ROS production. further revealed induces ferroptosis MDA-MB-231 under light irradiation (650 nm, 300 mW/cm2). Additional experiments showed binds to lysosomal integral membrane protein 2 (LIMP-2), confirmed fact selectively localizes lysosomes significantly augments levels LIMP-2. Molecular docking simulations an isothermal titration calorimetry assay also high affinity Finally, vivo studies tumor-bearing (MDA-MB-231 cells) nude mice exerts therapeutic effects on TNBC tumors. In summary, uridine-modified been developed potential LIMP-2 targeting agent treatment enhancing production promoting ferroptosis.

Language: Английский

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Glycyrrhetinic Acid as a Hepatocyte Targeting Ligand-Functionalized Platinum(IV) Complexes for Hepatocellular Carcinoma Therapy and Overcoming Multidrug Resistance

Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 67(10), P. 8020 - 8042

Published: May 10, 2024

Promising targeted therapy options to overcome drug resistance and side effects caused by platinum(II) drugs for treatment in hepatocellular carcinoma are urgently needed. Herein, six novel multifunctional platinum(IV) complexes through linking agents glycyrrhetinic acid (GA) were designed synthesized. Among them, complex 20 showed superior antitumor activity against tested cancer cells including cisplatin than simultaneously displayed good liver-targeting ability. Moreover, can significantly cause DNA damage mitochondrial dysfunction, promote reactive oxygen species generation, activate endoplasmic reticulum stress, eventually induce apoptosis. Additionally, effectively inhibit cell migration invasion trigger autophagy ferroptosis HepG-2 cells. More importantly, demonstrated stronger tumor inhibition ability or the combo of cisplatin/GA with almost no systemic toxicity A549 xenograft models. Collectively, could be developed as a potential anti-HCC agent treatment.

Language: Английский

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Photoacidolysis-Mediated Iridium(III) Complex for Photoactive Antibacterial Therapy

Journal of Medicinal Chemistry, Journal Year: 2023, Volume and Issue: 66(7), P. 4840 - 4848

Published: March 26, 2023

Photoactive antibacterial therapy is one of the novel therapeutic methods that has great application potential and prospects for curbing bacterial infections. In this work, a photoactivated iridium complex (Ir–Cl) synthesized photoactive research. Ir–Cl exhibits photoacidolysis, which can generate H+ be converted into photolysis product Ir–OH under blue light irradiation. At meantime, process accompanied by 1O2 generation. Notably, selectively permeate S. aureus exhibit excellent activity. Mechanism studies show ablate membranes biofilms Metabolomics analysis proves with exposure mainly disturbs some amino acids' degradation (e.g., valine, leucine, isoleucine, arginine) pyrimidine metabolism, indirectly causes ablation ultimately produces irreversible damage to aureus. This work provides guidance metal complexes in application.

Language: Английский

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Ferroptosis, pyroptosis and necroptosis in hepatocellular carcinoma immunotherapy: Mechanisms and immunologic landscape (Review)

International Journal of Oncology, Journal Year: 2024, Volume and Issue: 64(6)

Published: May 9, 2024

Hepatocellular carcinoma (HCC), one of the leading causes cancer‑related mortality worldwide, is challenging to identify in its early stages and prone metastasis, prognosis patients with this disease poor. Treatment options for HCC are limited, even radical treatments being associated a risk recurrence or transformation short term. Furthermore, multi‑tyrosine kinase inhibitors approved first‑line therapy have marked drawbacks, including drug resistance side effects. The rise breakthrough immune checkpoint (ICIs) provided novel direction immunotherapy but these drawback low response rates. Since avoiding apoptosis universal feature cancer, induction non‑apoptotic regulatory cell death (NARCD) strategy immunotherapy. At present, NARCD pathways, ferroptosis, pyroptosis necroptosis, potential forms immunogenic death, which synergistic effects antitumor immunity, transforming 'cold' tumors into 'hot' exerting Therefore, pathways may be targeted as treatment HCC. In present review, roles necroptosis immunity discussed, relevant targets signaling current status combined ICIs summarized. prospects targeting also considered.

Language: Английский

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Synthesis and Bio-evaluation of Aminoferrocene-Based Anticancer Prodrugs as Potent Ferroptosis Inducers

Inorganic Chemistry Frontiers, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

Novel ROS-responsive N -alkylaminoferrocene (NAAF)-appended GPX4 inhibitors have been designed and prepared as potent ferroptosis-inducing prodrugs.

Language: Английский

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Antitumor studies evaluation of triphenylphosphine ruthenium complexes with 5,7-dihalo-substituted-8-quinolinoline targeting mitophagy pathways

Journal of Inorganic Biochemistry, Journal Year: 2023, Volume and Issue: 248, P. 112361 - 112361

Published: Aug. 25, 2023

Language: Английский

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Advances in Targeted Drug Resistance Associated with Dysregulation of Lipid Metabolism in Hepatocellular Carcinoma

Journal of Hepatocellular Carcinoma, Journal Year: 2024, Volume and Issue: Volume 11, P. 113 - 129

Published: Jan. 1, 2024

Abstract: Hepatocellular carcinoma is the prevailing malignant neoplasm affecting liver, often diagnosed at an advanced stage and associated with unfavorable overall prognosis. Sorafenib Lenvatinib have emerged as first-line therapeutic drugs for hepatocellular carcinoma, improving prognosis these patients. Nevertheless, issue of tyrosine kinase inhibitor (TKI) resistance poses a substantial obstacle in management carcinoma. The pathogenesis advancement exhibit close association metabolic reprogramming, yet attention given to lipid metabolism dysregulation development remains relatively restricted. This review summarizes potential significance research progress dysfunction Targeting holds promising effective strategy overcome drug future. Keywords: metabolism, sorafenib, lenvatinib, targeted

Language: Английский

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Photoactivatable Ruthenium Complexes Containing Minimal Straining Benzothiazolyl-1,2,3-triazole Chelators for Cancer Treatment

Inorganic Chemistry, Journal Year: 2024, Volume and Issue: 63(14), P. 6202 - 6216

Published: Feb. 22, 2024

Ruthenium(II) complexes containing diimine ligands have contributed to the development of agents for photoactivated chemotherapy. Several approaches been used obtain photolabile Ru(II) complexes. The two most explored use monodentate and incorporation steric effects between bidentate Ru(II). However, introduction electronic in has less explored. Herein, we report a systematic experimental, theoretical, photocytotoxicity study novel series Ru1–Ru5 general formula [Ru(phen)2(N∧N′)]2+, where N∧N′ are different minimal strained based on 1-aryl-4-benzothiazolyl-1,2,3-triazole (BTAT) scaffold, being CH3 (Ru1), F (Ru2), CF3 (Ru3), NO2 (Ru4), N(CH3)2 (Ru5) substituents R4 phenyl ring. stable solution dark, but upon irradiation water with blue light (λex = 465 nm, 4 mW/cm2) photoejection ligand BTAT was observed by HPLC-MS spectrometry UV–vis spectroscopy, t1/2 ranging from 4.5 14.15 min depending properties corresponding BTAT, Ru4 (the one more electron withdrawing substituent, NO2). ground state singlet excited triplet using density functional theory (DFT) time-dependent DFT (TD-DFT) calculations. A mechanism Ru complexes, H2O, is proposed. Phototoxicity studies A375 HeLa human cancer cell lines showed that new were strongly phototoxic. An enhancement emission intensity cells treated Ru5 response increasing doses due ligand. These suggest could serve as photocleavable protecting group cytotoxic bis-aqua ruthenium warhead [Ru(phen)2(OH2)2]2+.

Language: Английский

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Discovery of a tribenzophenazine analog for binding to the KRAS mRNA G-quadruplex structures in the cisplatin-resistant non-small cell lung cancer

Journal of Biological Chemistry, Journal Year: 2025, Volume and Issue: unknown, P. 108164 - 108164

Published: Jan. 1, 2025

Lung cancer is the malignant tumor with highest morbidity and mortality rate worldwide, of which non-small cell lung (NSCLC) accounts for approximately 85%. KRAS mutations are one significant mechanisms underlying occurrence, development, immune escape, chemotherapy resistance NSCLC. Two inhibitors approved by FDA treatment NSCLC in past three years. However, they only effective to G12C mutant, moreover, innate acquired drug already reported, leaving an urgent need block pathways through novel targets. In this study, we focused on discovery ligands targeting RNA G-quadruplexes (RG4s) 5'-untranslated region (5'-UTR) mRNA, a tribenzophenazine analog (MBD) was identified as lead compound. Further were discussed A549/DDP cells, cisplatin-resistant KRAS-mutant line. Antitumor efficacy verified both vitro vivo nude mouse xenograft model implanted cells. To sum up, our results suggest potential MBD prominent anti-KRAS-driven agent, propose new idea development small molecule RG4s.

Language: Английский

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