دورية أكاديمية
Ruthenium-Cathepsin Inhibitor Conjugates for Green Light-Activated Photodynamic Therapy and Photochemotherapy.
العنوان: | Ruthenium-Cathepsin Inhibitor Conjugates for Green Light-Activated Photodynamic Therapy and Photochemotherapy. |
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المؤلفون: | Denison M; Department of Chemistry, Wayne State University, 5101 Cass Ave, Detroit, Michigan 48202, United States., Garcia SP; Department of Chemistry and Biochemistry, The Ohio State University, Columbus, Ohio 43210, United States., Ullrich A; Department of Oncology, Wayne State University, Detroit, Michigan 48201, United States., Podgorski I; Department of Pharmacology, School of Medicine, Wayne State University, Detroit, Michigan 48201, United States.; Karmanos Cancer Institute, Detroit, Michigan 48201, United States., Gibson H; Department of Oncology, Wayne State University, Detroit, Michigan 48201, United States.; Karmanos Cancer Institute, Detroit, Michigan 48201, United States., Turro C; Department of Chemistry and Biochemistry, The Ohio State University, Columbus, Ohio 43210, United States., Kodanko JJ; Department of Chemistry, Wayne State University, 5101 Cass Ave, Detroit, Michigan 48202, United States.; Karmanos Cancer Institute, Detroit, Michigan 48201, United States. |
المصدر: | Inorganic chemistry [Inorg Chem] 2024 Apr 29; Vol. 63 (17), pp. 7973-7983. Date of Electronic Publication: 2024 Apr 14. |
نوع المنشور: | Journal Article |
اللغة: | English |
بيانات الدورية: | Publisher: American Chemical Society Country of Publication: United States NLM ID: 0366543 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1520-510X (Electronic) Linking ISSN: 00201669 NLM ISO Abbreviation: Inorg Chem Subsets: MEDLINE |
أسماء مطبوعة: | Original Publication: [Easton, Pa.] American Chemical Society. |
مواضيع طبية MeSH: | Cathepsins*/antagonists & inhibitors , Cathepsins*/metabolism , Green Light* , Photochemotherapy* , Photosensitizing Agents*/pharmacology , Photosensitizing Agents*/chemistry , Photosensitizing Agents*/chemical synthesis , Ruthenium*/chemistry , Ruthenium*/pharmacology, Animals ; Humans ; Mice ; Antineoplastic Agents/pharmacology ; Antineoplastic Agents/chemistry ; Antineoplastic Agents/chemical synthesis ; Cell Line, Tumor ; Cell Survival/drug effects ; Coordination Complexes/pharmacology ; Coordination Complexes/chemistry ; Coordination Complexes/chemical synthesis ; Molecular Structure |
مستخلص: | Dysregulated cathepsin activity is linked to various human diseases including metabolic disorders, autoimmune conditions, and cancer. Given the overexpression of cathepsin in the tumor microenvironment, cathepsin inhibitors are promising pharmacological agents and drug delivery vehicles for cancer treatment. In this study, we describe the synthesis and photochemical and biological assessment of a dual-action agent based on ruthenium that is conjugated with a cathepsin inhibitor, designed for both photodynamic therapy (PDT) and photochemotherapy (PCT). The ruthenium-cathepsin inhibitor conjugate was synthesized through an oxime click reaction, combining a pan-cathepsin inhibitor based on E64d with the Ru(II) PCT/PDT fragment [Ru(dqpy)(dppn)], where dqpy = 2,6-di(quinoline-2-yl)pyridine and dppn = benzo[i]dipyrido[3,2-a:2',3'-c]phenazine. Photochemical investigations validated the conjugate's ability to release a triazole-containing cathepsin inhibitor for PCT and to generate singlet oxygen for PDT upon exposure to green light. Inhibition studies demonstrated the conjugate's potent and irreversible inactivation of purified and intracellular cysteine cathepsins. Two Ru(II) PCT/PDT agents based on the [Ru(dqpy)(dppn)] moiety were evaluated for photoinduced cytotoxicity in 4T1 murine triple-negative breast cancer cells, L929 fibroblasts, and M0, M1, and M2 macrophages. The cathepsin inhibitor conjugate displayed notable selectivity for inducing cell death under irradiation compared to dark conditions, mitigating toxicity in the dark observed with the triazole control complex [Ru(dqpy)(dppn)(MeTz)] 2+ (MeTz = 1-methyl-1 H -1,2,4-triazole). Notably, our lead complex is among a limited number of dual PCT/PDT agents activated with green light. |
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معلومات مُعتمدة: | R01 GM098285 United States GM NIGMS NIH HHS; S10 OD028488 United States OD NIH HHS; T32 GM142519 United States GM NIGMS NIH HHS |
المشرفين على المادة: | 0 (Antineoplastic Agents) EC 3.4.- (Cathepsins) 0 (Coordination Complexes) 0 (Photosensitizing Agents) 7UI0TKC3U5 (Ruthenium) |
تواريخ الأحداث: | Date Created: 20240415 Date Completed: 20240429 Latest Revision: 20240731 |
رمز التحديث: | 20240801 |
مُعرف محوري في PubMed: | PMC11066580 |
DOI: | 10.1021/acs.inorgchem.4c01008 |
PMID: | 38616353 |
قاعدة البيانات: | MEDLINE |
تدمد: | 1520-510X |
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DOI: | 10.1021/acs.inorgchem.4c01008 |