Unlocking the Power of Human Ferritin: Enhanced Drug Delivery of Aurothiomalate in A2780 Ovarian Cancer Cells.

Autor: Cosottini L; Department of Chemistry 'Ugo Schiff', University of Florence, 50019, Sesto Fiorentino, FI, Italy., Geri A; Department of Chemistry 'Ugo Schiff', University of Florence, 50019, Sesto Fiorentino, FI, Italy., Ghini V; Department of Chemistry 'Ugo Schiff', University of Florence, 50019, Sesto Fiorentino, FI, Italy., Mannelli M; Department of Experimental and Clinical Biomedical Sciences 'Mario Serio', University of Florence, 50134, Florence, Italy., Zineddu S; Department of Chemistry 'Ugo Schiff', University of Florence, 50019, Sesto Fiorentino, FI, Italy., Di Paco G; Department of Chemistry 'Ugo Schiff', University of Florence, 50019, Sesto Fiorentino, FI, Italy., Giachetti A; Consorzio Interuniversitario Risonanze Magnetiche di Metallo Proteine (CIRMMP), 50019, Sesto Fiorentino, FI, Italy., Massai L; Department of Chemistry 'Ugo Schiff', University of Florence, 50019, Sesto Fiorentino, FI, Italy., Severi M; Department of Chemistry 'Ugo Schiff', University of Florence, 50019, Sesto Fiorentino, FI, Italy., Gamberi T; Department of Experimental and Clinical Biomedical Sciences 'Mario Serio', University of Florence, 50134, Florence, Italy., Rosato A; Department of Chemistry 'Ugo Schiff', University of Florence, 50019, Sesto Fiorentino, FI, Italy.; Magnetic Resonance Center, University of Florence, 50019, Sesto Fiorentino, FI, Italy., Turano P; Department of Chemistry 'Ugo Schiff', University of Florence, 50019, Sesto Fiorentino, FI, Italy.; Magnetic Resonance Center, University of Florence, 50019, Sesto Fiorentino, FI, Italy., Messori L; Department of Chemistry 'Ugo Schiff', University of Florence, 50019, Sesto Fiorentino, FI, Italy.
Jazyk: angličtina
Zdroj: Angewandte Chemie (International ed. in English) [Angew Chem Int Ed Engl] 2024 Oct 01; Vol. 63 (40), pp. e202410791. Date of Electronic Publication: 2024 Aug 19.
DOI: 10.1002/anie.202410791
Abstrakt: Aurothiomalate (AuTM) is an FDA-approved antiarthritic gold drug with unique anticancer properties. To enhance its anticancer activity, we prepared a bioconjugate with human apoferritin (HuHf) by attaching some AuTM moieties to surface protein residues. The reaction of apoferritin with excess AuTM yielded a single adduct, that was characterized by ESI MS and ICP-OES analysis, using three mutant ferritins and trypsinization experiments. The adduct contains ~3 gold atoms per ferritin subunit, arranged in a small cluster bound to Cys90 and Cys102. MD simulations provided a plausible structural model for the cluster. The adduct was evaluated for its pharmacological properties and was found to be significantly more cytotoxic than free AuTM against A2780 cancer cells mainly due to higher gold uptake. NMR-metabolomics showed that AuTM bound to HuHf and free AuTM induced qualitatively similar changes in treated cancer cells, indicating that the effects on cell metabolism are approximately the same, in agreement with independent biochemical experiments. In conclusion, we have demonstrated here that a molecularly precise bioconjugate formed between AuTM and HuHf exhibits anticancer properties far superior to the free drug, while retaining its key mechanistic features. Evidence is provided that human ferritin can serve as an excellent carrier for this metallodrug.
(© 2024 The Author(s). Angewandte Chemie International Edition published by Wiley-VCH GmbH.)
Databáze: MEDLINE
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