A trackable trinuclear platinum complex for breast cancer treatment
Journal article, 2025
Cancer remains a leading cause of death, with triple-negative breast cancer (TNBC) being particularly significant due to limited treatment options. As such, there is interest in anticancer polynuclear platinum(II) complexes, attributed to their unique DNA-binding modes and potential against therapy-resistant cancer phenotypes. However, a persistent challenge with polynuclear compounds is their lack of cellular trackability, hindering their effectiveness and monitoring in clinical settings. Here, we report the preparation of a new azide-appended trinuclear platinum complex, N3-TriplatinNC, and characterize its DNA-targeting, cytotoxicity, and topoisomerase relaxation properties from the nanoscale to the macroscale. Using single-molecule biophysics and in-liquid atomic force microscopy, N3-TriplatinNC was identified as a powerful DNA recognition agent with remarkable potential towards the TNBC cell line, MDA-MB-231. Installation of the azide handle on the polynuclear complex was achieved using a first-in-class approach to produce a complex that retained analogous biological activity to the parent TriplatinNC. Importantly, the azide handle facilitates in situ click chemistry for tracking cellular localization, with subsequent xenograft studies demonstrating in vivo antitumoural potential.
Author
Sinead O'Carroll
Dublin City University
Creina Slator
Dublin City University
Raphael E. F. de Paiva
Dublin City University
Conor Newsome
Dublin City University
Bethany Searle
Dublin City University
Sriram Kesarimangalam
Chalmers, Life Sciences, Chemical Biology
Sylvia Whittle
University of Sheffield
Thomas E. Catley
University of Sheffield
Stefano Scoditti
Donostia International Physics Center
University of Calabria
University of the Basque Country (UPV/EHU)
Katarzyna Mnich
National University of Ireland Galway
Erica J. Peterson
Virginia Commonwealth University
Bin Hu
Virginia Commonwealth University
Jennifer E. Koblinski
Virginia Commonwealth University
Afshin Samali
National University of Ireland Galway
Vickie McKee
Dublin City University
Alice L. B. Pyne
University of Sheffield
Fredrik Westerlund
Chalmers, Life Sciences, Chemical Biology
Nicholas P. Farrell
Virginia Commonwealth University
Andrew Kellett
Dublin City University
Nucleic Acids Research
0305-1048 (ISSN) 1362-4962 (eISSN)
Vol. 53 13 gkaf628Real-Time Visualization of DNA Repair - One Molecule at a Time
Swedish Research Council (VR) (2020-03400), 2021-01-01 -- 2024-12-31.
Next Generation Nanofluidic Devices for Single Molecule Analysis of DNA Repair Dynamics
European Commission (EC) (EC/H2020/866238), 2020-04-01 -- 2025-03-31.
Subject Categories (SSIF 2025)
Medical Biotechnology
Inorganic Chemistry
Cancer and Oncology
DOI
10.1093/nar/gkaf628
PubMed
40671528