A trackable trinuclear platinum complex for breast cancer treatment
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.
Authors
- Andrew Kellett (ORCID: https://orcid.org/0000-0002-8947-1401)
- Stefano Scoditti (ORCID: https://orcid.org/0000-0001-9384-703X)
- Katarzyna Mnich (ORCID: https://orcid.org/0000-0003-2137-9163)
- Sylvia Whittle (ORCID: https://orcid.org/0009-0008-9164-9513)
- Creina Slator (ORCID: https://orcid.org/0000-0002-1778-5217)
- Afshin Samali (ORCID: https://orcid.org/0000-0002-8610-8375)
- Sriram KK (ORCID: https://orcid.org/0000-0002-4661-242X)
- Bin Hu (ORCID: https://orcid.org/0000-0002-0278-8466)
- Bethany Searle
- Conor Newsome
- Erica J. Peterson (ORCID: https://orcid.org/0000-0002-0339-9171)
- Thomas E. Catley (ORCID: https://orcid.org/0000-0002-8919-2701)
- Raphael Enoque Ferraz de Paiva
- Jennifer E. Koblinski (ORCID: https://orcid.org/0000-0002-7156-2030)
- Nicholas P. Farrell (ORCID: https://orcid.org/0000-0001-7160-7182)
- Alice L. B. Pyne (ORCID: https://orcid.org/0000-0002-2658-8987)
- Fredrik Westerlund (ORCID: https://orcid.org/0000-0002-4767-4868)
- Sinéad O’Carroll (ORCID: https://orcid.org/0000-0003-4901-3542)
- Vickie McKee (ORCID: https://orcid.org/0000-0002-7780-5814)
Institutions
- University of the Basque Country (ES)
- Virginia Commonwealth University (US)
- Ollscoil na Gaillimhe – University of Galway (IE)
- COPE Galway (IE)
- Dublin City University (IE)
- University of Calabria (IT)
- Donostia International Physics Center (ES)
- Chalmers University of Technology (SE)
- University of Sheffield (GB)
Publication Details
- Journal
- Nucleic Acids Research
- Published
- 2025-06-24
- DOI
- https://doi.org/10.1093/nar/gkaf628
- Citations
- 2
- Primary Topic
- Advanced biosensing and bioanalysis techniques
- Type
- article
- Field-Weighted Citation Impact
- 1.61
Funders
- Swedish Cancer Foundation
- Ministerio de Ciencia, Innovación y Universidades
- Science Foundation Ireland
- Irish Research Council
- Vetenskapsrådet
- Novo Nordisk Fonden
- Engineering and Physical Sciences Research Council
- European Social Fund
- H2020 European Research Council