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A trackable trinuclear platinum complex for breast cancer treatment
Sinéad O'Carroll1, Creina Slator1, Raphael E F de Paiva1
1School of Chemical Sciences, Dublin City University, Glasnevin, Dublin, D09 K20V, Ireland.
Abstract:
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.
Insights
Researchers developed a new platinum complex, N3-TriplatinNC, for triple-negative breast cancer (TNBC). This complex shows potential for tracking and treating TNBC, offering a new avenue for cancer therapy.
Area of Science:
- Inorganic Chemistry
- Biophysics
- Cancer Research
Background:
- Triple-negative breast cancer (TNBC) presents limited therapeutic options.
- Polynuclear platinum(II) complexes show promise against resistant cancers but lack cellular trackability.
- Developing traceable anticancer agents is crucial for effective monitoring and treatment.
Purpose of the Study:
- To synthesize and characterize a new azide-appended trinuclear platinum complex, N3-TriplatinNC.
- To evaluate its DNA-targeting, cytotoxicity, and topoisomerase relaxation properties.
- To assess its potential for cellular tracking and in vivo anticancer activity.
Main Methods:
- Synthesis of azide-appended trinuclear platinum complex (N3-TriplatinNC).
- Single-molecule biophysics and in-liquid atomic force microscopy for DNA interaction studies.
- Cytotoxicity assays against TNBC cell lines (MDA-MB-231) and in vivo xenograft studies.
Main Results:
- N3-TriplatinNC effectively targets DNA and exhibits potent cytotoxicity against MDA-MB-231 TNBC cells.
- The azide handle allows for in situ click chemistry-based cellular tracking.
- The complex demonstrated in vivo antitumor efficacy in xenograft models.
Conclusions:
- N3-TriplatinNC is a traceable polynuclear platinum complex with significant potential for TNBC treatment.
- The azide modification enables monitoring of cellular localization, aiding therapeutic development.
- This approach offers a promising strategy for developing advanced platinum-based anticancer drugs.
