O'Carroll Sinéad, Slator Creina, de Paiva Raphael E F, Newsome Conor, Searle Bethany, Kk Sriram, Whittle Sylvia, Catley Thomas E, Scoditti Stefano, Mnich Katarzyna, Peterson Erica J, Hu Bin, Koblinski Jennifer E, Samali Afshin, McKee Vickie, Pyne Alice L B, Westerlund Fredrik, Farrell Nicholas P, Kellett Andrew
School of Chemical Sciences, Dublin City University, Glasnevin, Dublin, D09 K20V, Ireland.
Department of Life Sciences, Chalmers University of Technology, Kemivägen 10, 412 96 Gothenburg, Sweden.
Nucleic Acids Res. 2025 Jul 8;53(13). doi: 10.1093/nar/gkaf628.
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.
癌症仍然是主要的死亡原因，三阴性乳腺癌（TNBC）由于治疗选择有限而尤为突出。因此，人们对抗癌多核铂（II）配合物感兴趣，这归因于它们独特的DNA结合模式以及对抗治疗抗性癌症表型的潜力。然而，多核化合物一直面临的挑战是它们缺乏细胞追踪能力，这阻碍了它们在临床环境中的有效性和监测。在此，我们报告了一种新的叠氮基附加三核铂配合物N3-TriplatinNC的制备，并从纳米尺度到宏观尺度对其DNA靶向、细胞毒性和拓扑异构酶松弛特性进行了表征。使用单分子生物物理学和液内原子力显微镜，N3-TriplatinNC被鉴定为一种强大的DNA识别剂，对TNBC细胞系MDA-MB-231具有显著潜力。通过一种一流的方法在多核配合物上安装叠氮基手柄，以产生一种保留与母体TriplatinNC类似生物活性的配合物。重要的是，叠氮基手柄便于进行原位点击化学以追踪细胞定位，随后的异种移植研究证明了其体内抗肿瘤潜力。
