Unusual enantioselective cytoplasm-to-nucleus translocation and photosensitization of the chiral Ru(II) cationic complex via simple ion-pairing with lipophilic weak acid counter-anions

• Published in: Nucleic acids research 2023-04, Vol.51 (7), p.3041-3054
• Main Authors: Chao, Xi-Juan, Huang, Chun-Hua, Tang, Miao, Yan, Zhu-Ying, Huang, Rong, Li, Yan, Zhu, Ben-Zhan
• Format: Article
• Language: English
• Subjects: Anions; Cell Nucleus - metabolism; Chemistry; DNA - metabolism; Light; Ruthenium; Stereoisomerism
• ISSN: 0305-1048; 1362-4962
• DOI: 10.1093/nar/gkad155

Abstract Targeted and enantioselective delivery of chiral diagnostic-probes and therapeutics into specific compartments inside cells is of utmost importance in the improvement of disease detection and treatment. The classical DNA ‘light-switch’ ruthenium(II)-polypyridyl complex, [Ru(DIP)2(dppz)]Cl2 (DIP = 4,7-diphenyl-1,10-phenanthroline, dppz = dipyridophenazine) has been shown to be accumulated only in the cytoplasm and membrane, but excluded from its intended nuclear DNA target. In this study, the cationic [Ru(DIP)2(dppz)]2+ is found to be redirected into live-cell nucleus in the presence of lipophilic 3,5-dichlorophenolate or flufenamate counter-anions via ion-pairing mechanism, while maintaining its original DNA recognition characteristics. Interestingly and unexpectedly, further studies show that only the Δ-enantiomer is selectively translocated into nucleus while the Λ-enantiomer remains trapped in cytoplasm, which is found to be mainly due to their differential enantioselective binding affinities with cytoplasmic proteins and nuclear DNA. More importantly, only the nucleus-relocalized Δ-enantiomer can induce obvious DNA damage and cell apoptosis upon prolonged visible-light irradiation. Thus, the use of Δ-enantiomer can significantly reduce the dosage needed for maximal treatment effect. This represents the first report of enantioselective targeting and photosensitization of classical Ru(II) complex via simple ion-pairing with suitable weak acid counter-anions, which opens new opportunities for more effective enantioselective cancer treatment. Graphical Abstract Graphical Abstract Translocation of the positively-charged chiral [Ru(DIP)2(dppz)]2+ into nucleus as a unique enantioselective nuclear DNA-imaging and photosensitizing agent via forming neutral and stable Yin-Yang ion-pair with the negatively-charged chlorophenolate counter-anion.