期刊
NUCLEIC ACIDS RESEARCH
卷 51, 期 7, 页码 3041-3054出版社
OXFORD UNIV PRESS
DOI: 10.1093/nar/gkad155
关键词
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Targeted and enantioselective delivery of chiral diagnostic-probes and therapeutics into specific compartments inside cells is crucial for disease detection and treatment improvement. The cationic [Ru(DIP)(2)(dppz)](2+) is found to be redirected into live-cell nucleus through ion-pairing with suitable weak acid counter-anions, maintaining its original DNA recognition characteristics. Interestingly, only the Delta-enantiomer is selectively translocated into the nucleus, inducing DNA damage and cell apoptosis upon prolonged visible-light irradiation. This opens new opportunities for more effective enantioselective cancer treatment.
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)]Cl-2 (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 Delta-enantiomer is selectively translocated into nucleus while the Lambda-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 Delta-enantiomer can induce obvious DNA damage and cell apoptosis upon prolonged visible-light irradiation. Thus, the use of Delta-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.
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