46 - Redirecting Ru(II)-Complex Into Live-Cell Nucleus for Enantioselective DNA-Imaging and Photosensitizing Via Simple Yin-Yang Ion-Pairing

Abstract

Targeted delivery of diagnostic-probes and therapeutics into specific compartments inside a cell is of utmost importance in the improvement of disease detection and treatment. The molecular DNA “light-switch” Ru(II)-polypyridyl complex [Ru(DIP)2(dppz)]2+ has been shown to be accumulated only in the cytoplasm and membrane, but excluded from its intended nuclear DNA target. Here we show that chlorophenolate and flufenamate drugs can redirect [Ru(DIP)2(dppz)]2+ into live-cell nucleus while maintaining its original DNA recognition characteristics, where it acts as an unparalleled nuclear DNA imaging agent which is enantioselective, resistant to photo-bleaching, and suitable for both luminescent and transmission electron microscopy. The underlying molecular mechanism for the preferential nuclear uptake was found to be due to formating a neutral and relatively strong ion-pair between the Ru(II) cationic complex and chlorophenolate or flufenamate counter-anion, which may help the Ru(II) complex escape cytoplasmic traps, and cross the nuclear membrane via passive diffusion. More interestingly, enantioselective apoptosis was induced for cells pretreated with [Ru(DIP)2(dppz)]2+/chlorophenol (or flufenamic acid) upon prolonged visible-light irradiation. We suggest that this novel ion-pairing method and concept can be employed to deliver other similar cationic and bioactive metal complexes with promising theranostic potentials to their preferred intracellular targets.