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Mitochondrial targeted osmium polypyridyl probe shows concentration dependent uptake, localisation and mechanism of cell death

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Abstract

A symmetric osmium(II) [bis-(4′-(4-carboxyphenyl)-2,2′:6′,2′′-terpyridine)] was prepared and conjugated to two mitochondrial-targeting peptide sequences; FrFKFrFK (r = D-arginine). The parent and conjugate complexes showed strong near infra-red emission centred at λmax 745 nm that was modestly oxygen dependent in the case of the parent and oxygen independent in the case of the conjugate, attributed in the latter case, surprisingly, to a shorter emission lifetime of the conjugate compared to the parent. Confocal fluorescence imaging of sub-live HeLa and MCF 7 cells showed the parent complex was cell impermeable whereas the conjugate was rapidly internalised into the cell and distributed in a concentration dependent manner. At concentrations below approximately 30 μmol, the conjugate localised to the mitochondria of both cell types where it was observed to trigger apoptosis induced by the collapse of the mitochondrial membrane potential (MPP). At concentrations exceeding 30 μmol the conjugate was similarly internalised rapidly but distributed throughout the cell, including to the nucleus and nucleolus. At these concentrations, it was observed to precipitate a caspase-dependent apoptotic pathway. The combination of concentration dependent organelle targeting, NIR emission coincident with the biological window, and distribution dependent cytotoxicity offers an interesting approach to theranostics with the possibility of eliciting site dependent therapeutic effect whilst monitoring the therapeutic effect with luminescence imaging.

Graphical abstract: Mitochondrial targeted osmium polypyridyl probe shows concentration dependent uptake, localisation and mechanism of cell death

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Publication details

The article was received on 19 Jul 2019, accepted on 04 Sep 2019 and first published on 04 Sep 2019


Article type: Paper
DOI: 10.1039/C9DT02967B
Dalton Trans., 2019, Advance Article

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    Mitochondrial targeted osmium polypyridyl probe shows concentration dependent uptake, localisation and mechanism of cell death

    K. S. Gkika, A. Byrne and T. E. Keyes, Dalton Trans., 2019, Advance Article , DOI: 10.1039/C9DT02967B

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