A luminescent ruthenium( ii ) complex for light-triggered drug release and live cell imagingby Nora Karaoun, Anna K. Renfrew

Chem. Commun.

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Karaoun, Chem. Commun., 2015, DOI: 10.1039/C5CC05172J.

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This journal is © The Royal Society of Chemistry 2013 J. Name., 2013, 00, 1-3 | 1

Cite this: DOI: 10.1039/x0xx00000x

Received 00th January 20xx,

Accepted 00th January 20xx

DOI: 10.1039/x0xx00000x www.rsc.org/

A luminescent ruthenium(II) complex for light-triggered drug release and live cell imaging

Nora Karaoun and Anna K. Renfrew*

We report a novel ruthenium(II) complex for selective release of the imidazole-based drug econazole. While the complex is highly stable and luminescent in the dark, irradiation with green light induces release of one of the econazole ligands, which is accompanied by a turn-off luminescence response and up to a 34-fold increase in cytotoxicity towards tumour cells.

Over 50% of all anticancer drug candidates that enter clinical trials fail due to problems such as poor pharmacokinetics, limited accumulation in tumour cells, and low selectivity, with a significant proportion of therapeutics currently in clinical use also suffering problems of this nature.1, 2 A viable strategy to overcome these limitations is to reversibly modify the physiochemical properties of a drug through coordination to a metal complex.3, 4 This is a synthetically simple approach that can improve both the pharmacokinetic and pharmacodynamic properties of the parent drug. Furthermore, complexes can be designed where the metal-drug bond is selectively cleaved in the tumour environment. A number of rationally designed metal prodrug complexes have been reported in recent years that are activated by an intrinsic feature of tumour cells, including bioreductive drug chaperones,5-7 enzyme-activated cobalamin conjugates,8 and metallo-cages that can exploit the EPR effect for the transport of small hydrophobic molecules.9, 10 An alternative approach is the use of localised light to activate a prodrug through photodynamic therapy (PDT), allowing both spatial and temporal control over the release of the active drug.11 This approach has been explored in detail for the delivery of the gas molecules, CO12-15 and NO,16-18 and is receiving increasing attention as a means of selectively releasing small molecules.

Ruthenium(II) polypyridyl complexes are a promising platform for light-activated drug delivery with photolabile bonds that can be activated by visible19-22 and even infrared light,23 the optimum region for photodynamic therapy.

Pioneering work by Etchenique et al. demonstrated the use of the complex [Ru(bpy)2(4-aminopyridine)2] 2+ (bpy = 2,2’bipyridine) for the delivery of the neurochemical 4aminopyridine24 and later other biologically active amines.25

More recently, Turro and Kodanko have used Rubpy, Ruterpy (terpy = 2,2′:6′,2′′-terpyridine) and Rutpa (tpa = tris(2pyridlymethyl)amine) complexes to cage and release two nitrile-based potential anticancer agents, 5-cyanouracil and a cathepsin K inhibitor.26-28 Similarly, Bonnet and coworkers used Ruterpy complexes to cage and release the bioactive thioethers N-acetylmethionine and biotin.29 Ruthenium(II) complexes have also been investigated for the reduction of inert cobalt(III) complexes through photoelectron transfer. 30, 31

In addition to applications in drug delivery, a number of luminescent ruthenium(II) polypyridyl complexes have been evaluated as cellular probes and organelle stains.32 Here we investigate the possibility of combining these properties to develop a luminescent and photolabile ruthenium complex for dual applications in cell imaging and light-activated drug delivery. Towards this aim, we began our investigations using

Ru(II) polypyridyl complexes with imidazole-based ligands, as several recent papers have highlighted the application of ruthenium(II) polypyridyl imidazole complexes, both as luminescent and cytotoxic agents,33 and for the photouncaging of histamine and histidine.34, 35

As a prototype complex, we began with the imidazole-based

Figure 1: Chemical structures of complexes 1 and 2.

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DOI: 10.1039/C5CC05172J

COMMUNICATION Journal Name 2 | J. Name., 2012, 00, 1-3 This journal is © The Royal Society of Chemistry 20xx antifungal agent econazole. Econazole is currently being investigated for oral and intravenous applications in the treatment of cancer,36, 37 mycobacterium tuberculosis,38 and leishmania.39 Despite showing promising activity in vitro against each of these diseases, oral and intravenous administration have proven ineffective due to the poor pharmacokinetics of the drug, which has no gastrointestinal absorption, and rapidly undergoes metabolism and protein binding in the blood stream.36, 40 As such, a prodrug system capable of increasing the effective dose of econazole could be beneficial to the treatment of a number of conditions.