Thermoresponsive organometallic arene ruthenium complexes for tumour targeting

Catherine M Clavel,Emilia Păunescu,Patrycja Nowak-Sliwinska,Paul J Dyson

doi:10.1039/c3sc53185f

Catherine M Clavel, Emilia Păunescu + Show 2 more

Open Access

https://doi.org/10.1039/c3sc53185f

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Abstract

Application of mild hyperthermia can increase the cytotoxicity of anticancer drugs in tumour cells. In this report, we describe low molecular weight thermoactive ruthenium-based drugs with fluorous chains that are selectively triggered by mild hyperthermia. The organometallic complexes were prepared, characterized, and evaluated for their in vitro cytotoxicity against a panel of human cancer cell lines and non-cancerous immortalized cells. The compounds show considerable chemo-thermal selectivity towards cancer cells (ca. 5 μM versus >500 μM for healthy cells) for the compound with the longest fluorous chain.

Highlights

Platinum-based anticancer drugs including cisplatin, carboplatin and oxaliplatin lack selectivity towards cancerous cells and their therapeutic application causes severe sideeffects such as nephrotoxicity,[1,2,3] neurotoxicity,[4,5] nausea and vomiting.[6,7] In contrast, ruthenium-based chemotherapeutics present fewer side-effects compared to platinum-based drugs
Application of mild hyperthermia can increase the cytotoxicity of anticancer drugs in tumour cells
We describe low molecular weight thermoactive ruthenium-based drugs with fluorous chains that are selectively triggered by mild hyperthermia

Summary

Introduction

Platinum-based anticancer drugs including cisplatin, carboplatin and oxaliplatin lack selectivity towards cancerous cells and their therapeutic application causes severe sideeffects such as nephrotoxicity,[1,2,3] neurotoxicity,[4,5] nausea and vomiting.[6,7] In contrast, ruthenium-based chemotherapeutics present fewer side-effects compared to platinum-based drugs. Rationally designed thermoactive derivatives of the organic drug chlorambucil (CLB)[27,28] have been recently designed and were found to be essentially inactive at 37 C and activated by mild hyperthermia (41 C) in vitro.[29] Recently, the synthesis and biological evaluation (under normal conditions) of some short to medium length uorous chain bipyridine cisplatin derivatives have been reported.[30,31] Similar types of compounds (amphiphilic uoroalkylated bipyridine platinum and palladium complexes) have been tested in liposomal formulations.[32,33,34] Liposomal formulations of platinum-based drugs, with the rational that liposomal delivery can increase drug bioavailability and accumulation at the tumour site as a consequence of the enhanced permeability and retention (EPR) effect, are in clinical trials.[35,36,37,38] ruthenium(II)–arene derivatives (Fig. 1) modi ed with uorous chains in order to endow them with thermoresponsive properties[39,40,41] are described. Ester linker that may, in principle, be hydrolysed by intracellular enzymes such as esterases.[41,52,53]

Results and discussion

96 Æ 8 391 Æ 14 123 Æ 8 86 Æ 10 42 Æ 1

Conclusions