A just published ASAP paper in Inorganic Chemistry from the Dyson group describes their efforts in preparing potential anti-cancer agents which selectively target tumor cells. The selection criteria that they are attempting to exploit is temperature dependent solubility differences. Cancer cells are known to run hotter than normal cells, while cryogenic and thermotherapy in conjunction with various anti-cancer drugs is known to provide a synergistic effect. According to the paper, however, no chemotherapy agents have been designed with thermoresponsiveness specifically in mind.
The authors chose to make ruthenium complexes containing fluorous tagged phosphines as potential thermomorphic chemotherapy agents. They chose ruthenium complexes, since Ru has been shown to have excellent activity in tumors. Two ruthenium complexes, NAMI-1 and KP1019, are in early clinical trials.
Fluorous ligands were selected due to their well-known steep temperature solubility curves. This behavior has been exploited by various research groups for the design and synthesis of thermomorphic catalysts. Thermomorphic catalysts are completely soluble at elevated reaction temperatures, resulting in homogeneous catalysis. Once the reaction is complete, the mixture is cooled resulting in precipitation of the catalyst which can then be removed as a heterogeneous catalyst.
By making fluorous modified ruthenium compounds the authors hoped that they could produce cytotoxic compounds that are specifically designed to be thermoresponsive. The solubility and uptake of these agents would be temperature dependent. Application of heat to the tumor could then result in more selective therapies.
The researchers produced the compounds shown above and examined their solubility at 37º C and at 42º C. What they found was that compounds 1 and 5 showed the most promising behavior with a 4-fold increase in aqueous solubility at 42º C than at 37º C. When tested in vitro against two cell lines, one cisplatin resistant, a modest temperature dependence in IC50 was observed. The authors attribute this to the increase solubility at higher temperatures resulting in greater cellular uptake, although they caution that other phenomena could be at work.
All in all, an interesting paper which highlights a novel application of an unique physical property of fluorous domains, in this case thermomorphism. While these are probably not viable drug candidates by any means, it does show that the idea of a fluorous thermomorphic therapeutic is feasible.