Improved potency of cisplatin by hydrophobic ion pairing

Cisplatin is one of the most widely used and effective chemotherapeutic drugs ever discovered against certain forms of cancer. However, its use is limited by toxicity. A more potent form might allow lower doses to be used and would diminish the toxicity. A new analog of cisplatin has been synthesized by stoichiometric replacement of the chloride ligands with the anionic surfactant, Aerosol OT (AOT). The new compound has a very low aqueous solubility (about 2 mg/l) and a log P value of 2.17, which is more than 4 log units higher than cisplatin itself, indicating a dramatic increase in hydrophobicity. While hydrophobic cisplatin analogs have been synthesized previously, this is the first one with readily dissociable ligands replacing the chlorides. The resultant AOT complex is able to penetrate cellular membranes more efficiently, resulting in a threefold to fivefold increase in intracellular platinum levels. These increased intracellular concentrations correlate with lower IC50 values in a number of cancer and normal cell lines. These findings suggest that further development of the AOT complex as a chemotherapeutic agent is warranted, given its marked increase in potency over the parent compound.