COMPARISON OF SOLUTOL HS-15, CREMOPHOR EL AND NOVEL ETHOXYLATED FATTY-ACID SURFACTANTS AS MULTIDRUG-RESISTANCE MODIFICATION AGENTS

Some well-known fatty acid ester surfactants, e.g., Cremophor EL and S olutol HS 15, are modulators of multidrug resistance in vitro and in v ivo. Because they are polydisperse, and their active component(s) have not been identified, the therapeutic potential of such surfactants is unclear. To better define the active components of Solutol HS 15 and to make more potent surfactant multidrug resistance modulators, highly purified C-18 fatty acids were esterified with ethylene oxide at 5-20 0 molar ratios. Unexpectedly, ethylene oxide esters of pure 12-hydroxy stearic acid, the major components of Solutol HS 15, displayed neglig ible resistance modification activity compared with Solutol HS 15 itse lf or to stearic and oleic acid esters synthesized under identical con ditions. Since oleic acid esters appeared to have good activity, a ser ies of these compounds was prepared to determine the optimal ethylene oxide/fatty acid ratio. The optimal ratio was found to be 20 mole ethy lene oxide:1 mole fatty acid, with a steep decline in activity for pro ducts made with ratios above and below the optimum. The most active ol eic acid ester, designated CRL 1337, was 8.4-fold as potent as Solutol HS 15 and over 19-fold as potent as Cremophor EL in promoting rhodami ne 123 accumulation in multidrug-resistant KB 8-5-11 cells in vitro. O ur results show that the structure of the hydrophobic domain (fatty ac id) of surfactants as well as its hydrophile-lipophile balance are cri tical in determining the potency of surfactants as reversing agents. ( C) 1995 Wiley-Liss, Inc.