Taxol-lipid interactions: taxol-dependent effects on the physical properties of model membranes.

Abstract

Taxol (paclitaxel) is a diterpenoid anticancer agent undergoing intensive human clinical evaluation. The poor aqueous solubility of taxol necessitates administration in excipients causing a variety of adverse effects, including anaphylactoid hypersensitivity reactions. Recently, taxol has been formulated in better-tolerated drug carriers such as liposomes. We investigated the conformation of taxol and the interaction of taxol with dipalmitoylphosphatidylcholine (DPPC) liposomes using fluorescence, circular dichroism, differential scanning calorimetry, fluorescence polarization, and X-ray diffraction. The conformation of taxol in DPPC membranes was similar to that observed in nonpolar solvents such as chloroform. Taxol was found to partition into the bilayer, perturbing the hydrocarbon chain conformation. The taxol C13 side chain was found to be fluorescent, and it displays an environment-sensitive shift in emission spectrum; taxol fluorescence was used to confirm the insertion of the drug into the bilayer. Taxol induces a broadening of the DPPC phase transition, and the location of the drug in the bilayer depends on drug concentration. Incorporation of taxol affects other physical properties of the bilayer such as the lipid order parameter, and this fluidizing effect was also observed upon incorporation of taxol in biological membranes isolated from basolateral plasma membranes of rat liver. These studies demonstrate that taxol incorporated into liposomes penetrates into the acyl chain domain of the bilayer and alters the physical properties of both artificial and biological membranes.