Paclitaxel partitioning into lipid bilayers

Paclitaxel (taxol) is a diterpenoid anticancer drug with a new mechanism of cytostatic action. It is under investigation in clinical trials for treatment of various types of human cancer. A major difficulty in developing paclitaxel as a chemotherapeutic agent is its poor water solubility. In order to improve the bioavailability of paclitaxel, novel vehicle systems such as mixed micelles or liposome-based formulations are being developed. In this study we determined the partition coefficient of paclitaxel partitioning into small unilamellar lipid vesicles composed of 1-palmitoyl-2-oleoyl-sn-glycero- 3-phosphocholine using two different methods, namely high-sensitivity titration calorimetry and fluorescence spectroscopy. We measured a partition coefficient of K(p) ≃ 9500 M^-1, a partition enthalpy of ΔH = -25 ± 3 kcal mol^-1 and a free energy of binding of ΔG = -7.9 kcal mol^-1. The binding reaction is enthalpy-driven, which can be explained by van der Waals interactions between the hydrophobic drug and the hydrophobic region of the lipid bilayer. The large ΔH value leads to a strong temperature dependence of the partition equilibrium. A temperature increase of 10 °C reduces the paclitaxel solubility in the lipid phase by a factor of 4.