Résumé
It has been shown that mixtures of palmitic acid (PA) and cholesterol (Chol) or cholesterol sulfate (Schol) can form fluid bilayers. These bilayers could be extruded using standard extrusion techniques to obtain nonphospholipid large unilamellar vesicles (LUVs). These L U Vs displayed a very limited passive permeability, associated with their high sterol content (typically 70 mol %). In addition, they showed a pH-dependent behavior dictated by the electrostatic interfacial interactions, which are drastically modulated by the protonation state of PA. Interestingly, the LUVs prepared with cholesterol were stable at high pH and the release of the content could be triggered by a pH decrease (i.e., the protonation of PA). In contrast, the LUVs including Schol were stable at low pH and a pH increase (leading to the deprotonation of PA) would induce the release. In the present study, we demonstrate that the pH triggering the release in these two systems can be dictated in a predictable manner by selecting a fatty acid with an appropriate pK(a). The pK(a) of the fatty acids was modulated by the presence of an electro-withdrawing group (hydroxyl or fluoro) in the alpha position of the carboxylic function. The fatty acid protonation state is shown to be a critical factor for the modulation of the liposome permeability. The described systems display a remarkable versatility regarding the pH-sensitivity because the nature of the sterol controls the overall stability of the LUVs while the fatty acid pK(a) fine-tunes the pH-induced release. Therefore, it is possible to rationally design LUVs with controlled release at a specific pH; this original aspect is beneficial to the use of LUVs for encapsulation, vectorization, and controlled release of active agents.