Lipid bilayer heterogeneities controlled by pH: Basic studies and applications in liposome based drug delivery

Studies on heterogeneous lipid bilayer membranes are presented. The aim is to understand the formation and properties of model membrane heterogeneities with the ultimate goal to engineer devices based on these materials that can be tuned to perform specific tasks. Some applications of these materials as environmentally responsive vesicles for drug delivery to vascularized cancer are presented.;Gel phase membranes containing lipid pairs with variable chain lengths and titratable headgroups were studied in the form of vesicles. Lowering of pH was shown to reversibly increase the formation of lipid heterogeneities on the plane of the bilayer membranes probably due to decrease of electrostatic repulsion and increase of interlipid hydrogen bonding. Phase separation was shown to cause changes in membrane permeability only for lipid pairs with non-matching chain lengths suggesting a role of potential discontinuities in lipid packing within the hydrophobic region of the bilayer in the gel state. pH-dependent lipid heterogeneities on functionalized rigid bilayers were also engineered to control the surface topography and the effective reactivity of these bilayers. Cholesterol was shown to enable tuning of the membrane reorganization to occur at pH values not necessarily close to the reported pKa's of the constituent titratable lipids. This information was translated into pH-triggered leaky heterogeneities on rigid lipid bilayers in the form of vesicles for delivery of chemotherapeutics, and was shown to accelerate intracellular trafficking of encapsulated doxorubicin and to improve the therapeutic potential of targeted liposomal immunochemotherapy.