We Acknowledge Support for This Project from Nih Grants Gm40162 and Ca87630 and from Nsf Grant Cdr-8622201 and Thank Our Collaborators and Co-workers, [7] Tunable Ph-sensitive Liposomes

Liposomes are membrane-enclosed vesicles composed of a lipid bilayer shell surrounding an aqueous core. Liposomes have historically been studied and developed as biophysical models of cellular membranes and as drug delivery systems—an application for which an appropriate response to a physiological stimulus such as bilayer lysis or lipid chemical breakdown is highly desirable. Smart liposome systems that are able to alter their permeability or change their chemical composition in response to external signals have utility in drug delivery applications and as components of biosensor elements in the emerging fields of nano and biotechnology. One of the most attractive stimuli to exploit in vivo for drug delivery applications is that of local pH change. During the cellular process of endocytosis, early endosomal vesicles become acidified by the vacuolar-ATPase proton pump, producing a large vesicular proton gradient versus cytosolic pH. The pH inside endosomal compartments can become as low as pH 5.5–4.5, sufficiently acidic to be exploited by microbial and viral agents to trigger mechanisms that allow the escape of pathogens and toxins from endosomal membranes and access to the cell interior. Liposome systems that contain pH-sensitive components can be designed to respond appropriately to low pH environments encountered during endocytosis. pH-sensitive liposome systems are traditionally composed of a mixture of a titratable anionic lipid and a neutral or zwitterionic lipid. The neutral lipids used, such as dioleoylphospatidylethanolamine (DOPE), adopt nonbilayer lipid phases in isolation, but mixtures with titratable anionic lipids, such as cholesteryl hemisuccinate (CHEMS), can be stabilized into