Membrane-destabilizing polyanions: interaction with lipid bilayers and endosomal escape of biomacromolecules

Water-soluble synthetic polyanions are employed nowadays in a multitude of industrial and biomedical applications and are studied extensively as simplified models of natural polyelectrolytes. The most interesting feature of carboxylated polymers is undoubtedly their ability to undergo coil-to-globule conformational change upon a decrease in pH of the surrounding environment. Over the years, scientists have gained better insights into the conformational behavior of these polymers in solution and in the presence of membrane bilayers. In addition, when used as protein models, anionic polyelectrolytes can provide valuable information on physiological processes such as domain formation in biological membranes. Recently, polyanions have been evaluated as part of drug delivery systems, either as complexes/conjugates with biomolecules, or in the preparation of pH-sensitive liposomal formulations. This article reviews the fundamental and practical aspects of pH-responsive synthetic polyanions in drug delivery. The pH-dependent conformational behavior of these polymers in aqueous solution is described in detail using poly(methacrylic acid) as the model polymer. Since binding to cellular membranes is a fundamental issue in understanding the mechanism of action of polyanions in cytoplasmic drug delivery, studies characterizing their interactions with phospholipid bilayers at neutral as well as at acidic pH are reviewed. Finally, pH-responsive delivery systems based on these polymers are described. As the conformational properties of pH-sensitive polyanions can be easily modulated by carefully adjusting their composition, such formulations may represent an attractive strategy to improve the escape of active biomolecules from acidic endosomal compartments. (C) 2004 Elsevier B.V. All rights reserved.