Biomembrane-Active Molecular Switches as Tools for Intracellular Drug Delivery

Abstract

Many therapeutic strategies, such as gene therapy and vaccine development require the delivery of polar macromolecules (e.g. DNA, RNA, and proteins) to intracellular sites at a therapeutic concentration. For such macromolecular therapeutics, cellular membranes constitute a major transport barrier that must be overcome before these drugs can exert their biological activity inside cells. A number of biological organisms, e.g. viruses and toxins, efficiently destabilize the cellular membranes upon a trigger, such as low pH, and facilitate the delivery of their biological cargo to the cytoplasm of host cell. pH-responsive synthetic peptides and polymers have been designed to mimic the function of membrane-destabilizing natural organisms and evaluated as a part of drug delivery systems. In this Review, pH-dependent membrane activity of natural and synthetic systems is reviewed, focussing on fundamental and practical aspects of pH-responsive, membrane-disruptive synthetic polymers in intracellular drug delivery.