Exploitation of intracellular pH gradients in the cellular delivery of macromolecules.

Most cellular components such as the cytoplasm, endosomes, lysosomes, endoplasmic reticulum, Golgi bodies, mitochondria, and nuclei are known to maintain their own characteristic pH values. These pH values range from as low as 4.5 in the lysosome to about 8.0 in the mitochondria. Given these proton gradients around a neutral pH, weak acids, and bases with a pKa between 5.0 and 8.0 can exhibit dramatic changes in physicochemical properties. These compounds can be conjugated as such to macromolecules or incorporated into polymeric or liposomal formulations to promote the efficient cellular delivery of macromolecules. Mechanistically, the carrier molecules can facilitate favorable membrane partition, membrane fusion, transient pore formation, or membrane disruption. Drug carriers equipped with such pH-sensitive triggers and switches are able to significantly enhance the cellular delivery of macromolecules in vitro. However, the successful application of these molecules for efficient delivery in vivo requires the design of noncytotoxic, nonimmunogenic, serum compatible and biochemically labile carriers, systematic analysis of their mechanisms of action, and extensive animal studies. Copyright 2002 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 91: 903-913, 2002