Understanding the Biological Interactions of pH-Swellable Nanoparticles

pH-responsive nanoparticles have generated significant interest for use as drug delivery systems due to their potential for inducible release at low pH. The pH variation from the bloodstream (pH 7.4) to intracellular compartments of cells called endosomes/lysosomes (pH < 5.0) has been of particular interest. However, one of the limitations with nanoparticle delivery systems is the inability to migrate out of these compartments to the cytosol or other organelles, via a process termed endosomal escape. Previous studies have postulated that pH-responsive nanoparticles can facilitate endosomal escape through a range of mechanisms including membrane interaction, pH-induced swelling, and the proton-sponge effect. In this study, a series of pH-swellable nanoparticles (85-100 nm) are designed and their impact on biological interactions, particularly endosomal escape, are investigated. The particles exhibit tunable pH-induced swelling (from 120% to 200%) and have good buffering capacity. The cellular association is studied using flow cytometry and endosomal escape is determined using a calcein leakage assay. Interestingly, no endosomal escape with all nanoparticle formulations is found, which suggests there are limitations with both the proton-sponge effect and pH-induced swelling mechanism as the primary methods for inducing endosomal escape.