pH-Sensitive Core-Shell Nanoparticles for Intracellular Drug Delivery

Therapeutics such as proteins, DNA, or siRNA, can only exert their function in the cell cytosol or nucleus. However, most of them are cell membrane impermeable molecules that can only be taken up by cells via endocytosis or phagocytosis. Such drug molecules are thus confined in endolysosomes, where reduced pH and degradative enzymes may destroy them without therapeutic gain. Efficient escape of drug molecules to the cytosol before destruction in endolysosomes is a major challenge for intracellular drug delivery. To address this issue, we designed a pH-sensitive core-shell nanoparticle to segregate the functions of the particle into an endosome-disrupting pH-responsive core that would absorb protons at endolysosomal pH, and a shell whose composition could be tuned to facilitate particle targeting, cell binding, and drug binding. Two-stage surfactant-free emulsion polymerization of 2-diethylamino ethyl methacrylate (DEAEMA) (core) and 2-amino ethyl methacrylate (AEMA) (shell) in the presence of a crosslinker was used for the synthesis of monodisperse core-shell hydrogel nanoparticles of 200 nm in diameter. The protonation of tertiary amine groups on the polyDEAEMA core on moving from extracellular to endolysosomal pH resulted in reversible swelling of the nanoparticles with a 2.8-fold diameter change.