Multi-layered nanogels with MMP-sheddable PEG masks: Preparation and promotion of tumor cell uptake by controlling surface characteristics

We describe a facile and effective poly(ethylene glycol) (PEG) coating method that has not been used previously for decoration of nanogels. Layer-by-layer (LbL) assembly was the technique of choice to introduce PEG onto the surface of multi-layered nanogels (MLNGs). Pegylated MLNGs were prepared simply by sequentially dispersing nanogels in solutions of cationic polymer, anionic polymer, and modified PEGs, and each coating step was validated by measuring changes in size and surface charge. Particularly, a peptide linker that is cleavable by matrix metalloproteinase-2 (MMP-2) in the tumor microenvironment was introduced between PEG layer and nanogels because it is known that PEG reduces the uptake of nanoparticles in tumor cells due to its high mobility. In vitro cell studies demonstrated that MLNGs with MMP-cleavable PEGs enhanced the particle uptake up to 3 times in tumor cells due to unmasking of PEG brushes as compared to pegylated MLNGs without MMP-sensitive peptide linkers.