Control of Surface Ligand Density on PEGylated Gold Nanoparticles for Optimized Cancer Cell Uptake

Surface chemistry plays a critical role in the solution phase behavior of gold nanoparticles (Au NPs) for applications such as in situ diagnostics and drug delivery. Polyethylene glycol (PEG), a hydrophilic polymer with low immunogenicity, is most commonly used for protecting Au NPs for biomedical applications. The ligand density and molecular weight of PEG on the gold nanoparticle surface are key factors that control the particles’ behavior. Specifically, the total density of PEG ligands gives rise to a transition from a disorganized, deformable polymer “mushroom” orientation to a more rigid “brush” orientation. Here, it is investigated how to rationally control this transition for Au NPs coated with PEG‐SH molecules within the weight range of 0.55 to 5 kDa, and evaluate their subsequent interaction with cancer cells. Several complementary methods are used to evaluate the effect of PEGylation on biologically relevant aspects, including surface ligand density, hydrodynamic size, dispersity, and cellular toxicity. In this work, the optimal synthesis ratios of PEG:Au NPs for achieving stability and maximum dispersity with 0.55, 1, 2, and 5 kDa PEG are determined to be 2500, 700, 500, and 300, respectively. Importantly, ratios that exceed those necessary for maximum dispersion of the Au NPs as determined by UV–vis and DLS are found to be the best ratios for highest cell viability.