Modulation of cell responses to Ag-(MeO MA-co-OEGMA): Effects of nanoparticle surface hydrophobicity and serum proteins on cellular uptake and toxicity.

Nanoparticle (NP) interactions with cellular systems are influenced by both NP physico-chemical properties and the presence of surface-bound proteins that are adsorbed in biological environments. Here, we characterize cellular responses to silver nanoparticles (AgNPs) functionalized with poly(di(ethylene glycol) methyl ether methacrylate-co-oligo(ethylene glycol) methyl methacrylate) (poly(MeO MA -co-OEGMA )) brushes with tunable hydrophobicity and explore how these responses are modulated by the presence or absence of serum proteins. Poly(MeO MA -co-OEGMA ) with variable composition (5-10% OEGMA) was fabricated to elicit differential hydrophobicity at 37°C for AgNPs capped with these copolymers. The increase in Ag-(MeO MA -co-OEGMA ) surface hydrophobicity from (x:y) = 90:10 to (x:y) = 95:5 led to enhanced cytotoxicity of L-929 fibroblasts and a concomitant increase in cell uptake and reactive oxygen species generation in the presence of serum proteins. These responses were attenuated significantly in serum-free environments. Broad inhibition of PI3 kinase-mediated endocytosis reduced both cell uptake and cytotoxicity in the presence or absence of serum proteins. In contrast, selective inhibition of clathrin- and caveolae-mediated endocytosis markedly decreased cell uptake and cytotoxicity in response to Ag-(MeO MA -co-OEGMA ) exclusively in the presence of serum proteins, whereas cell responses to the more hydrophilic Ag-(MeO MA -co-OEGMA ) were less affected by the inhibition of these pathways with or without serum proteins. This study demonstrates an important role for both NP surface hydrophobicity and the presence of serum proteins in directing cell uptake and subsequent cellular responses, which we suggest has broad application in the design of polymer-functionalized NPs for specific biological outcomes. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 1061-1071, 2018.