(632h) Regulation of Cytotoxicity By Thermoresponsive Polymer Grafted Nanoparticles

Nanoparticles (NPs) can promote cytotoxic and pro-inflammatory effects in cellular targets such as macrophages, T cells, dendritic cells, and epithelial cells, which play a role in the pathogenesis of lung and cardiovascular diseases.  Due to their strong antimicrobial activity, silver nanoparticles (NPs) with diameters <50um have been efficacious in inhibiting the growth of bacteria and fungi, making them an attractive commercial additives. However, several studies have also demonstrated the toxic effects of gold NPs in a variety of different cell types, and the mechanism is thought to be mediated by oxidative stress. Progress in NP toxicity testing to date has been challenging due to an exponential increase in new nanomaterials, an array of physicochemical properties, and a general uncertainty about NP-biological interactions. The objective of this study was to investigate the effects of nanoparticle functionalization and aggregation on mechanistic toxicity in mammalian cells. We developed NPs functionalized with thermoresponsive polymers that result in steric and/or electrosteric interactions at the particle/particle interface that impart stability to the suspensions and affect their aggregation state with time.  Thermoresponsive polymers Poly(MeO₂MA_x-co-OEGMA_y) were fabricated from a disulphide functionalized atom transfer radical polymerization (ATRP) initiator.  The lower critical solution temperature (LCST) was adjusted by varying the OEGMA content and ranged from 22.5 to 31°C.  Gold nanoparticles (Au NPs) were functionalized with different formulations of the thermoresponsive polymers by grafting the ATRP polymers to Au@citrate. We quantified NP stability and aggregation rate constants using dynamic light scattering technology.  The aggregation rate increased with salt concentration, and the critical coagulation constant decreased with increased temperature. Cell cytotoxic and inflammatory responses were investigated by quantifying changes in relevant gene and protein expression.  The inflammatory cytokine IL-6 was differentially regulated in response to various LCST, and cytotoxicity was sensitive to aggregation state.  Future studies will aim to further elucidate the relationship between physicochemical properties and cellular response.