Abstract
Understanding the toxicity of nanomaterials remains largely limited to acute cellular response, i.e., short-term in vitro cell-death based assays, and analyses of tissue- and organ-level accumulation and clearance patterns in animal models, which have produced very little information about how these materials (from the toxicity point of view) interact with the complex intracellular machinery. In particular, understanding the mechanism of toxicity caused by the gradual accumulation of nanomaterials due to prolonged exposure times is essential yet still continue to be a largely unexplored territory. Herein, we show intracellular accumulation and the associated toxicity of gold nanoparticles (AuNPs) for over two-months in the cultured vascular endothelial cells. We observed that steady exposure of AuNPs at low (non-lethal) dose leads to rapid intracellular accumulation without causing any detectable cell death while resulting in elevated endoplasmic reticulum (ER) stress. Above a certain intracellular AuNP threshold, inhibition of macropinocytosis mechanism ceases further nanoparticle uptake. Interestingly, the intracellular depletion of nanoparticles is irreversible. Once reaching the maximum achievable intracellular dose, a steady depletion is observed, while no cell death is observed at any stage of this overall process. This depletion is important for reducing the ER stress. To our knowledge, this is the first report suggesting active regulation of nanoparticle uptake by cells and the impact of long-term exposure to nanoparticles in vitro.
Highlights
Advances in nanotechnology have resulted in the development of a large variety of engineered nanomaterials for numerous applications in chemistry, engineering and biomedical sciences[1,2,3,4]
The location of surface plasmon resonance peak (SPR) signal is informative about the electronic properties of the surrounding medium and the state of nanoparticle aggregations that may potentially result from the formation of surface corona from macromolecular species
A slight red shift in the absorption spectrum of AuNPs when placed in fetal bovine serum suggested the formation of a corona on the nanoparticle surface that is caused by the displacement of weakly-bound citrate ions with multivalent macromolecules present in the serum (Fig. 2C, Figure S1B,C and D)
Summary
Understanding the toxicity of nanomaterials remains largely limited to acute cellular response, i.e., short-term in vitro cell-death based assays, and analyses of tissue- and organ-level accumulation and clearance patterns in animal models, which have produced very little information about how these materials (from the toxicity point of view) interact with the complex intracellular machinery. The toxicity of nanomaterials is difficult to predict and stems from a combination of their physicochemical properties, including size[6,7], morphology[7], surface chemistry[8], agglomeration/aggregation state[9], solubility[10] and biological milieu[11], and may vary depending on the cell types involved[12,13,14] Both the short- and long-term effects of engineered nanomaterials should be investigated in great detail to eliminate the possibility of unforeseen health hazards prior to their use in industrial and, in particular, biomedical applications. The in vitro study model described is very practical and informative for the future studies regarding the accumulation of a wide scope of engineered nanomaterials
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