title: Intracellular Accumulation of Gold Nanoparticles Leads to Inhibition of Macropinocytosis to Reduce the Endoplasmic Reticulum Stress.
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.
authors.affiliation: Institute of Materials Science and Nanotechnology, National Nanotechnology Research Center (UNAM), Bilkent University, Ankara 06800, Turkey.
authors.forename: Nuray
authors.initials: N
authors.lastname: Gunduz
authors.affiliation: Max-Planck Institute for Intelligent Systems, 70569 Stuttgart, Germany.
authors.forename: Hakan
authors.initials: H
authors.lastname: Ceylan
authors.affiliation: Institute of Materials Science and Nanotechnology, National Nanotechnology Research Center (UNAM), Bilkent University, Ankara 06800, Turkey.
authors.forename: Mustafa O
authors.initials: MO
authors.lastname: Guler
authors.affiliation: Institute of Materials Science and Nanotechnology, National Nanotechnology Research Center (UNAM), Bilkent University, Ankara 06800, Turkey.|Neuroscience Graduate Program, Bilkent University, Ankara 06800, Turkey.
authors.forename: Ayse B
authors.initials: AB
authors.lastname: Tekinay
mesh_terms: D016923:Cell Death; D059865:Endoplasmic Reticulum Stress; D005089:Exocytosis; D005453:Fluorescence; D006046:Gold / Q000737:chemistry*; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism*; D053768:Metal Nanoparticles / Q000737:chemistry* / Q000648:ultrastructure; D010873:Pinocytosis
chemical_list: D006046:Gold