title: Impact of polymer-modified gold nanoparticles on brain endothelial cells: exclusion of endoplasmic reticulum stress as a potential risk factor.
abstract: A library of polymer-coated gold nanoparticles (AuNPs) differing in size and surface modifications was examined for uptake and induction of cellular stress responses in the endoplasmic reticulum (ER stress) in human brain endothelial cells (hCMEC/D3). ER stress is known to affect the physiology of endothelial cells (ECs) and may lead to inflammation or apoptosis. Thus, even if applied at non-cytotoxic concentrations ER stress caused by nanoparticles should be prevented to reduce the risk of vascular diseases and negative effects on the integrity of barriers (e.g. blood-brain barrier). We exposed hCMEC/D3 to twelve different AuNPs (three sizes: 18, 35, and 65 nm, each with four surface-modifications) for various times and evaluated their effects on cytotoxicity, proinflammatory mediators, barrier functions and factors involved in ER stress. We demonstrated a time-dependent uptake of all AuNPs and no cytotoxicity for up to 72 h of exposure. Exposure to certain AuNPs resulted in a time-dependent increase in the proinflammatory markers IL-8, MCP-1, sVCAM, sICAM. However, none of the AuNPs induced an increase in expression of the chaperones and stress sensor proteins BiP and GRP94, respectively, or the transcription factors ATF4 and ATF6. Furthermore, no upregulation of the UPR stress sensor receptor PERK, no active splicing product of the transcription factor XBP1 and no upregulation of the transcription factor CHOP were detectable. In conclusion, the results of the present study indicate that effects of different-sized gold nanoparticles modified with various polymers were not related to the induction of ER stress in brain microvascular endothelial cells or led to apoptosis.
authors: a REPAIR-Lab, Institute of Pathology, University Medical Center of the Johannes Gutenberg University Mainz and European Institute of Excellence on Tissue Engineering and Regenerative Medicine , Mainz , Germany .
authors: Laura
authors: L
authors: Anspach
authors: a REPAIR-Lab, Institute of Pathology, University Medical Center of the Johannes Gutenberg University Mainz and European Institute of Excellence on Tissue Engineering and Regenerative Medicine , Mainz , Germany .
authors: Ronald E
authors: RE
authors: Unger
authors: a REPAIR-Lab, Institute of Pathology, University Medical Center of the Johannes Gutenberg University Mainz and European Institute of Excellence on Tissue Engineering and Regenerative Medicine , Mainz , Germany .
authors: Christoph
authors: C
authors: Brochhausen
authors: b Department of Chemistry , University of Warwick , Coventry , UK , and.
authors: Matthew I
authors: MI
authors: Gibson
authors: c École Polytechnique Fédérale De Lausanne (EPFL), Institut Des Matériaux and Institut Des Sciences Et Ingénierie Chimiques, Laboratoire Des Polymères, Bâtiment MXD , Lausanne , Switzerland.
authors: Harm-Anton
authors: HA
authors: Klok
authors: a REPAIR-Lab, Institute of Pathology, University Medical Center of the Johannes Gutenberg University Mainz and European Institute of Excellence on Tissue Engineering and Regenerative Medicine , Mainz , Germany .
authors: C James
authors: CJ
authors: Kirkpatrick
authors: a REPAIR-Lab, Institute of Pathology, University Medical Center of the Johannes Gutenberg University Mainz and European Institute of Excellence on Tissue Engineering and Regenerative Medicine , Mainz , Germany .
authors: Christian
authors: C
authors: Freese
mesh_terms: D051701:Activating Transcription Factor 4 / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D006046:Gold / Q000737:chemistry / Q000633:toxicity*; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D053768:Metal Nanoparticles / Q000737:chemistry / Q000633:toxicity*; D010316:Particle Size; D011108:Polymers / Q000737:chemistry*; D012307:Risk Factors; D051742:Transcription Factor CHOP / Q000378:metabolism
chemical_list: D018840:HSP70 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D016209:Interleukin-8; D008565:Membrane Proteins; D011108:Polymers; C018551:glucose-regulated proteins; D051701:Activating Transcription Factor 4; D051742:Transcription Factor CHOP; D006046:Gold
keywords: BiP; blood-brain barrier; cell stress; tight junction proteins; unfolded protein response