title: Gold nanoparticles of diameter 1.4 nm trigger necrosis by oxidative stress and mitochondrial damage.
abstract: Gold nanoparticles (AuNPs) are generally considered nontoxic, similar to bulk gold, which is inert and biocompatible. AuNPs of diameter 1.4 nm capped with triphenylphosphine monosulfonate (TPPMS), Au1.4MS, are much more cytotoxic than 15-nm nanoparticles (Au15MS) of similar chemical composition. Here, major cell-death pathways are studied and it is determined that the cytotoxicity is caused by oxidative stress. Indicators of oxidative stress, reactive oxygen species (ROS), mitochondrial potential and integrity, and mitochondrial substrate reduction are all compromised. Genome-wide expression profiling using DNA gene arrays indicates robust upregulation of stress-related genes after 6 and 12 h of incubation with a 2 x IC50 concentration of Au1.4MS but not with Au15MS nanoparticles. The caspase inhibitor Z-VAD-fmk does not rescue the cells, which suggests that necrosis, not apoptosis, is the predominant pathway at this concentration. Pretreatment of the nanoparticles with reducing agents/antioxidants N-acetylcysteine, glutathione, and TPPMS reduces the toxicity of Au1.4MS. AuNPs of similar size but capped with glutathione (Au1.1GSH) likewise do not induce oxidative stress. Besides the size dependency of AuNP toxicity, ligand chemistry is a critical parameter determining the degree of cytotoxicity. AuNP exposure most likely causes oxidative stress that is amplified by mitochondrial damage. Au1.4MS nanoparticle cytotoxicity is associated with oxidative stress, endogenous ROS production, and depletion of the intracellular antioxidant pool.
authors.affiliation: Biomedical Engineering, Biointerface Laboratory, RWTH Aachen University, Aachen, Germany.
authors.forename: Yu
authors.initials: Y
authors.lastname: Pan
authors.forename: Annika
authors.initials: A
authors.lastname: Leifert
authors.forename: David
authors.initials: D
authors.lastname: Ruau
authors.forename: Sabine
authors.initials: S
authors.lastname: Neuss
authors.forename: Jörg
authors.initials: J
authors.lastname: Bornemann
authors.forename: Günter
authors.initials: G
authors.lastname: Schmid
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Brandau
authors.forename: Ulrich
authors.initials: U
authors.lastname: Simon
authors.forename: Willi
authors.initials: W
authors.lastname: Jahnen-Dechent
mesh_terms: D006046:Gold; D006367:HeLa Cells; D006801:Humans; D008024:Ligands; D053768:Metal Nanoparticles; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D009336:Necrosis; D020411:Oligonucleotide Array Sequence Analysis; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D008024:Ligands; D017382:Reactive Oxygen Species; D006046:Gold