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.

Gold nanoparticles and ions – friends or foes? As they are seen by human cells U-937 and HL-60

“…[35] Equally important seems to be their size, for example, 1.4 nm gold nanospheres resulted in necrosis, damage to mitochondria and induction of oxidative stress, while 15 nm gold nanospheres did not harm the cells. [32] Many authors focused on the impact of physical and chemical parameters, such as particle size, shape or charge, while the effect of a degree of nanoparticle purification on the biological model was not tested. Today, many preparations of gold sols are available in commercial sales, but they are not equipped with information on the degree of purification from the residues after synthesis.…”

In vitro and in vivo toxicity assessment of nanoparticles

“…In vitro studies have revealed CNTs disrupt the membrane potential, membrane integrity, metabolic activity and cellular reproduction [137,138]. Gold nanoparticles are responsible for mitochondrial damage, affecting cellular micro mobility, autophagy and oxidative stress [119,139]. In vitro studies on silver nanoparticles' toxicity have suggested that interference with DNA replication, fidelity, apoptosis, oxidative stress, cytotoxicity, chromosome instability, intracellular calcium transients, JNK activation and cell cycle arrest in mammalian cells [121-125, 140, 141].…”

Differential hERG ion channel activity of ultrasmall gold nanoparticles

“…The binding of such functional molecules to the surface of AuNPs is facilitated via thiol groups, resulting in a relatively stable gold-sulfur bond. Established cytotoxicity tests including gene expression studies have proved those AuNPs to be nontoxic (7)(8)(9). In contrast, ultrasmall AuNPs (sub-2 nm) may become cytotoxic, when the capping ligands are weaker binding phosphines instead of thiols.…”

“…This cytotoxicity was size dependent in several cell lines and most severe in the case of AuNPs comprising a 55-gold-atom cluster core with a diameter of 1.4 nm and a shell consisting of 12 TPPMS molecules (Au1.4MS) (10). Toxicity was caused by oxidative stress (8). We further showed that cytotoxicity (i) was abolished by replacing the phosphine ligands by thiols, which bind more strongly to the gold core, and (ii) decreases with increasing particle size with a significantly reduced toxicity already at 1.8 nm.…”