Surface Functionalization of Pegylated Gold Nanoparticles with Antioxidants Suppresses Nanoparticle-Induced Oxidative Stress and Neurotoxicity

Abstract

Because of their biocompatibility and biosafety, pegylated Au NPs (Au@PEG), as a nanodrug-carrier, have been widely applied in different biomedical applications, including imaging and drug delivery systems. Under such conditions, the biosafety of Au@PEG has attracted tremendous attention. However, only a small number of studies focused on the neurotoxicity of Au@PEG used as drug delivery carriers not to mention reducing the neurotoxicity of Au@PEG. To address this issue, the adverse effects of Au@PEG on human neuroblastoma SHSY5Y cells were first investigated. The results showed that 4.5 nm Au@PEG significantly induced cell apoptosis through upregulating reactive oxygen species (ROS) production and disordering the mitochondrial membrane potential. To further evaluate whether the neurotoxicity of Au@PEG could be improved through conjugating antioxidants on the surface of Au@PEG, Trolox (a vitamin E analogue)-functionalized Au@PEG (Au@Trolox) was synthesized. The results showed that the neurotoxicity of Au@PEG on SHSY5Y cells could be significantly improved by Au@Trolox. Next, mice were subjected to administration of 4.5 nm Au@PEG and Au@Trolox for 3 months. An increase of oxidative stress and a decrease in the activity of key antioxidant enzymes including glutathione peroxidase (GSH-Px), superoxide dismutase (SOD), and catalase (CAT) were observed after long-term injection of Au@PEG. More importantly, both the apoptosis of neurons and the activation of astrocytes were observed in the hippocampus of mice injected with Au@PEG. In contrast, the adverse effects of Au@PEG could be improved when injected with Au@Trolox. In short, the present study provided new insights into the toxicity evaluation of nanoparticles and would help to better understand and prevent the neurotoxicity of nanomaterials used in pharmaceutics.

Current Knowledge of Silver and Gold Nanoparticles in Laboratory Research—Application, Toxicity, Cellular Uptake

“…Their concentrations in cellular organelles are strongly regulated by various detoxifying enzymes, such as superoxide dismutase (SOD), glutathione peroxidase (GPx), and catalase (CAT), or by different antioxidants including flavonoids, ascorbic acids, vitamin E, and glutathione (GSH). The production of free radicals induced by nanoparticles leads to a reduction of GSH to oxidized form, followed by induction of oxidative stress [ 2 , 12 , 72 , 73 , 74 , 75 ].…”

“…Application of AuPEG at 25 mg/kg for three months caused a decrease in MDA and antioxidant enzyme levels (SOD, CAT, GSH-Px) in the hippocampus, compared to AuTrolox [ 72 ].…”

“…Inhibition of this process through the use of an antioxidant—Trolox—was also noted. This research provides a reasonable basis for the potential development of a nanoparticle drug delivery system [ 72 ].…”

“…After isolating and homogenizing the hippocampus, LDH (lactate dehydrogenase) levels were investigated. After treatment of cells with AuPEG at a 25 mg/kg concentration, a two-fold increase in LDH levels was observed, indicating that AuPEG may cause cell death [ 72 ].…”

Advances in the application of gold nanoparticles in bone tissue engineering

“…In addition, the intracellular response of GNPs still needs further study. Previous studies have shown that GNPs can cause mitochondrial membrane destruction and cell content loss, which is related to the production of reactive oxygen species (ROS) [138] Recently, antioxidant conjugation has been used to remedy this problem [139] The study of complex cytological effects of materials is also urgently needed. For example, cell damage and apoptosis caused by PEG-coated GNPs can be inhibited by antibodies formed after peptide functionalization [140].…”