State Key Laboratory for Structural Chemistry of Unstable and Stable Species, Center for Molecular Science, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, P. R. China.
Laboratory of Molecular Iron Metabolism, College of Life Science, Hebei Normal University, Shijiazhuang, Hebei 050024, P. R. China.
Chem Res Toxicol. 2020 May 18;33(5):1195-1205. doi: 10.1021/acs.chemrestox.9b00368. Epub 2020 Mar 13.
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.
由于其生物相容性和生物安全性，聚乙二醇化金纳米粒子（Au@PEG）作为纳米药物载体，已广泛应用于不同的生物医学应用，包括成像和药物传递系统。在这种情况下，Au@PEG 的生物安全性引起了极大的关注。然而，只有少数研究关注用作药物载体的 Au@PEG 的神经毒性，更不用说降低 Au@PEG 的神经毒性了。为了解决这个问题，首先研究了 Au@PEG 作为药物传递载体对人神经母细胞瘤 SH-SY5Y 细胞的不良影响。结果表明，4.5nm 的 Au@PEG 通过上调活性氧（ROS）的产生和扰乱线粒体膜电位显著诱导细胞凋亡。为了进一步评估通过在 Au@PEG 表面接枝抗氧化剂是否可以改善 Au@PEG 的神经毒性，合成了 Trolox（维生素 E 类似物）功能化的 Au@PEG（Au@Trolox）。结果表明，Au@Trolox 可显著改善 Au@PEG 对 SH-SY5Y 细胞的神经毒性。接下来，用 4.5nm 的 Au@PEG 和 Au@Trolox 对小鼠进行了 3 个月的给药。长期注射 Au@PEG 后，观察到氧化应激增加和关键抗氧化酶（包括谷胱甘肽过氧化物酶（GSH-Px）、超氧化物歧化酶（SOD）和过氧化氢酶（CAT））的活性降低。更重要的是，在注射 Au@PEG 的小鼠海马中观察到神经元凋亡和星形胶质细胞激活。相比之下，注射 Au@Trolox 可以改善 Au@PEG 的不良反应。总之，本研究为纳米颗粒的毒性评价提供了新的见解，并有助于更好地理解和预防药物制剂中纳米材料的神经毒性。
