Gold Nanoparticles Increase Endothelial Paracellular Permeability by Altering Components of Endothelial Tight Junctions, and Increase Blood-Brain Barrier Permeability in Mice

• Published in: Toxicological sciences 2015-11, Vol.148 (1), p.192-203
• Main Authors: Li, Ching-Hao, Shyu, Ming-Kwang, Jhan, Cheng, Cheng, Yu-Wen, Tsai, Chi-Hao, Liu, Chen-Wei, Lee, Chen-Chen, Chen, Ruei-Ming, Kang, Jaw-Jou
• Format: Article
• Language: English
• Subjects: Animals; Blood-Brain Barrier - cytology; Blood-Brain Barrier - drug effects; Capillary Permeability - drug effects; Cell Line, Tumor; Cells, Cultured; Drug Carriers; Endothelium, Vascular - cytology; Endothelium, Vascular - drug effects; Endothelium, Vascular - metabolism; Gene Expression Regulation - drug effects; Gold - chemistry; Gold - toxicity; Humans; Male; Metal Nanoparticles - toxicity; Metal Nanoparticles - ultrastructure; Mice, Inbred ICR; Nerve Tissue Proteins - antagonists & inhibitors; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Particle Size; Phosphorylation - drug effects; Proteasome Endopeptidase Complex - drug effects; Proteasome Endopeptidase Complex - metabolism; Protein Kinase C - antagonists & inhibitors; Protein Kinase C - genetics; Protein Kinase C - metabolism; Protein Processing, Post-Translational - drug effects; Tight Junction Proteins - antagonists & inhibitors; Tight Junction Proteins - genetics; Tight Junction Proteins - metabolism; Tight Junctions - drug effects; Tight Junctions - metabolism; Toxicokinetics
• ISSN: 1096-6080; 1096-0929
• DOI: 10.1093/toxsci/kfv176

Gold nanoparticles (Au-NPs) are being increasingly used as constituents in cosmetics, biosensors, bioimaging, photothermal therapy, and targeted drug delivery. This elevated exposure to Au-NPs poses systemic risks in humans, particularly risks associated with the biodistribution of Au-NPs and their potent interaction with biological barriers. We treated human umbilical vein endothelial cells with Au-NPs and comprehensively examined the expression levels of tight junction (TJ) proteins such as occludin, claudin-5, junctional adhesion molecules, and zonula occludens-1 (ZO-1), as well as endothelial paracellular permeability and the intracellular signaling required for TJ organization. Moreover, we validated the effects of Au-NPs on the integrity of TJs in mouse brain microvascular endothelial cells in vitro and obtained direct evidence of their influence on blood-brain barrier (BBB) permeability in vivo. Treatment with Au-NPs caused a pronounced reduction of PKCζ-dependent threonine phosphorylation of occludin and ZO-1, which resulted in the instability of endothelial TJs and led to proteasome-mediated degradation of TJ components. This impairment in the assembly of TJs between endothelial cells increased the permeability of the transendothelial paracellular passage and the BBB. Au-NPs increased endothelial paracellular permeability in vitro and elevated BBB permeability in vivo. Future studies must investigate the direct and indirect toxicity caused by Au-NP-induced endothelial TJ opening and thereby address the double-edged-sword effect of Au-NPs.