Lithium-Charged Gold Nanoparticles: A New Powerful Tool for Lithium Delivery and Modulation of Glycogen Synthase Kinase 3 Activity

Abstract

"A Trojan Horse for Lithium Delivery". Lithium has important pharmacological applications, although its use is severely limited due to its narrow therapeutic window of administrable concentrations. This study presents a novel nanocarrier for this metal cation based on glutathione-stabilized gold nanoparticles (LiG-AuNPs), which enable targeted release of lithium. LiG-AuNPs are easily synthesized, with dimensions of ≈2 nm, with a lithium loading of 2 wt%. These particles show a tendency to aggregate and a narrow size distribution. Aggregates of LiG-AuNPs (a-LiG-AuNPs) are non-toxic to cells at concentrations lower than 2 mg mL^-1 and are rapidly internalized into cells, where they release lithium in the cytosol through cation exchange, effectively modulating Glycogen Synthase Kinase-3 (GSK-3β) activity, especially the β isoform. Administration of a-LiG-AuNPs in murine models increased the inhibitory phosphorylation of GSK-3β at Ser9. Intranasal administration of a-LiG-AuNPs modulated GSK-3β activity in the brain, particularly in the hippocampus, without significantly altering plasma lithium levels, even when the administration lasted several months. LiG-AuNPs thus represent a powerful tool for the targeted administration of lithium, enhancing its therapeutic effects in modulating GSK-3β. They have potential applications for treating illnesses depending on GSK-3β (hyper)activation, such as mood disorders, Alzheimer's disease, and viral infections.

Keywords: Alzheimer's disease; HSV‐1 infection; bipolar disorder; glycogen synthase kinase 3; gold nanoparticle; lithium.