Gold nanoparticle-capped mesoporous silica-based H₂O₂-responsive controlled release system for Alzheimer's disease treatment.

Abstract

Metal ions promote Alzheimer's disease (AD) pathogenesis by accelerating amyloid-β (Aβ) aggregation and inducing formation of neurotoxic reactive oxygen species (ROS) such as hydrogen peroxide (H₂O₂). Although metal chelators can block these effects, their therapeutic potential is marred by their inability to cross the blood-brain barrier (BBB) and by their non-specific interactions with metal ions necessary for normal cellular processes, which could result in adverse side effects. To overcome these limitations, we created a novel gold nanoparticle-capped mesoporous silica (MSN-AuNPs) based H₂O₂-responsive controlled release system for targeted delivery of the metal chelator CQ. In this system, CQ is released only upon exposure to conditions in which H₂O₂ levels are high, such as those in Aβ plaques. The conjugation of AuNPs on the surface of MSN did not affect their ability to cross the BBB. The AuNPs also help in decrease the Aβ self-assembly, due to this, MSN-CQ-AuNPs were more efficient than MSN-CQ in inhibiting Cu²⁺-induced Aβ₄₀ aggregation. Furthermore, MSN-CQ-AuNPs reduced the cell membrane disruption, microtubular defects and ROS-mediated apoptosis induced by Aβ₄₀-Cu²⁺ complexes. The high BBB permeability, efficient anti-Aβ aggregation, and good biocompatibility of MSN-CQ-AuNPs, together with the specific conditions necessary for its release of CQ, demonstrate its potential for future biomedical applications. Due to the low ability to cross the blood-brain barrier (BBB) and non-specific interactions with metal ions necessary for normal cellular processes of metal chelator or Aβ inhibitors, we created a novel gold nanoparticle-capped mesoporous silica (MSN-AuNPs)-based H₂O₂-responsive controlled release system for targeted delivery of the metal chelator CQ and AuNPs (Aβ inhibitor). In this system, CQ and AuNPs are released only upon exposure to conditions in which H₂O₂ levels are high, such as those in Aβ plaques. The AuNPs on the surface of MSN also help in decrease the Aβ self-assembly, due to this, MSN-CQ-AuNPs were more efficient than MSN-CQ in inhibiting Cu²⁺-induced Aβ₄₀ aggregation. Furthermore, MSN-CQ-AuNPs reduced the cell membrane disruption, microtubular defects and ROS-mediated apoptosis induced by Aβ₄₀-Cu²⁺ complexes. Our data suggest that this controlled release system may have widespread application in the field of medicine for Alzheimer's disease.