Dual-targeted magnetic mesoporous silica nanoparticles reduce brain amyloid-β burden via depolymerization and intestinal metabolism
Geoffrey Liu, Xiaohan Liang, Changwen Yang, Shun Hu, Qingming Luo, Haiming Luo
Abstract
Rationale: Active removal of excess peripheral amyloid- (A) can potentially treat Alzheimer's disease (AD). However, the peripheral clearance of A using an anti-A monoclonal antibody (mAb) cannot remove PET-detectable A within the brain. This may be due to the inability of mAb to cross the blood-brain barrier (BBB) to degrade insoluble brain A plaques and block liver dysfunction. Methods: We developed a dual-targeted magnetic mesoporous silica nanoparticle (HA-MMSN-1F12) through surface-coupled A42-targeting antibody 1F12 and CD44-targeting ligand hyaluronic acid (HA). Results: HA-MMSN-1F12 had a high binding affinity toward A42 oligomers (Kd = 1.27 0.34 nM) and revealed robust degradation of A42 aggregates. After intravenous administration of HA-MMSN-1F12 into ten-month-old APP/PS1 mice for three weeks (4 mg/kg/week), HA-MMSN-1F12 could cross the BBB and depolymerize brain A plaques into soluble A species. In addition, it also avoided hepatic uptake and excreted captured A species through intestinal metabolism, thereby reducing brain A load and neuroinflammation and improving memory deficits of APP/PS1 mice. Furthermore, the biochemical analysis showed that HA-MMSN-1F12 did not detect any toxic side effects on the liver and kidney. Thus, the efficacy of HA-MMSN-1F12 is associated with the targeted degradation of insoluble brain A plaques, avoidance of non-specific hepatic uptake, and excretion of peripheral A through intestinal metabolism.