Targeted Brain Delivery of RVG29-Modified Rifampicin-Loaded Nanoparticles for Treatment and Diagnosis of Alzheimer Disease

Alzheimer's disease (AD) is a neurodegenerative disease related to age. The main pathological features of AD are β-amyloid protein (Aβ) deposition and tau protein hyperphosphorylation. Currently, there are not an effective drug for the etiological treatment of AD. Rifampicin (RIF) is a semi-synthetic broad-spectrum antibiotic with anti-β-amyloid deposition, anti-inflammatory, anti-apoptosis and neuroprotective effects, but its application in AD treatment has been limited by its strong hydrophobicity, high toxicity, short half-life, low bioavailability and blood-brain barrier (BBB) hindrance. We designed a novel brain-targeted and MRI-characteristic nanomedicine through loading rabies virus protein 29 (RVG29), rifampicin and Gd on poly(L-lactide) nanoparticles (RIF@PLA-PEG-Gd/Mal-RVG29). The cytotoxicity assay demonstrated that RIF@PLA-PEG-Gd/Mal-RVG29 had good biocompatibility and security. The results of cellular uptake and fluorescence in vivo imaging showed that PLA-PEG-Gd/Mal-RVG29 could deliver rifampicin into brain by enhancing cellular uptake and brain targeting performance, so that improving the bioavailability of rifampicin. In vivo study, compared with rifampicin, RIF@PLA-PEG-Gd/Mal-RVG29 improved the spatial learning and memory capability of APP/PS1 mice in the Morris water maze. Immunofluorescence, TEM, immunoblotting and HE test showed that RIF@PLA-PEG-Gd/Mal-RVG29 could reduce Aβ deposition in hippocampal and cortex of APP/PS1 mice, improve the damage of synaptic ultrastructure, increase the expression level of PSD95 and SYP, as well as reduce the necrosis of neurons. These findings suggest that RIF@PLA-PEG-Gd/Mal-RVG29 may be an effective strategy for the treatment and diagnosis of AD.