Intranasal H102 Peptide-Loaded Liposomes for Brain Delivery to Treat Alzheimer's Disease.

PURPOSE: H102, a novel ß-sheet breaker peptide, was encapsulated into liposomes to reduce its degradation and increase its brain penetration through intranasal administration for the treatment of Alzheimer's disease (AD). METHODS: The H102 liposomes were prepared using a modified thin film hydration method, and their transport characteristics were tested on Calu-3 cell monolayers. The pharmacokinetics in rats' blood and brains were also investigated. Behavioral experiments were performed to evaluate the improvements on AD rats' spatial memory impairment. The neuroprotective effects were tested by detecting acetylcholinesterase (AchE), choline acetyltransferase (ChAT) and insulin degrading enzyme (IDE) activity and conducting histological assays. The safety was evaluated on rats' nasal mucosa and cilia. RESULTS: The liposomes prepared could penetrate Calu-3 cell monolayers consistently. After intranasal administration, H102 could be effectively delivered to the brain, and the AUC of H102 liposomes in the hippocampus was 2.92-fold larger than that of solution group. H102 liposomes could excellently ameliorate spatial memory impairment of AD model rats, increase the activities of ChAT and IDE and inhibit plaque deposition, even in a lower dosage compared with H102 intranasal solution. H102 nasal formulations showed no toxicity on nasal mucosa. CONCLUSIONS: The H102-loaded liposome prepared in this study for nasal administration is stable, effective and safe, which has great potential for AD treatment.

Dual-functional nanoparticles for precise drug delivery to Alzheimer's disease lesions: Targeting mechanisms, pharmacodynamics and safety.

Alzheimer's disease (AD) is the most common form of dementia and is characterized by the cerebral accumulation of extracellular amyloid plaques. In a previous study, this histopathological hallmark was used as a target on a dual-functional nanoparticle (TQNP) to deliver biotechnological drugs, such as the H102 peptide, a ß-sheet breaker, to AD lesions precisely. This delivery system could reduce the amyloid-ß (Aß) burden in the brains of AD model mice, as well as ameliorated the memory impairment of the mice. Regretfully, the mechanism how nanoparticles penetrated the BBB and subsequently targeted to the plaques is still unclear. In this study, the internalization, subcellular fate and transportation of the nanoparticles on bEnd.3 cells and an in vitro BBB model, demonstrated that TQNP could be taken up through various routes, including caveolae-mediated endocytosis, suggesting that some of TQNP were able to cross the BBB intact. Then, the TQNP were visualized to specifically bind to the Aß plaques. TQNP targeting to amyloid plaques might lead to enhanced therapeutic efficacy, which was further evaluated in APP/PS1 transgenic mice. The TQNP/H102 obtained better ability in decreasing amyloid plaques, increasing Aß-degrading enzymes, reducing tau protein phosphorylation, protecting synapses and improving the spatial learning and memory of transgenic mice than nanoparticles modified with a single ligand. And good biocompatibility of TQNP was indicated with subacute toxicity assays. In conclusion, TQNP was a valuable nanodevice for the precise delivery for biotechnological drugs to treat AD.