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

Abstract

Purpose

H102, a novel β-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.

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Abbreviations

AChE:

Acetylcholinesterase

AD:

Alzheimer’s disease

Aβ:

β-amyloid protein

BBB:

Blood–brain barrier

CD:

Circular dichroism

ChAT:

Choline acetyltransferase

CNS:

Central nervous system

CL:

Cerebellum

CR:

Cerebrum

EPC:

Egg phosphatidylcholine

HI:

Hippocampus

IDE:

Insulin degrading enzyme

OB:

Olfactory bulb

PEG:

Poly ethylene glycol

TEER:

Transendothelial electrical resistance

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ACKNOWLEDGMENTS AND DISCLOSURES

This work was supported by grants from the National Science and Technology Major Project 2009ZX09103-029 and The Open Project Program of Key Lab of Smart Drug Delivery (Fudan University), Ministry of Education, China.

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Correspondence to Qizhi Zhang.

Additional information

Xiaoyao Zheng and Xiayan Shao contributed equally to this work.

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Zheng, X., Shao, X., Zhang, C. et al. Intranasal H102 Peptide-Loaded Liposomes for Brain Delivery to Treat Alzheimer’s Disease. Pharm Res 32, 3837–3849 (2015). https://doi.org/10.1007/s11095-015-1744-9

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KEY WORDS

  • H102 peptide
  • Liposome
  • Intranasal administration
  • Brain delivery
  • Alzheimer’s disease (AD)