Zheng Xiaoyao, Shao Xiayan, Zhang Chi, Tan Yuanzhen, Liu Qingfeng, Wan Xu, Zhang Qizhi, Xu Shumei, Jiang Xinguo
Key Laboratory of Smart Drug Delivery, Ministry of Education (Fudan University), Shanghai, 201203, People's Republic of China.
Department of Physiology, Tianjin Medical University, Tianjin, 300070, People's Republic of China.
Pharm Res. 2015 Dec;32(12):3837-49. doi: 10.1007/s11095-015-1744-9. Epub 2015 Jun 26.
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).
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.
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.
The H102-loaded liposome prepared in this study for nasal administration is stable, effective and safe, which has great potential for AD treatment.
将新型β-折叠破坏肽H102包裹于脂质体中，以减少其降解，并通过鼻腔给药增加其脑内渗透，用于治疗阿尔茨海默病（AD）。
采用改良薄膜水化法制备H102脂质体，并在Calu-3细胞单层上测试其转运特性。还研究了其在大鼠血液和脑中的药代动力学。进行行为实验以评估对AD大鼠空间记忆损伤的改善情况。通过检测乙酰胆碱酯酶（AchE）、胆碱乙酰转移酶（ChAT）和胰岛素降解酶（IDE）活性并进行组织学分析来测试神经保护作用。对大鼠鼻黏膜和纤毛进行安全性评估。
制备的脂质体能够持续穿透Calu-3细胞单层。鼻腔给药后，H102能够有效递送至脑内，H102脂质体在海马体中的AUC比溶液组大2.92倍。与H102鼻腔溶液相比，即使在较低剂量下，H102脂质体也能显著改善AD模型大鼠的空间记忆损伤，增加ChAT和IDE的活性并抑制斑块沉积。H102鼻腔制剂对鼻黏膜无毒性。
本研究制备的用于鼻腔给药的载H102脂质体稳定、有效且安全，在AD治疗方面具有巨大潜力。
