Transferrin-Modified Osthole PEGylated Liposomes Travel the Blood-Brain Barrier and Mitigate Alzheimer's Disease-Related Pathology in APP/PS- I Mice
Transferrin-Modified Osthole PEGylated Liposomes Travel the Blood-Brain Barrier and Mitigate Alzheimer's Disease-Related Pathology in APP/PS- I Mice
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DOI：
10.2147/ijn.s239608
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发表时间：
2020-01-01
影响因子：
8
通讯作者：
Cheng, Lan
中科院分区：
文献类型：
--
作者：
Kong, Liang;Li, Xue-tao;Cheng, Lan
简介：蛇床子素（Ost）是一种香豆素化合物，可增强小鼠海马神经元和神经干细胞对A β寡聚体诱导的神经毒性的抵抗能力，是治疗阿尔茨海默病（AD）的潜在药物。然而，药物的有效性受到其溶解度和生物利用度以及血脑屏障（BBB）低渗透性的限制。本研究以转铁蛋白修饰的Ost脂质体（Tf-Ost-Lip）为研究对象，采用薄膜水化法制备Tf-Ost-Lip。使用体外BBB模型研究脂质体制剂易位穿过BBB的能力。以APP-SH-SY 5 Y细胞为模型，观察Tf-Ost-Lip对APP-SH-SY 5 Y细胞的保护作用。此外，我们还进行了脂质体制剂的体内药代动力学研究和脑组织分布分析。结果：Tf-Ost-Lip能增加hCMEC/D3细胞和APP-SH-SY 5 Y细胞的细胞内摄取，并能增加药物在血脑屏障中的浓度。此外，发现Tf-Ost-Lip对APP-SH-SY 5 Y细胞发挥保护作用。体内药代动力学和脑组织中Ost分布的研究表明，Tf-Ost-Lip延长了小鼠的循环时间，并增加了脑中Ost的蓄积。结论：转铁蛋白修饰的脂质体具有治疗AD的潜力。
Introduction: Osthole (Ost) is a coumarin compound that strengthens hippocampal neurons and neural stem cells against A beta oligomer-induced neurotoxicity in mice, and is a potential drug for the treatment of Alzheimer's disease (AD). However, the effectiveness of the drug is limited by its solubility and bioavailability, as well as by the low permeability of the blood-brain barrier (BBB). In this study, a kind of transferrin-modified Ost liposomes (Tf-Ost-Lip) was constructed, which could improve the bioavailability and enhance brain targeting.Methods: Tf-Ost-Lip was prepared by thin-film hydration method. The ability of liposomal formulations to translocate across BBB was investigated using in vitro BBB model. And the protective effect of Tf-Ost-Lip was evaluated in APP-SH-SY5Y cells. In addition, we performed pharmacokinetics study and brain tissue distribution analysis of liposomal formulations in vivo. We also observed the neuroprotective effect of the varying formulations in APP/PS-1 mice.Results: In vitro studies reveal that Tf-Ost-Lip could increase the intracellular uptake of hCMEC/D3 cells and APP-SH-SY5Y cells, and increase the drug concentration across the BBB. Additionally, Tf-Ost-Lip was found to exert a protective effect on APP-SH-SY5Y cells. In vivo studies of pharmacokinetics and the Ost distribution in brain tissue indicate that Tf-Ost-Lip prolonged the cycle time in mice and increased the accumulation of Ost in the brain. Furthermore, Tf-Ost-Lip was also found to enhance the effect of Ost on the alleviation of Alzheimer's disease-related pathology.Conclusion: Transferrin-modified liposomes for delivery of Ost has great potential for AD treatment.