Endo/Lysosome-Escapable Delivery Depot for Improving BBB Transcytosis and Neuron Targeted Therapy of Alzheimer's Disease
Endo/Lysosome-Escapable Delivery Depot for Improving BBB Transcytosis and Neuron Targeted Therapy of Alzheimer's Disease
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Endo/溶酶体逃逸递送库可改善 BBB 转胞吞作用和阿尔茨海默病的神经元靶向治疗
DOI：
10.1002/adfm.201909999
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发表时间：
2020-05-15
影响因子：
19
通讯作者：
Gao, Huile
中科院分区：
文献类型：
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作者：
Cai, Lulu;Yang, Chuanyao;Gao, Huile
阿尔茨海默病（Alzheimer's disease，AD）的有效治疗由于血脑屏障（blood-brain barrier，BBB）难以穿透和药物在脑内的非选择性分布而受到阻碍。此外，AD复杂的病理机制涉及多种途径功能障碍，限制了单一治疗药物的有效性。在本文中，设计了基于树枝状移植物聚-I-赖氨酸（DGL）的siRNA和D肽（Dp）负载的纳米颗粒，其可以靶向并穿透BBB，进入脑实质，并进一步在AD病变处积累。在该系统中，特异性靶向BBB上的转铁蛋白受体的T7肽通过酸可裂解的长聚乙二醇（PEG）与DGL连接，以实现高度内化、快速逃离内/溶酶体和有效的转胞吞作用。然后，特异性靶向患病神经元的Tet 1通过短PEG修饰到DGL上。暴露后，Tet 1可以驱动纳米颗粒到达AD病变并释放药物。因此，β淀粉样蛋白斑块（A β）的产生受到抑制。A β斑块和tau蛋白磷酸化（p-tau）缠结诱导的神经毒性也得到减轻，AD小鼠的认知能力得到显著改善。总的来说，该系统以编程方式靶向BBB和神经元，因此显著增强了脑内药物积累和AD治疗功效。
The effective treatment of Alzheimer's disease (AD) is hindered due to the hard blood-brain barrier (BBB) penetration and non-selective distribution of drugs in the brain. Moreover, the complicated pathological mechanism of AD involves various pathway dysfunctions that limit the effectiveness of a single therapeutic drug. Herein, a dendrigraft poly-l-lysines (DGL)-based siRNA and D peptide (Dp) loaded nanoparticle is designed that could target and penetrate through the BBB, enter the brain parenchyma, and further accumulate at the AD lesion. In this system, T7 peptide, which specifically targets transferrin receptors on the BBB, is linked to DGL via acid-cleavable long polyethylene glycol (PEG) to achieve high internalization, quick escape from endo/lysosome, and effective transcytosis. Then, the Tet1, which specifically targets diseased neurons, is modified onto DGL by short PEG. After being exposed, Tet1 could drive the nanoparticles to the AD lesion and release the drugs. As a result, the production of beta amyloid plaques (A beta) is inhibited. Neurotoxicity induced by A beta plaques and tau proten phosphorylation (p-tau) tangle is also alleviated, and the cognition of AD mice is significantly improved. Overall, this system programmatically targets BBB and neurons, thus, significantly enhances the intracephalic drug accumulation and AD treatment efficacy.