纳米载体
血脑屏障
载脂蛋白E
化学
体内
药物输送
β淀粉样蛋白
药理学
脂质体
药物输送到大脑
生物物理学
LRP1型
体内分布
细胞生物学
体外
脂蛋白
生物化学
胆固醇
生物
医学
中枢神经系统
病理
神经科学
低密度脂蛋白受体
肽
有机化学
生物技术
疾病
作者
Qingxiang Song,Huahua Song,Jianrong Xu,Jialin Huang,Hu Meng,Xiao Gu,Juan Chen,Gang Zheng,Hongzhuan Chen,Xiaoling Gao
标识
DOI:10.1021/acs.molpharmaceut.6b00781
摘要
Amyloid beta (Aβ) and its aggregation forms in the brain have been suggested as key targets for the therapy of Alzheimer's disease (AD). Therefore, the development of nanocarriers that possess both blood–brain barrier permeability and Aβ-targeting ability is of great importance for the intervention of AD. Here we constructed a biomimetic nanocarrier named apolipoprotein E (ApoE)-reconstituted high density lipoprotein nanocarrier (ANC) from recombinant ApoE and synthetic lipids to achieve the above goals. α-Mangostin (α-M), a polyphenolic agent that can inhibit the formation of Aβ oligomers and fibrils and accelerate Aβ cellular degradation, was used as the model drug. Compared with the control liposome, ANC demonstrated about 54-fold higher cellular uptake in brain endothelial cell line in vitro in an ApoE-dependent manner and much higher brain delivery efficiency in vivo. Confocal microscopy analysis witnessed the penetration of ANC across the brain vessels and its accumulation at the surrounding of Aβ aggregates. Following the loading of α-M, the Aβ-binding affinity of the nanoformulation (ANC-α-M) was not reduced but even enhanced. The effect of ANC-α-M on facilitating the microglia-mediated uptake and degradation of Aβ1–42 was enhanced by 336% and 29-fold when compared with that of the nontreated control and also much higher than that of ANC. Following intravenous administration for 2 to 4 weeks, ANC-α-M exhibited the most efficient efficacy in decreasing amyloid deposition, attenuating microgliosis, and rescuing memory defect in SAMP8 mice, an AD mouse model. Taken together, the findings of this work provided strong evidence that the ApoE-based biomimetic nanocarrier could provide a promising platform for brain drug delivery toward the treatment of AD.
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