Original articles
Ting Lei, Zhihang Yang, Xue Xia, Yuxiu Chen, Xiaotong Yang, Rou Xie, Fan Tong, Xiaolin Wang, Huile Gao. A nanocleaner specifically penetrates the blood-brain barrier at lesions to clean toxic proteins and regulate inflammation in Alzheimer's disease[J]. Acta Pharmaceutica Sinica B, 2021, 11(12): 4032-4044

A nanocleaner specifically penetrates the blood-brain barrier at lesions to clean toxic proteins and regulate inflammation in Alzheimer's disease
Ting Leia, Zhihang Yanga, Xue Xiaa, Yuxiu Chena, Xiaotong Yanga, Rou Xiea, Fan Tonga, Xiaolin Wangb, Huile Gaoa
a. Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China;
b. School of Pharmacy and State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau 999078, China
Abstract:
Insurmountable blood-brain barrier (BBB) and complex pathological features are the key factors affecting the treatment of Alzheimer's disease (AD). Poor accumulation of drugs in lesion sites and undesired effectiveness of simply reducing Aβ deposition or TAU protein need to be resolved urgently. Herein, a nanocleaner is designed with a rapamycin-loaded ROS-responsive PLGA core and surface modification with KLVFF peptide and acid-cleavable DAG peptide [R@(ox-PLGA)-KcD]. DAG can enhance the targeting and internalization effect of nanocleaner towards neurovascular unit endothelial cells in AD lesions, and subsequently detach from nanocleaner in response to acidic microenvironment of endosomes to promote the transcytosis of nanocleaner from endothelial cells into brain parenchyma. Then exposed KLVFF can capture and carry Aβ to microglia, attenuating Aβ-induced neurotoxicity. Strikingly, rapamycin, an autophagy promoter, is rapidly liberated from nanocleaner in the high ROS level of lesions to improve Aβ degradation and normalize inflammatory condition. This design altogether accelerates Aβ degradation and alleviates oxidative stress and excessive inflammatory response. Collectively, our finding offers a strategy to target the AD lesions precisely and multi-pronged therapies for clearing the toxic proteins and modulating lesion microenvironment, to achieve efficient AD therapy.
Key words:    Alzheimer's disease    Aβ-capturing    Autophagy    ROS-responsive    Anti-inflammatory    Blood-brain barrier transcytosis    Microenvironment modulation    Lesion targeting   
Received: 2021-02-21     Revised: 2021-03-29
DOI: 10.1016/j.apsb.2021.04.022
Funds: The work was supported by National Natural Science Foundation of China (No. 81872806), 111 Project (No. B18035, China) and the Fundamental of Research Funds for the Central University (China). Macau Science and Technology Development Foundation (No. FDCT 0009/2019/A, China). The authors also acknowledge the technical support from Chenghui Li in Analytical & Testing Center, Sichuan University, China.
Corresponding author: Huile Gao,E-mail:gaohuilescu@163.com     Email:gaohuilescu@163.com
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Ting Lei
Zhihang Yang
Xue Xia
Yuxiu Chen
Xiaotong Yang
Rou Xie
Fan Tong
Xiaolin Wang
Huile Gao

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