Combining Multifunctional Delivery System with Blood–Brain Barrier Reversible Opening Strategy for the Enhanced Treatment of Alzheimer's Disease

Author:

Ke Jia12,Yu Caini3,Li Sufen3,Hong Yiling3,Xu Yichong3,Wang Kai3,Meng Tingting3,Ping Yuan3,Fu Qiang2ORCID,Yuan Hong34,Hu Fuqiang34ORCID

Affiliation:

1. Liangzhu Laboratory Zhejiang University Medical Center Hangzhou 311121 China

2. Wuya College of Innovation Shenyang Pharmaceutical University Shenyang 110016 China

3. College of Pharmaceutical Science Zhejiang University Hangzhou 310058 China

4. Jinhua Institute of Zhejiang University Jinhua 321299 China

Abstract

AbstractAlzheimer's disease (AD) is a neurodegenerative illness characterized by intracellular tau‐phosphorylation, β‐amyloid (Aβ) plaques accumulation, neuroinflammation, and impaired behavioral ability. Owing to the lack of effective brain delivery approaches and the presence of the blood–brain barrier (BBB), current AD therapeutic endeavors are severely limited. Herein, a multifunctional delivery system (RVG‐DDQ/PDP@siBACE1) is elaborately combined with a protein kinase B (AKT) agonist (SC79) for facilitating RVG‐DDQ/PDP@siBACE1 to target and penetrate BBB, enter brain parenchyma, and further accumulate in AD brain lesion. Moreover, compared with the unitary dose of RVG‐DDQ/PDP@siBACE1, this collaborative therapy strategy exhibits a distinctive synergistic function including scavenging reactive oxygen species (ROS), decreasing of Aβ production, alleviating neuroinflammation by promoting the polarized microglia into the anti‐inflammatory M2‐like phenotype and significantly enhancing the cognitive functions of AD mice. More strikingly, according to these results, an innovative signaling pathway “lncRNA MALAT1/miR‐181c/BCL2L11” is found that can mediate the neuronal apoptosis of AD. Taken together, combining the brain targeted delivery system with noninvasive BBB opening can provide a promising strategy and platform for targeting treatment of AD and other neurodegenerative diseases.

Funder

Natural Science Foundation of Zhejiang Province

National Natural Science Foundation of China

Publisher

Wiley

Subject

Pharmaceutical Science,Biomedical Engineering,Biomaterials

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