期刊
ACS NANO
卷 14, 期 6, 页码 6729-6742出版社
AMER CHEMICAL SOC
DOI: 10.1021/acsnano.9b09991
关键词
blood-brain barrier; polymeric micelle; glucose transporter-1; Alzheimer's disease; amyloid beta; anti-A beta antibody
类别
资金
- JSPS KAKENHI from the Ministry of Education, Culture, Sports, Science, and Technology (MEXT) of Japan [18K14100, 25000006]
- Center of Innovation (COI) Program from the Japan Science and Technology Agency (JST)
- Strategic Research Program for Brain Sciences from Japan Agency for Medical Research and Development (AMED)
- Japan Society for the Promotion of Science (JSPS) [P16357]
- Nanotechnology Platform of the Ministry of Education, Culture, Sports, Science and Technology (MEXT)
- Grants-in-Aid for Scientific Research [25000006, 18K14100] Funding Source: KAKEN
Delivering therapeutic antibodies into the brain across the blood-brain barrier at a therapeutic level is a promising while challenging approach in the treatment of neurological disorders. Here, we present a polymeric nanomicelle (PM) system capable of delivering therapeutically effective levels of 3D6 antibody fragments (3D6-Fab) into the brain parenchyma for inhibiting A beta aggregation. PM assembly was achieved by charge-converting 3D6-Fab through pH-sensitive citraconylation to allow complexation with reductive-sensitive cationic polymers. Brain targeting was achieved by functionalizing the PM surface with glucose molecules to allow interaction with recycling glucose transporter (Glut)-1 proteins. Consequently, 41-fold enhanced 3D6-Fab accumulation in the brain was achieved by using the PM system compared to free 3D6-Fab. Furthermore, therapeutic benefits were obtained by successfully inhibiting A beta(1-42) aggregation in Alzheimer's disease mice systemically treated with 3D6-Fab-loaded glucosylated PM. Hence, this nanocarrier system represents a promising method for effectively delivering functional antibody agents into the brain and treating neurological diseases.
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