Dual-Sensitive Nanomicelles Enhancing Systemic Delivery of Therapeutically Active Antibodies Specifically into the Brain
| Autor: | Kazuko Toh, Tao Yang, Zengtao Wang, Shigeto Fukushima, Junjie Li, Takanori Yokota, Kazunori Kataoka, Yonger Xue, Sabina Quader, Anjaneyulu Dirisala, Xueying Liu, Jinbing Xie, Nakamura Noriko, Kouhei Tsumoto, Yasutaka Anraku, Makoto Nakakido, Daniel Gonzalez-Carter, Hiroki Akiba, Theofilus A. Tockary |
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| Rok vydání: | 2020 |
| Předmět: |
Amyloid beta
General Physics and Astronomy Mice Transgenic 02 engineering and technology Pharmacology 010402 general chemistry Blood–brain barrier 01 natural sciences Antibody fragments Mice Alzheimer Disease Parenchyma medicine Animals General Materials Science Amyloid beta-Peptides biology Chemistry General Engineering Glucose transporter Brain 021001 nanoscience & nanotechnology 0104 chemical sciences Brain targeting medicine.anatomical_structure Blood-Brain Barrier biology.protein Nanocarriers Antibody 0210 nano-technology |
| Zdroj: | ACS Nano. 14:6729-6742 |
| ISSN: | 1936-086X 1936-0851 |
| DOI: | 10.1021/acsnano.9b09991 |
| Popis: | 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 Aβ 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 Aβ1-42 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. |
| Databáze: | OpenAIRE |
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