Systemic Brain Delivery of Antisense Oligonucleotides across the Blood–Brain Barrier with a Glucose‐Coated Polymeric Nanocarrier
| Autor: | Kotaro Hayashi, Yasutaka Anraku, Hyun Jin Kim, Mitsuru Naito, Shigeto Fukushima, Satomi Ogura, Kazuko Toh, Kanjiro Miyata, Beob Soo Kim, Kazunori Kataoka, Hyun Su Min |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
Polymers
micelles Central nervous system Pharmacology blood–brain barrier 010402 general chemistry Blood–brain barrier 01 natural sciences Catalysis Mice Cell Line Tumor medicine Animals Humans Drug Delivery | Hot Paper Particle Size Research Articles Fluorescent Dyes Drug Carriers Gene knockdown 010405 organic chemistry Chemistry Brain RNA self-assembly General Medicine General Chemistry Oligonucleotides Antisense Nanostructures 0104 chemical sciences Glucose medicine.anatomical_structure Blood-Brain Barrier Cerebral cortex drug delivery Antisense oligonucleotides Drug delivery RNA Long Noncoding antisense oligonucleotides Nanocarriers Research Article |
| Zdroj: | Angewandte Chemie (International Ed. in English) |
| ISSN: | 1521-3773 1433-7851 |
| DOI: | 10.1002/anie.201914751 |
| Popis: | Current antisense oligonucleotide (ASO) therapies for the treatment of central nervous system (CNS) disorders are performed through invasive administration, thereby placing a major burden on patients. To alleviate this burden, we herein report systemic ASO delivery to the brain by crossing the blood–brain barrier using glycemic control as an external trigger. Glucose‐coated polymeric nanocarriers, which can be bound by glucose transporter‐1 expressed on the brain capillary endothelial cells, are designed for stable encapsulation of ASOs, with a particle size of about 45 nm and an adequate glucose‐ligand density. The optimized nanocarrier efficiently accumulates in the brain tissue 1 h after intravenous administration and exhibits significant knockdown of a target long non‐coding RNA in various brain regions, including the cerebral cortex and hippocampus. These results demonstrate that the glucose‐modified polymeric nanocarriers enable noninvasive ASO administration to the brain for the treatment of CNS disorders. The sweet spot: Antisense‐oligonucleotide‐loaded glucosylated‐polyion‐complex micelles can be used for RNA knockdown in various brain regions using blood‐glucose level as an external trigger. Glucose transporter‐1 expressed on the brain capillary endothelial cells binds the glucose‐coated nanocarrier and transports it, along with its cargo, across the blood–brain barrier. This could be used for the treatment of disorders of the central nervous system. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Plný text