| Autor: |
Kalina Hristova, Chengyan Chu, Peter C. Searson, Raleigh M. Linville, Alexander Komin, Jackson G. DeStefano, Xiaoyan Lan, Guanshu Liu, Piotr Walczak |
| Rok vydání: |
2021 |
| Předmět: |
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| DOI: |
10.1101/2021.02.09.430012 |
| Popis: |
The blood-brain barrier (BBB) tightly controls entry of molecules and cells into the brain, restricting the delivery of therapeutics. Blood-brain barrier opening (BBBO) utilizes reversible disruption of cell-cell junctions between brain microvascular endothelial cells to enable transient entry into the brain. Development of BBBO techniques has been hindered by a lack of physiological models for in vitro study. Here, we utilize an in vitro tissue-engineered microvessel model to demonstrate that melittin, a membrane active peptide present in bee venom, supports BBBO. From endothelial and neuronal viability studies, we identify the accessible concentration range for BBBO. We then use a tissue-engineered model of the human BBB to optimize dosing and elucidate the mechanism of opening. Melittin and other membrane active variants transiently increase paracellular permeability via disruption of cell-cell junctions. In mice, we demonstrate a minimum clinically effective intra-arterial dose of 3 μM·min melittin, which is reversible within one day and neurologically safe. Melittin-induced BBBO represents a novel platform for delivery of therapeutics into the brain. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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