期刊
BIOMATERIALS
卷 275, 期 -, 页码 -出版社
ELSEVIER SCI LTD
DOI: 10.1016/j.biomaterials.2021.120942
关键词
Blood-brain barrier; Drug delivery; Peptide; Melittin; Tissue engineering
资金
- NIH/NINDS [R01NS106008, R01NS09111, R01NS102675]
- DTRA [HDTRA1-15-1-0046]
- NSF [DMR 1709892]
- National Science Foundation [DGE1746891]
- Kirschstein-NRSA Individual Predoctoral Fellowship (F31) [NINDS 1F31NS101875]
- Nanotechnology for Cancer Research training program
Melittin, a membrane active peptide found in bee venom, enables transient blood-brain barrier opening for delivery of therapeutics into the brain. Studies on endothelial and neuronal viability identified the effective concentration range for BBB opening, and a tissue-engineered model was used to optimize dosing and understand the mechanism. Melittin and other membrane active variants increase paracellular permeability temporarily by disrupting cell-cell junctions.
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. Here, we demonstrate that melittin, a membrane active peptide present in bee venom, supports transient BBBO. From endothelial and neuronal viability studies, we first 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 that result in transient focal leaks. To validate the results from the tissue-engineered model, we then demonstrate that transient BBBO can be reproduced in a mouse model. We identify a minimum clinically effective intra-arterial dose of 3 mu M min melittin, which is reversible within one day and neurologically safe. Melittin-induced BBBO represents a novel technology for delivery of therapeutics into the brain.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据