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bioRxiv · 10.1101/2021.02.09.430012

Reversible blood-brain barrier opening utilizing the membrane active peptide melittin in vitro and in vivo

Linville, R. M.·Komin, A.·Lan, X.·DeStefano, J. G.·Chu, C.·Liu, G.·Walczak, P.·Hristova, K.·Searson, P. C.
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Abstract

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 M{middle dot}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.

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Linville, R. M., Komin, A., Lan, X., DeStefano, J. G., Chu, C., Liu, G., Walczak, P., Hristova, K., Searson, P. C.. 2021-02-10. Reversible blood-brain barrier opening utilizing the membrane active peptide melittin in vitro and in vivo. https://doi.org/10.1101/2021.02.09.430012

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