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Methamphetamine enhances caveolar transport of therapeutic agents across the rodent blood-brain barrier

Chang, J-H; Greene, C; Frudd, K; Araujo dos Santos, L; Futter, C; Nichols, BJ; Campbell, M; (2022) Methamphetamine enhances caveolar transport of therapeutic agents across the rodent blood-brain barrier. Cell Reports Medicine , 3 (1) , Article 100497. 10.1016/j.xcrm.2021.100497. Green open access

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Abstract

Summary The blood-brain barrier (BBB) restricts clinically relevant accumulation of many therapeutics in the CNS. Low-dose methamphetamine (METH) induces fluid-phase transcytosis across BBB endothelial cells in vitro and could be used to enhance CNS drug delivery. Here, we show that low-dose METH induces significant BBB leakage in rodents ex vivo and in vivo. Notably, METH leaves tight junctions intact and induces transient leakage via caveolar transport, which is suppressed at 4°C and in caveolin-1 (CAV1) knockout mice. METH enhances brain penetration of both small therapeutic molecules, such as doxorubicin (DOX), and large proteins. Lastly, METH improves the therapeutic efficacy of DOX in a mouse model of glioblastoma, as measured by a 25% increase in median survival time and a significant reduction in satellite lesions. Collectively, our data indicate that caveolar transport at the adult BBB is agonist inducible and that METH can enhance drug delivery to the CNS.

Type: Article
Title: Methamphetamine enhances caveolar transport of therapeutic agents across the rodent blood-brain barrier
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.xcrm.2021.100497
Publisher version: https://doi.org/10.1016/j.xcrm.2021.100497
Language: English
Additional information: This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third-party material in this article are included in the Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Ophthalmology
URI: https://discovery.ucl.ac.uk/id/eprint/10142221
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