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

Jui-Hsien Chang, Chris Greene, Clare Futter, Benjamin J. Nichols, Matthew Campbell, Patric Turowski
doi: https://doi.org/10.1101/2020.05.13.093336
Jui-Hsien Chang
1UCL Institute of Ophthalmology, University College London, London, United Kingdom
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Chris Greene
2Smurfit Institute of Genetics, Trinity College Dublin, Dublin 2, Ireland
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Clare Futter
1UCL Institute of Ophthalmology, University College London, London, United Kingdom
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Benjamin J. Nichols
3MRC Laboratory of Molecular Biology, Cambridge, United Kingdom
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Matthew Campbell
2Smurfit Institute of Genetics, Trinity College Dublin, Dublin 2, Ireland
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Patric Turowski
1UCL Institute of Ophthalmology, University College London, London, United Kingdom
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  • For correspondence: p.turowski@ucl.ac.uk
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Abstract

The blood-brain barrier (BBB) is a multifactorial and multicellular vascular interface separating the systemic environment from the central nervous system (CNS). It gates cerebral penetration of circulating molecules and cells and is the principal reason for low accumulation of many therapeutics in the brain. Low dose methamphetamine (METH) induces fluid phase transcytosis across the BBB in vitro and could therefore be used to enhance CNS drug delivery. Here we show, that low dose intravascular METH induced significant leakage exclusively via caveolar transport at the intact BBB in rodents ex vivo. Notably, METH-induced leakage was suppressed at 4°C and in Caveolin-1 (CAV1) knockout mice. Furthermore, METH strongly enhanced brain penetration of therapeutic molecules, namely doxorubicin (DOX), a small chemotherapeutic agent, and aflibercept (AFL), a ca. 100 kDA recombinant protein. Lastly, METH improved the therapeutic efficacy of DOX in a mouse model of human glioblastoma (GBM), as measured by a 25% increase in median survival time (p = 0.0024). Collectively, our data indicated that METH can facilitate preclinical assessment of novel experimental treatments and has the potential to enhance drug delivery to the diseased CNS.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted May 15, 2020.
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Methamphetamine enhances caveolar transport of therapeutic drugs across the rodent blood-brain barrier
Jui-Hsien Chang, Chris Greene, Clare Futter, Benjamin J. Nichols, Matthew Campbell, Patric Turowski
bioRxiv 2020.05.13.093336; doi: https://doi.org/10.1101/2020.05.13.093336
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Methamphetamine enhances caveolar transport of therapeutic drugs across the rodent blood-brain barrier
Jui-Hsien Chang, Chris Greene, Clare Futter, Benjamin J. Nichols, Matthew Campbell, Patric Turowski
bioRxiv 2020.05.13.093336; doi: https://doi.org/10.1101/2020.05.13.093336

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