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

Jui-Hsien Chang,Chris Greene,Karen Frudd,Leonardo Araujo Dos Santos,Clare Futter,Benjamin J Nichols,Matthew Campbell,Patric Turowski

doi:10.1016/j.xcrm.2021.100497

Jui-Hsien Chang, Chris Greene + Show 6 more

Open Access

https://doi.org/10.1016/j.xcrm.2021.100497

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Abstract

SummaryThe 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.

Highlights

The CNS is highly vascularized such that the disproportional metabolic demand associated with neuronal activity is fully met.[1]
The blood-brain barrier (BBB) is embedded within the neurovascular unit (NVU), comprising vascular endothelial cells, pericytes, astrocytes, and neurons, all of which cooperate tightly to establish and regulate the BBB, both during development and its postnatal maintenance.[1]
To enable the entry of nutrients to the CNS, BBB endothelial cells express an array of substrate-specific proteins, which either feed into substrate-specific vesicular transport systems or form highly specific channels or membrane transporters.[4]

Summary

Introduction

The CNS is highly vascularized such that the disproportional metabolic demand associated with neuronal activity is fully met.[1] While meeting the metabolic demands of the CNS, its vasculature is selectively and dynamically impermeable to protect the delicate ionic neural environment, a feature referred to as the blood-brain barrier (BBB). To enable the entry of nutrients to the CNS, BBB endothelial cells express an array of substrate-specific proteins, which either feed into substrate-specific vesicular transport systems or form highly specific channels or membrane transporters.[4] Small hydrophobic molecules, which may penetrate the NVU, are mostly eliminated by molecular efflux pumps of the ATP-binding cassette transporter family of proteins.[5] the BBB constitutes a major impediment for the delivery of therapeutics to the CNS, and most drugs do not accumulate at therapeutically required levels in the brain.[6,7]

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