Post-capillary venules are the key locus for transcytosis-mediated brain delivery of therapeutic nanoparticles

Krzysztof Kucharz, Kasper Kristensen, Kasper Bendix Johnsen, Mette Aagaard Lund, Micael Lønstrup, Torben Moos, Thomas Lars Andresen, Martin Johannes Lauritzen

Abstract

Effective treatments of neurodegenerative diseases require drugs to be actively transported across the blood-brain barrier (BBB). However, nanoparticle drug carriers explored for this purpose show negligible brain uptake, and the lack of basic understanding of nanoparticle-BBB interactions underlies many translational failures. Here, using two-photon microscopy in mice, we characterize the receptor-mediated transcytosis of nanoparticles at all steps of delivery to the brain in vivo. We show that transferrin receptor-targeted liposome nanoparticles are sequestered by the endothelium at capillaries and venules, but not at arterioles. The nanoparticles move unobstructed within endothelium, but transcytosis-mediated brain entry occurs mainly at post-capillary venules, and is negligible in capillaries. The vascular location of nanoparticle brain entry corresponds to the presence of perivascular space, which facilitates nanoparticle movement after transcytosis. Thus, post-capillary venules are the point-of-least resistance at the BBB, and compared to capillaries, provide a more feasible route for nanoparticle drug carriers into the brain.

OriginalsprogEngelsk
Artikelnummer4121
TidsskriftNature Communications
Vol/bind12
Udgave nummer1
Sider (fra-til)4121
Antal sider17
ISSN2041-1722
DOI
StatusUdgivet - 5 jul. 2021

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