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 and Martin Johannes Lauritzen ()
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Krzysztof Kucharz: University of Copenhagen
Kasper Kristensen: Technical University of Denmark
Kasper Bendix Johnsen: Technical University of Denmark
Mette Aagaard Lund: Technical University of Denmark
Micael Lønstrup: University of Copenhagen
Torben Moos: Aalborg University
Thomas Lars Andresen: Technical University of Denmark
Martin Johannes Lauritzen: University of Copenhagen

Nature Communications, 2021, vol. 12, issue 1, 1-17

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-24323-1

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