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

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...

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Bibliographic Details
Published in:	Nature communications Vol. 12; no. 1; pp. 4121 - 17
Main Authors:	Kucharz, Krzysztof, Kristensen, Kasper, Johnsen, Kasper Bendix, Lund, Mette Aagaard, Lønstrup, Micael, Moos, Torben, Andresen, Thomas Lars, Lauritzen, Martin Johannes
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 05-07-2021 Nature Publishing Group Nature Portfolio
Subjects:	13/1 14/35 14/69 631/1647/245/2225 631/378/1341 631/443/592 631/61/350/354 639/925/352 64/60 96/34 Animals Arterioles Biological Transport Blood-Brain Barrier Brain - metabolism Capillaries Capillaries - metabolism Capillaries - pathology Drug Carriers Drug delivery Endothelium Endothelium - diagnostic imaging Endothelium - pathology Humanities and Social Sciences Kinetics Liposomes - metabolism Mice Microscopy multidisciplinary Nanoparticles Nanoparticles - therapeutic use Neurodegenerative diseases Photons Receptors Receptors, Transferrin - metabolism Science Science (multidisciplinary) Transcytosis - physiology Transferrin Translation Venules - metabolism Venules - pathology
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Summary:	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. Limited understanding of the interactions between nanoparticle drug carriers and the blood-brain barrier underlies many translational failures in treatments of brain disorders. Here the authors use two-photon microscopy in mice to characterize the receptor-mediated transcytosis of nanoparticles at all steps of delivery from the blood to the brain in vivo.
ISSN:	2041-1723 2041-1723
DOI:	10.1038/s41467-021-24323-1