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Cited by 123Barrier Structure and Function StudiesNanoparticle-Based Drug DeliveryDrug Transport and Resistance Mechanisms

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

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Kucharz, Krzysztof, Kristensen, Kasper, Johnsen, Kasper Bendix, Lund, Mette Aagaard, Lønstrup, Micael, Moos, Torben, Andresen, Thomas Lars, Lauritzen, Martin Johannes·2021·Nature Communications
DOI 10.1038/s41467-021-24323-1PMC PMC8257611
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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.

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Cited by

Sorted by citations

Authors
Kucharz, K., Kristensen, K., Johnsen, K. B., Lund, M. A., Lønstrup, M., Moos, T., Andresen, T. L., & Lauritzen, M. J.
Affiliations
  • University of Copenhagen (DK)
  • Technical University of Denmark (DK)
  • Aalborg University (DK)
Corresponding author
  • Kucharz, Krzysztof
  • Lauritzen, Martin Johannes
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2021-07-05
Volume
12
Issue
1
Pages
4121-4121
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-021-24323-1
PMC
PMC8257611
OpenAlex
W3182913217
Cited by
123
References
9
Citations by year
2026: 24 · 2025: 26 · 2024: 16 · 2023: 26 · 2022: 24 · 2021: 6 · 2020: 1
FWCI
7.21
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • VBN Forskningsportal (Aalborg Universitet) (publishedVersion, cc-by)
  • Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, cc-by)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Technical University of Denmark, DTU Orbit (Technical University of Denmark, DTU) (submittedVersion, other-oa)
Funders
  • Lundbeckfonden (#R392-2018-2266)
  • Det Frie Forskningsråd (#0602-01965B)
  • Nordea-fonden (#114995)
Topics
  • Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
  • Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
  • Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
Keywords
postcapillary venules, blood-brain barrier, transcytosis, nanoparticle drug delivery, transferrin receptor, nanoliposomes, endothelium, perivascular spaces, capillaries, arterioles, neurodegenerative diseases
MeSH terms
Animals, Arterioles, Biological Transport, Blood-Brain Barrier, Brain, Capillaries, Drug Carriers, Endothelium, Kinetics, Liposomes, Receptors, Transferrin, Venules, Mice, Nanoparticles, Transcytosis

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