Size-Selective Transfer of Lipid Nanoparticle-Based Drug Carriers Across the Blood Brain Barrier Via Vascular Occlusions Following Traumatic Brain Injury

Igor Khalin, Nagappanpillai Adarsh, Martina Schifferer, Antonia Wehn, Bernhard Groschup, Thomas Misgeld, Andrey Klymchenko, Nikolaus Plesnila

Research output: Contribution to journalArticlepeer-review

18 Scopus citations

Abstract

The current lack of understanding about how nanocarriers cross the blood-brain barrier (BBB) in the healthy and injured brain is hindering the clinical translation of nanoscale brain-targeted drug-delivery systems. Here, the bio-distribution of lipid nano-emulsion droplets (LNDs) of two sizes (30 and 80 nm) in the mouse brain after traumatic brain injury (TBI) is investigated. The highly fluorescent LNDs are prepared by loading them with octadecyl rhodamine B and a bulky hydrophobic counter-ion, tetraphenylborate. Using in vivo two-photon and confocal imaging, the circulation kinetics and bio-distribution of LNDs in the healthy and injured mouse brain are studied. It is found that after TBI, LNDs of both sizes accumulate at vascular occlusions, where specifically 30 nm LNDs extravasate into the brain parenchyma and reach neurons. The vascular occlusions are not associated with bleedings, but instead are surrounded by processes of activated microglia, suggesting a specific opening of the BBB. Finally, correlative light-electron microscopy reveals 30 nm LNDs in endothelial vesicles, while 80 nm particles remain in the vessel lumen, indicating size-selective vesicular transport across the BBB via vascular occlusions. The data suggest that microvascular occlusions serve as “gates” for the transport of nanocarriers across the BBB.

Original languageEnglish
Article number2200302
JournalSmall
Volume18
Issue number18
DOIs
StatePublished - 5 May 2022
Externally publishedYes

Keywords

  • blood-brain barrier
  • brain injury
  • correlative light-electron microscopy
  • drug delivery
  • nanoparticles

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