A filter-free blood-brain barrier model to quantitatively study transendothelial delivery of nanoparticles by fluorescence spectroscopy

Edwin De Jong, David S. Williams, Loai K.E.A. Abdelmohsen, Jan C.M. van Hest, Inge S. Zuhorn

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

The delivery of therapeutics to the brain is greatly hampered by the blood-brain barrier (BBB). The use of nanoparticles that can cross the BBB via the process of receptor-mediated transcytosis at blood-brain barrier endothelial cells seems a promising strategy to transport therapeutics into the brain. To screen for suitable nanocarriers, and to study the process of transcytosis, a cultured polarized monolayer of brain microvascular endothelial cells on an extracellular matrix-coated porous membrane filter is widely used as an in vitro BBB model. However, due to the adhesion of numerous types of nanoparticles to the membrane filter and within the filter pores, such a model is unsuitable for the quantification of transendothelial delivery of nanoparticles. Hence, there is a pressing need for a filter-free in vitro BBB model. Ideally, the model is inexpensive and easy to use, in order to allow for its wide use in nanomedicine and biology laboratories around the world. Here, we developed a filter-free in vitro BBB model that consists of a collagen gel covered with a monolayer of brain microvascular endothelial (hCMEC/D3) cells. The paracellular leakage of differently sized dextrans and the transcellular transport of LDL were measured to demonstrate the validity of the filter-free model. Finally, the transendothelial delivery of fluorescently-labelled PEG-P(CL-g-TMC) polymersomes that were functionalized with GM1-targeting peptides was assessed by fluorescence spectroscopy measurement of the luminal, cellular, and abluminal parts of the filter-free BBB model. Our data confirm the effectiveness of the G23 peptide to mediate transport of polymersomes across the BBB and the suitability of this filter-free in vitro model for quantification of nanoparticle transcytosis.

LanguageEnglish
Pages14-22
Number of pages9
JournalJournal of Controlled Release
Volume289
DOIs
StatePublished - 10 Nov 2018

Fingerprint

Fluorescence Spectrometry
Blood-Brain Barrier
Nanoparticles
Transcytosis
Brain
Endothelial Cells
Nanomedicine
Peptides
Membranes
Dextrans
Extracellular Matrix
Collagen
Gels
In Vitro Techniques
Therapeutics

Keywords

  • Blood-brain barrier
  • Filter-free BBB model
  • G23 peptide
  • Polymersomes
  • Transcytosis

Cite this

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title = "A filter-free blood-brain barrier model to quantitatively study transendothelial delivery of nanoparticles by fluorescence spectroscopy",
abstract = "The delivery of therapeutics to the brain is greatly hampered by the blood-brain barrier (BBB). The use of nanoparticles that can cross the BBB via the process of receptor-mediated transcytosis at blood-brain barrier endothelial cells seems a promising strategy to transport therapeutics into the brain. To screen for suitable nanocarriers, and to study the process of transcytosis, a cultured polarized monolayer of brain microvascular endothelial cells on an extracellular matrix-coated porous membrane filter is widely used as an in vitro BBB model. However, due to the adhesion of numerous types of nanoparticles to the membrane filter and within the filter pores, such a model is unsuitable for the quantification of transendothelial delivery of nanoparticles. Hence, there is a pressing need for a filter-free in vitro BBB model. Ideally, the model is inexpensive and easy to use, in order to allow for its wide use in nanomedicine and biology laboratories around the world. Here, we developed a filter-free in vitro BBB model that consists of a collagen gel covered with a monolayer of brain microvascular endothelial (hCMEC/D3) cells. The paracellular leakage of differently sized dextrans and the transcellular transport of LDL were measured to demonstrate the validity of the filter-free model. Finally, the transendothelial delivery of fluorescently-labelled PEG-P(CL-g-TMC) polymersomes that were functionalized with GM1-targeting peptides was assessed by fluorescence spectroscopy measurement of the luminal, cellular, and abluminal parts of the filter-free BBB model. Our data confirm the effectiveness of the G23 peptide to mediate transport of polymersomes across the BBB and the suitability of this filter-free in vitro model for quantification of nanoparticle transcytosis.",
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A filter-free blood-brain barrier model to quantitatively study transendothelial delivery of nanoparticles by fluorescence spectroscopy. / De Jong, Edwin; Williams, David S.; Abdelmohsen, Loai K.E.A.; van Hest, Jan C.M.; Zuhorn, Inge S.

In: Journal of Controlled Release, Vol. 289, 10.11.2018, p. 14-22.

Research output: Contribution to journalArticleAcademicpeer-review

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AU - De Jong,Edwin

AU - Williams,David S.

AU - Abdelmohsen,Loai K.E.A.

AU - van Hest,Jan C.M.

AU - Zuhorn,Inge S.

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