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Specific Binding, Uptake, and Transport of ICAM-1-Targeted Nanocarriers Across Endothelial and Subendothelial Cell Components of the Blood–Brain Barrier

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ABSTRACT

Purpose

The blood–brain barrier (BBB) represents a target for therapeutic intervention and an obstacle for brain drug delivery. Targeting endocytic receptors on brain endothelial cells (ECs) helps transport drugs and carriers into and across this barrier. While most receptors tested are associated with clathrin-mediated pathways, clathrin-independent routes are rather unexplored. We have examined the potential for one of these pathways, cell adhesion molecule (CAM)-mediated endocytosis induced by targeting intercellular adhesion molecule -1 (ICAM-1), to transport drug carriers into and across BBB models.

Methods

Model polymer nanocarriers (NCs) coated with control IgG or antibodies against ICAM-1 (IgG NCs vs. anti-ICAM NCs; ~250-nm) were incubated with human brain ECs, astrocytes (ACs), or pericytes (PCs) grown as monocultures or bilayered (endothelial+subendothelial) co-cultures.

Results

ICAM-1 was present and overexpressed in disease-like conditions on ECs and, at a lesser extent, on ACs and PCs which are BBB subendothelial components. Specific targeting and CAM-mediated uptake of anti-ICAM NCs occurred in these cells, although this was greater for ECs. Anti-ICAM NCs were transported across endothelial monolayers and endothelial+subendothelial co-cultures modeling the BBB.

Conclusions

CAM-mediated transport induced by ICAM-1 targeting operates in endothelial and subendothelial cellular components of the BBB, which may provide an avenue to overcome this barrier.

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Abbreviations

ACs:

Human astrocytes

ECs:

Human brain microvascular endothelial cells

EIPA:

5-(N-ethyl-N-isopropyl)amiloride

FITC:

Fluorescein isothiocyanate

ICAM-1:

Intercellular adhesion molecule-1

IgG:

Immunoglobulin G

MDC:

Monodansylcadaverine

NC:

Nanocarrier

PCs:

Human brain vascular pericytes

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ACKNOWLEDGMENTS And Disclosures

This work was supported by NIH grant R01-HL09816 (S.M.).

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Authors and Affiliations

  1. Fischell Department of Bioengineering, University of Maryland College Park, Maryland, USA

    Janet Hsu, Jeff Rappaport & Silvia Muro

  2. Institute for Biosciences and Biotechnology Research, University of Maryland College Park, 5115 Plant Sciences Building, College Park, Maryland, 20742-4450, USA

    Silvia Muro

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  1. Janet Hsu
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  2. Jeff Rappaport
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  3. Silvia Muro
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Correspondence to Silvia Muro.

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Hsu, J., Rappaport, J. & Muro, S. Specific Binding, Uptake, and Transport of ICAM-1-Targeted Nanocarriers Across Endothelial and Subendothelial Cell Components of the Blood–Brain Barrier. Pharm Res 31, 1855–1866 (2014). https://doi.org/10.1007/s11095-013-1289-8

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