Targeting Inflamed Endothelium under High Shear Stress

Cerebral vasospasm, the narrowing of a cerebral artery caused by a persistent contraction of the artery, can result in reduced blood supply to the brain and thus may be lethal. Additionally, narrowing of the vessel leads to local inflammation of the endothelium and results in abnormal high shear stress on the vessel wall. Vascular-targeted carriers (VTCs) may provide a promising approach for localized treatment of cerebral vasospasm. Here, we examine VTCs that can specifically localize at inflamed vessel walls as well as provide effective adhesion under high shear stress and thus can potentially provide targeted delivery to these sites. To test this, carboxylated fluorescent 200 nm polystyrene particles were coated with inflammatory ligands (aICAM-1) or control (BSA) using EDC/sulfo-NHS and avidin/biotin coupling approaches. The functionalized particles were perfused through micro‑fluidic models lined with inflamed endothelial cells, and their adhesion under different relevant shear stresses (10-300 dyne/cm2) was monitored via real-time confocal microscopy. Results of these experiments showed a higher specific adhesion of nanoparticles to inflamed cell at all of the examined shear stresses. Additionally, for the aICAM-1 functionalized nanoparticles the adhesion rate increased with shear stress. Contrary to aICAM-1 nanoparticles, control nanoparticles showed nonspecific adhesion to normal cells and no significant adhesion to inflamed cells. In summary, our results show that functionalized nanoparticles can be designed to target inflamed endothelial cells under the high shear stress. The results can provide a possible avenue for targeting sites of vasospasm.

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