Nanoparticle localization in blood vessels: dependence on fluid shear stress, flow disturbances, and flow-induced changes in endothelial physiology.

Nanoparticles in the bloodstream are subjected to complex fluid forces as they move through the curves and branches of healthy or tumor vasculature. While nanoparticles are known to preferentially accumulate in angiogenic vessels, little is known about the flow conditions in these vessels and how these conditions may influence localization. Here, we report a methodology which combines confocal imaging of nanoparticle-injected transgenic zebrafish embryos, 3D modeling of the vasculature, particle mapping, and computational fluid dynamics, to quantitatively assess the effects of fluid forces on nanoparticle distribution in vivo. Six-fold lower accumulation was found in zebrafish arteries compared to the lower velocity veins. Nanoparticle localization varied inversely with shear stress. Highest accumulation was present in regions of disturbed flow found at branch points and curvatures in the vasculature. To further investigate cell-particle association under flow, human endothelial cells were exposed to nanoparticles under hemodynamic conditions typically found in human vessels. Physiological adaptations of endothelial cells to 20 hours of flow enhanced nanoparticle accumulation in regions of disturbed flow. Overall our results suggest that fluid shear stress magnitude, flow disturbances, and flow-induced changes in endothelial physiology modulate nanoparticle localization in angiogenic vessels.