Nanoparticle localization in blood vessels: the effect of vascular flow

Assessment of nanoparticle distribution in the vasculature is important for determining drug delivery, molecular imaging efficacy, and risk profiles. Even though most medical nanoparticle applications require a vascular... [ view full abstract ]

Assessment of nanoparticle distribution in the vasculature is important for determining drug delivery, molecular imaging efficacy, and risk profiles. Even though most medical nanoparticle applications require a vascular administration, factors affecting nanoparticle association with vessel walls in the presence of fluid forces are poorly understood. We evaluated the effect of fluid flow on the distribution of 200 nm carboxylate-coated polystyrene nanoparticles in flow-exposed endothelial cell cultures and zebrafish embryos. We used a unique approach combining confocal imaging of nanoparticle injected transgenic zebrafish, 3D modeling, and computational fluid dynamics to assess nanoparticle distribution under flow. In the caudal zebrafish, lower nanoparticle accumulation was found in the arteries (average blood flow velocity 832±293 µm/s (n=12)) than veins (535±176 µm/s (n=24)). Highest nanoparticle localization occurred in regions of disturbed flow and large shear stress gradients found at branch points and downstream of bumps and curves in the vein segment. To further investigate the effect of shear stress magnitude and flow disturbance, we used sudden expansion flow chambers to expose human endothelial cells to nanoparticles under conditions typically found in human arteries, veins, and regions of flow disturbance. We found that cell association with nanoparticles increased with shear stress up to 2 dyn/cm2, above which adhesion dramatically decreased. Disturbed regions had more nanoparticle accumulation than downstream laminar flow regions after 20 hours of flow preconditioning of the endothelial cells. Overall, fluid shear stress magnitude, flow disturbances, and flow-induced changes in endothelial physiology contribute to the vascular localization of nanoparticles.