Blood vessel wall shear stress determines regions of liposome accumulation in angiogenic vasculature.

Abstract

Nanoparticles used for drug delivery often require intravenous administration exposing them to fluid forces within the vasculature, yet the impact of blood flow on nanoparticle delivery remains incompletely understood. Here, we utilized transgenic zebrafish embryos to investigate the relationship between the accumulation of fluorescently labeled PEGylated liposomes and various hemodynamic factors (such as flow velocity, wall shear stress (WSS), and flow pattern) across a wide range of angiogenic blood vessels. We reconstructed 3D models of vascular structures from confocal images and used computational fluid dynamics to calculate local WSS, velocities, and define flow patterns. The spatial distribution of fluorescently labeled liposomes was subsequently mapped within the same 3D space and correlated with local hemodynamic parameters. Through the integration of computational fluid dynamics and in vivo experimentation, we show that liposomes accumulated in vessel regions with WSS between 0.1-0.8 Pa, displaying an inverse linear correlation (R2 > 0.85) between time-averaged wall shear stress and liposome localization in vivo. Interestingly, flow pattern did not appear to impact liposome accumulation. Collectively, our findings suggest the potential of stealth liposomes for passive targeting of low-flow vasculature, including capillaries and intricate angiogenic vasculature resembling that of tumor vessel networks.