Gomez-Garcia M Juliana, Abdelkarim Mahmoud, Cramb David T, Childs Sarah J, Rinker Kristina D, Labouta Hagar I
Biomedical Engineering, Faculty of Engineering, University of Toronto, Toronto, ON, Canada.
Biomedical Engineering, Schulich School of Engineering, University of Calgary, Calgary, AB, Canada.
Drug Deliv Transl Res. 2024 Dec;14(12):3608-3620. doi: 10.1007/s13346-024-01671-1. Epub 2024 Jul 23.
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 (R > 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.
用于药物递送的纳米颗粒通常需要静脉注射，使其暴露于脉管系统内的流体作用力之下，然而血流对纳米颗粒递送的影响仍未被完全理解。在此，我们利用转基因斑马鱼胚胎，研究荧光标记的聚乙二醇化脂质体在广泛的血管生成血管中的积累与各种血流动力学因素（如流速、壁面剪应力（WSS）和血流模式）之间的关系。我们从共聚焦图像重建血管结构的三维模型，并使用计算流体动力学来计算局部WSS、流速并定义血流模式。随后在同一三维空间内绘制荧光标记脂质体的空间分布，并将其与局部血流动力学参数相关联。通过计算流体动力学与体内实验的结合，我们发现脂质体在壁面剪应力为0.1 - 0.8 Pa的血管区域积累，在体内时间平均壁面剪应力与脂质体定位之间呈现反线性相关性（R > 0.85）。有趣的是，血流模式似乎并未影响脂质体的积累。总体而言，我们的研究结果表明隐形脂质体具有被动靶向低血流脉管系统的潜力，包括毛细血管和类似于肿瘤血管网络的复杂血管生成血管。
