[论文解读] Mathematical modeling of shear-activated targeted nanoparticle drug delivery for the treatment of aortic diseases

Yonghui Qiao, Yan Wang+3 more|arXiv (Cornell University)|May 3, 2021

Electrospun Nanofibers in Biomedical Applications参考文献 23被引用 14

一句话总结

本研究提出一种剪切力激活的靶向纳米颗粒药物递送系统，用于治疗主动脉缩窄和主动脉瘤，采用计算流体动力学方法。将负载有纳米颗粒的微载体注入病变部位上游，其在异常剪切速率（SSR）下被激活：在主动脉缩窄处，高SSR触发药物释放；在主动脉瘤处，低SSR引起微载体塌陷。该方法可实现对病变主动脉壁的靶向药物递送，高扩散系数显著提升表面药物浓度，尤其在主动脉瘤中效果更明显。

ABSTRACT

The human aorta is a high-risk area for vascular diseases, which are commonly restored by thoracic endovascular aortic repair. In this paper, we report a promising shear-activated targeted nanoparticle drug delivery strategy to assist in the treatment of coarctation of the aorta and aortic aneurysm. Idealized three-dimensional geometric models of coarctation of the aorta and aortic aneurysm are designed, respectively. The unique hemodynamic environment of the diseased aorta is used to improve nanoparticle drug delivery. Micro-carriers with nanoparticle drugs would be targeting activated to release nanoparticle drugs by local abnormal shear stress rate (SSR). Coarctation of the aorta provides a high SSR hemodynamic environment, while the aortic aneurysm is exposed to low SSR. We propose a method to calculate the SSR thresholds for the diseased aorta. Results show that the upstream near-wall area of the diseased location is an ideal injection location for the micro-carriers, which could be activated by the abnormal SSR. Released nanoparticle drugs would be successfully targeted delivered to the aortic diseased wall. Besides, the high diffusivity of the micro-carriers and nanoparticle drugs has a significant impact on the surface drug concentrations of the diseased aortic walls, especially for aortic aneurysms. This study preliminary demonstrates the feasibility of shear-activated targeted nanoparticle drug delivery in the treatment of aortic diseases and provides a theoretical basis for developing the drug delivery system and novel therapy.

研究动机与目标

• 评估剪切力激活靶向纳米颗粒递送在治疗主动脉缩窄和主动脉瘤中的可行性。
• 基于血流动力学条件，确定最优微载体注射部位。
• 量化微载体和纳米颗粒扩散系数对病变主动脉壁表面药物浓度的影响。
• 开发一种计算SSR阈值的方法，以触发病变主动脉区域微载体的激活。

提出的方法

• 在SolidWorks中构建了主动脉缩窄（75%狭窄）和主动脉瘤的理想化三维几何模型。
• 采用非结构化四面体网格，并在壁面附近添加棱柱层（y+ < 1），以精确解析剪切应力。
• 使用Carreau-Yasuda非牛顿黏度模型模拟血流，并通过FEniCS求解Navier-Stokes方程。
• 采用带源项的对流-扩散方程模拟微载体和纳米颗粒的传输，实现SSR阈值下的药物释放。
• 定义SSR激活阈值：主动脉缩窄处为高SSR（释放），主动脉瘤处为低SSR（塌陷）。
• 进行了网格独立性测试，并通过壁面剪切应力差异小于2%验证了模型。

实验结果

研究问题

• RQ1 剪切力激活的微载体是否能被主动脉缩窄和主动脉瘤区域的异常SSR有效触发？
• RQ2 微载体的最优注射部位在哪里，以确保仅在病变区域被激活？
• RQ3 微载体和纳米颗粒的扩散系数如何影响主动脉壁表面的药物浓度？
• RQ4 血流动力学环境在通过SSR触发释放实现靶向递送中起什么作用？

主要发现

• 病变部位上游的近壁区域是微载体注射的最优位置，可确保仅在目标区域被激活。
• 在主动脉缩窄中，高扩散系数放大了脉动药物浓度的振荡，提高微载体浓度，同时降低纳米颗粒浓度。
• 在主动脉瘤中，高扩散系数导致纳米颗粒表面浓度持续上升，显著增强最终药物递送效果。
• 独特的血流动力学环境——主动脉缩窄处SSR高，主动脉瘤处SSR低——使微载体能根据疾病类型实现差异性激活。
• 在高扩散系数条件下，主动脉瘤中的表面药物浓度显著升高，表明靶向效率得到提升。
• 在类似模型中，刚性壁面假设合理，因其对壁面剪切应力影响甚微；但未来研究将引入流固耦合分析。