School of Engineering, Deakin University, Waurn Ponds, Geelong, VIC 3216, Australia.
School of Medicine, Deakin University, Geelong, VIC 3220, Australia; Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Deakin University, Geelong, VIC 3220, Australia.
Eur J Pharm Biopharm. 2022 Apr;173:121-131. doi: 10.1016/j.ejpb.2022.03.004. Epub 2022 Mar 10.
The blood-brain barrier (BBB) is a strong barrier against the entrance of drugs, which has made brain cancer treatment a major challenge. We have previously shown that targeting transferrin receptors using aptamers increased brain drug delivery. To get a better understanding of this phenomenon, in the present article, a mathematical model based on the finite element method was developed accounting for the fluid flow and mass transport of the aptamer molecule inside an 8 µm capillary vessel across a 14 µm blood-brain barrier domain. The fluid flow and mass transport equations were coupled to calculate the blood velocity and aptamer concentration profiles across the BBB. It was identified that the thickness of the astrocyte and endothelial cell layers are key parameters affecting the concentration of the aptamer delivered to the last neuron dendrites in the BBB. The predicted efficacy of the drug delivery (C/C) of 10.9% to 13.8% was calculated at a porosity of 0.5 to 0.9, respectively, at a blood velocity of 0.38 mm/s, which was independent of the inlet concentration of the aptamer. This low efficacy was attributed to the mass transfer resistance across endothelial cells, astrocyte and pericyte layers, which decreased the concentration by 6.7%. It was also identified that the main mechanism of drug delivery is switched from convective mass transport in the capillary layer (with Peclet number > 50) to mixed convection mass transport (1 < Peclet number < 5) in the porous layers and to diffusion only once aptamer reached the brain parenchyma (Peclet number < 1).
血脑屏障 (BBB) 是一种阻止药物进入的强大屏障，这使得脑癌治疗成为一个重大挑战。我们之前已经表明，使用适体靶向转铁蛋白受体可以增加脑内药物递送。为了更好地理解这一现象，在本文中，我们开发了一个基于有限元方法的数学模型，该模型考虑了适体分子在 8 µm 毛细血管内的流体流动和质量传输穿过 14 µm 的血脑屏障区域。将流体流动和质量传输方程耦合起来，以计算穿过 BBB 的血液速度和适体浓度分布。研究发现，星形胶质细胞和内皮细胞层的厚度是影响适体递送到 BBB 中最后一个神经元树突的浓度的关键参数。在血液速度为 0.38mm/s 时，预测药物输送的功效 (C/C) 分别为 10.9%到 13.8%，在孔隙率为 0.5 到 0.9 时，这与适体的入口浓度无关。这种低功效归因于穿过内皮细胞、星形胶质细胞和周细胞层的质量传递阻力，这将浓度降低了 6.7%。还确定了药物输送的主要机制从毛细血管层中的对流质量传递（Peclet 数>50）切换到多孔层中的混合对流质量传递（1<Peclet 数<5），一旦适体到达脑实质（Peclet 数<1），则仅通过扩散进行。
