Song Y, Han H B, Yang J, Wang A B, He Q Y, Li Y Y, Zhao G M, Gao Y J, Wang R, Han Y X, Liu A L, Song Q W
Department of Radiology, the First Affiliated Hospital of Dalian Medical University, Dalian 116011, Liaoning, China.
Institute of Medical Technology, Peking University Health Science Center, Beijing 100191, China.
Beijing Da Xue Xue Bao Yi Xue Ban. 2020 Apr 18;52(2):362-367. doi: 10.19723/j.issn.1671-167X.2020.02.026.
To compare the changes of extracellular space (ECS) structure and local drug distribution in adult brain and aged brain at different drug delivery rates in minimally invasive treatment of encephalopathy by convection enhanced delivery (CED) via ECS pathway.
Thirty-six SD male rats were divided into adult rats group (2-8 months, n=18) and aged rats group (18-24 months, n=18) according to the age of the month. According to the drug rates (0.1 μL/min, 0.2 μL/min, and 0.3 μL/min), they were randomly divided into 3 subgroups, 6 in each subgroup. Gadolinium-diethylene triamine pentaacetic acid (Gd-DTPA) with a concentration of 10 mmol/L were introduced into the caudate nucleus of each group of rats by stereotactic injection. Tracer-based magnetic resonance imaging (MRI) was used to dynamically monitor the diffusion and distribution images of the Gd-DTPA in the brain interstitial system (ISS). Using the self-developed MRI image measurement and analysis system software to process and analyze the obtained images, the diffusion coefficient, clearance rate, volume fraction, and half-life of each group of rats in the caudate nucleus ECS could be acquired. The effects and differences of drug clearance and ECS structural function in the brain of aged rats and adult rats were compared and analyzed at different drug delivery rates. Magnetic tracer D technique was used to observe the distribution and drainage of tracer in caudate nucleus.
At the injection rate of 0.1 μL/min, the volume fraction in the aged rats was increased compared with that in the adult rats (18.20%±0.04% vs. 17.20%±0.03%, t=3.752, P=0.004), and the degree of tortuosity was decreased (1.63±0.04 vs. 1.78±0.09, t=-3.680, P=0.004), the drug clearance rate was decreased [(1.94±0.68) mm/s vs. (3.25±0.43) mm/s, t=-3.971, P=0.003], and the molecular diffusion in ECS was increased [(3.99±0.21)×10 mm/s vs. (3.36±0.37)×10 mm/s, t=3.663, P=0.004]. When the rate of injection increased to 0.2 μL/min, the drug clearance in ECS of the aged rats was slowed down [(2.53±0.45) mmol/L vs. (3.37±0.72) mmol/L, t=-1.828, P=0.021]. However, there were no significant differences in volume fraction, molecular diffusion in ECS and macroscopic drug metabolism parameters. When the rate of injection increased to 0.3 μL/min, the volume fraction in the aged rats was decreased (17.20%±0.03% vs. 18.20%±0.05%, t=-0.869, P=0.045), and the drug clearance rate in ECS was significantly accelerated [(4.04±0.76) mmol/L vs. (3.26±0.55) mmol/L, t=1.786, P=0.014], and there was no significant difference in tortuosity and the rate of molecular diffusion in the ECS.
The drug clearance and ECS structural parameters of brain ECS in aged brain with CED administration were changed at different rates, and it has the least effect on ECS in the aged brain at the injection rate of 0.2 μL/min. For the application of CED for the treatment of encephalopathy, we should consider the influence of factors such as age and injection rate, and provide reference for the development of individualized clinical treatment plan for minimally invasive treatment of encephalopathy via ECS pathway.
通过细胞外间隙（ECS）途径对流增强递送（CED）微创治疗脑病，比较不同给药速率下成年脑和老年脑ECS结构变化及局部药物分布。
将36只SD雄性大鼠按月龄分为成年大鼠组（2 - 8个月，n = 18）和老年大鼠组（18 - 24个月，n = 18）。根据给药速率（0.1 μL/min、0.2 μL/min和0.3 μL/min）随机分为3个亚组，每组6只。通过立体定向注射将浓度为10 mmol/L的钆 - 二乙烯三胺五乙酸（Gd - DTPA）注入每组大鼠的尾状核。基于示踪剂的磁共振成像（MRI）动态监测Gd - DTPA在脑间质系统（ISS）中的扩散和分布图像。使用自行开发的MRI图像测量与分析系统软件对所得图像进行处理和分析，获取每组大鼠尾状核ECS的扩散系数、清除率、体积分数和半衰期。比较分析不同给药速率下老年大鼠和成年大鼠脑内药物清除及ECS结构功能的影响和差异。采用磁示踪剂D技术观察示踪剂在尾状核中的分布和引流情况。
注射速率为0.
