Abstract:

Objective: 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.Methods: 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_ECS-mapping technique was used to observe the distribution and drainage of tracer in caudate nucleus.Results: 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 ²/s vs. (3.25±0.43) mm ²/s, t=-3.971, P=0.003], and the molecular diffusion in ECS was increased [(3.99±0.21)×10 ^-4 mm ²/s vs. (3.36±0.37)×10 ^-4 mm ²/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. Conclusion: 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.

Key words: Radioactive tracers, Brain, Extracellular space, Convection enhanced delivery, Magnetic resonance imaging