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北京大学学报（医学版） ›› 2020, Vol. 52 ›› Issue (2): 362-367. doi: 10.19723/j.issn.1671-167X.2020.02.026

• 技术方法 • 上一篇    下一篇

脑对流增强给药对老年大鼠脑细胞外间隙微观结构的影响

宋宇1,2,韩鸿宾2,3,4,△(),杨军5,王艾博3,4,和清源3,4,李媛媛3,4,赵国梅3,4,高亚娟3,4,王睿3,4,韩易兴3,4,刘爱连1,△(),宋清伟1,△()   

  1. 1. 大连医科大学附属第一医院放射科, 辽宁大连 116011
    2. 北京大学医学部医学技术研究院, 北京 100191
    3. 北京市磁共振成像设备与技术重点实验室, 北京 100191
    4. 北京大学第三医院放射科, 北京 100191
    5. 北京大学第三医院神经外科, 北京 100191
  • 收稿日期:2019-09-02 出版日期:2020-04-18 发布日期:2020-04-18
  • 通讯作者: 韩鸿宾,刘爱连,宋清伟 E-mail:hanhongbin@bjmu.edu.cn;cjr.liuailian@163.com;songqw1964@163.com
  • 基金资助:
    北京市科技计划(Z181100001518004);国家重大科研仪器研制项目(61827808);首都科技领军人才培养工程(Z181100006318003)

Effect of convection enhanced delivery on the microstructure of brain extracellular space in aged rats

Yu SONG1,2,Hong-bin HAN2,3,4,△(),Jun YANG5,Ai-bo WANG3,4,Qing-yuan HE3,4,Yuan-yuan LI3,4,Guo-mei ZHAO3,4,Ya-juan GAO3,4,Rui WANG3,4,Yi-xing HAN3,4,Ai-lian LIU1,△(),Qing-wei SONG1,△()   

  1. 1. Department of Radiology, the First Affiliated Hospital of Dalian Medical University, Dalian 116011, Liaoning, China
    2. Institute of Medical Technology, Peking University Health Science Center, Beijing 100191, China
    3. Beijing Key Lab of Magnetic Resonance Imaging Device and Technique, Beijing 100191, China
    4. Department of Radiology, Peking University Third Hospital, Beijing 100191, China
    5. Department of Neurosurgery, Peking University Third Hospital, Beijing 100191, China
  • Received:2019-09-02 Online:2020-04-18 Published:2020-04-18
  • Contact: Hong-bin HAN,Ai-lian LIU,Qing-wei SONG E-mail:hanhongbin@bjmu.edu.cn;cjr.liuailian@163.com;songqw1964@163.com
  • Supported by:
    Supported by the Beijing Municipal Science & Technology Commission(Z181100001518004);the National Major Scientific Research Instrument Development Project(61827808);the Program for Training Capital Science and Technology Leading Talents(Z181100006318003)

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摘要：

目的 对比研究经细胞外间隙(extracellular space,ECS)途径的脑对流增强给药(convection enhanced delivery, CED)在进行脑病微创治疗时,不同给药速率下成年大鼠与老年大鼠脑ECS结构参数及局部药物分布的改变.方法: 36只SD雄性大鼠按照月龄分为成年大鼠组(2~8月龄,18只)和老年大鼠组(18~24月龄,18只),每组再按照不同的给药速率(0.1 μL/min,0.2 μL/min,0.3 μL/min)随机分为3个亚组,每亚组6只.采用立体定位注射法分别在各组鼠脑尾状核区导入浓度为10 mmol/L的磁示踪剂钆-二乙三胺五乙酸(gadolinium-diethylene triamine pentaacetic acid,Gd-DTPA)后,应用磁示踪法动态采集Gd-DTPA在脑间质系统(brain interstitial system, ISS)中的扩散和分布图像.利用自主研发的MRI影像测量分析系统软件对所获得的图像进行处理和分析,可获得各组大鼠脑尾状核区ECS内的有效扩散系数(DECS),清除率,容积占比和半衰期(T1/2)等参数.比较分析在不同给药速率下,老年大鼠与成年大鼠脑ECS内药物清除以及ECS结构功能的影响和差异.应用磁示踪DECS-mapping技术观察示踪剂在尾状核区的分布引流情况.结果: 0.1 μL/min注药速率下,与成年大鼠相比,老年大鼠的容积占比增加(18.20%±0.04% vs. 17.20%±0.03%,t=3.752,P=0.004),迂曲度下降(1.63±0.04 vs. 1.78±0.09, t=-3.680,P=0.004),药物清除速率下降[(1.94±0.68) mm 2/s vs. (3.25±0.43) mm 2/s,t=-3.971,P=0.003],ECS内分子扩散速率增快[(3.99±0.21)×10 -4mm 2/s vs. (3.36±0.37)×10 -4mm 2/s,t=3.663,P=0.004].注药速率增加到0.2 μL/min时,老年大鼠ECS内药物清除减慢[(2.53±0.45) mmol/L vs. (3.37±0.72) mmol/L,t=-1.828,P=0.021],但容积占比,ECS内分子扩散和宏观药物代谢参数无明显差异.注药速率增加到0.3 μL/min时,老年大鼠容积占比减小(17.20%±0.03% vs. 18.20%±0.05%,t=-0.869,P=0.045), ECS内药物清除明显加快[(4.04±0.76) mmol/L vs. (3.26±0.55) mmol/L,t=1.786,P=0.014],迂曲度和ECS内分子扩散速率无明显差异.结论: 老年脑CED给药在不同速率时ECS内药物清除及ECS结构参数发生改变,0.2 μL/min速率下CED给药对老年脑ECS影响最小.应用CED进行脑病治疗时应综合考虑年龄和注药速率等因素的影响,经ECS途径给药进行脑病微创治疗时应制定个体化临床治疗方案.

关键词: 放射性示踪剂, 脑, 细胞外间隙, 对流增强给药, 磁共振成像

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 DECS-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

中图分类号: 

  • R814.4

图1

示踪剂在成年大鼠尾状核区域的扩散分布"

图2

示踪剂在老年大鼠尾状核区域的扩散分布"

图3

磁示踪剂注入成年大鼠(A)和老年大鼠(B)后脑DECS-mapping图像显示分布引流情况不同"

图4

磁示踪测量DECS-mapping图像的等高线图显示成年大鼠(A)和老年大鼠(B)扩散系数的形态及幅值改变"

表1

成年大鼠与老年大鼠在不同给药速率下ECS结构与功能参数比较"

Items 0.1 μL/min 0.2 μL/min 0.3 μL/min
Volume fraction, $\bar{x}±s$
Adult rats 17.20%±0.03% 17.60%±0.04% 18.20%±0.05%
Aged rats 18.20%±0.04% 17.70%±0.03% 17.20%±0.03%
P 0.004 0.261 0.045
Degree of tortuosity, $\bar{x}±s$
Adult rats 1.78±0.09 1.77±0.07 1.76±0.10
Aged rats 1.63±0.04 1.69±0.06 1.79±0.11
P 0.004 0.135 0.896
Diffusion coefficient/(×10-4 mm2/s), $\bar{x}±s$
Adult rats 3.36±0.37 3.42±0.37 3.40±0.43
Aged rats 3.99±0.21 3.70±0.26 3.31±0.55
P 0.004 0.155 0.723
Clearance rate/(×10-4 mm2/s), $\bar{x}±s$
Adult rats 3.25±0.43 3.37±0.72 3.26±0.55
Aged rats 1.94±0.68 2.53±0.45 4.04±0.76
P 0.003 0.021 0.014
Half-life/min, $\bar{x}±s$
Adult rats 81.12±5.12 81.89±3.81 86.51±3.35
Aged rats 141.83±7.25 105.95±8.67 88.61±3.71
P 0.002 0.154 0.328
[1] Mehta AM, Sonabend AM, Bruce JN . Convection-enhanced deli-very[J]. Neurotherapeutics, 2017,14(2):358-371.
[2] Souweidane MM, Singh R, Zhou Z . Convection-enhanced delivery for diffuse intrinsic pontine glioma treatment[J]. Curr Neuropharmacol, 2017,15(1):116-128.
[3] Lei Y, Han H, Yuan F , et al. Brain interstitial system: anatomy, modeling, in vivo measurement, and application[J]. Prog Neurobiol, 2016,157:230-246.
[4] Nicholson C, Hrabětová S . Brain extracellular space: the final frontier of neuroscience[J]. Biophys J, 2017,113(10):1-10.
[5] Himes BT, Zhang L, Daniels DJ . Treatment strategies in diffuse midline gliomas with the H3K27M mutation: the role of convection-enhanced delivery in overcoming anatomic challenges[J]. Front Oncol, 2019,9:31.
[6] Oertel W, Schulz JB . Current and experimental treatments of Parkinson disease: A guide for neuroscientists[J]. J Neurochem, 2016,139(Suppl 1):325-337.
[7] Chen PY, Yeh CK, Hsu PH , et al. Drug-carrying microbubbles as a theranostic tool in convection-enhanced delivery for brain tumor therapy[J]. Oncotarget, 2017,8(26):42359-42371.
[8] Fan X, Nelson BD, Ai Y , et al. Continuous intraputamenal convection-enhanced delivery in adult rhesus macaques[J]. J Neurosurg, 2015,123(6):1569-1577.
[9] Sugiyama SI, Saito R, Nakamura T , et al. Safety and feasibility of convection-enhanced delivery of nimustine hydrochloride co-infused with free gadolinium for real-time monitoring in the primate brain[J]. Neurol Res, 2012,34(6):581-587.
[10] Hou J, Wang W, Quan X , et al. Quantitative visualization of dynamic tracer transportation in the extracellular space of deep brain regions using tracer-based magnetic resonance imaging[J]. Med Sci Monit, 2017,23:4260-4268.
[11] Han H, Shi C, Fu Y , et al. A novel mri tracer-based method for measuring water diffusion in the extracellular space of the rat brain[J]. IEEE J Biomed Health Inform, 2014,18(3):978-983.
[12] Daneman R, Prat A . The blood-brain barrier[J]. Cold Spring Harb Perspect Biol, 2015,7(1):a020412.
[13] Zhan W, Alamer M, Xu XY . Computational modelling of drug delivery to solid tumour: Understanding the interplay between chemotherapeutics and biological system for optimised delivery systems[J]. Adv Drug Deliv Rev, 2018,132:81-103.
[14] Miners JS, Barua N, Kehoe PG , et al. Aβ-degrading enzymes: potential for treatment of Alzheimer disease[J]. J Neuropathol Exp Neurol, 2011,70(11):944-959.
[15] Han HB, Xia ZL, Chen H , et al. Simple diffusion delivery via brain interstitial route for the treatment of cerebral ischemia[J]. Sci China Life Sci, 2011,54(3):235-239.
[16] Xu F, Han H, Yan J , et al. Greatly improved neuroprotective efficiency of citicoline by stereotactic delivery in treatment of ischemic injury[J]. Drug Deliv, 2011,18(7):461-467.
[17] Bobo RH, Laske DW, Akbasak A , et al. Convection-enhanced delivery of macromolecules in the brain[J]. Proc Natl Acad Sci USA, 1994,91(6):2076-2080.
[18] Chittiboina P, Heiss JD, Warren KE , et al. Magnetic resonance imaging properties of convective delivery in diffuse intrinsic pontine gliomas[J]. J Neurosurg Pediatr, 2014,13(3):276-282.
[19] Miranpuri GS, Kumbier L, Hinchman A , et al. Gene-based therapy of Parkinson's disease: Translation from animal model to human clinical trial employing convection enhanced delivery[J]. Ann of Neurosci, 2012,19(3):133-146.
[20] Whone A, Luz M, Boca M , et al. Randomized trial of intermittent intraputamenal glial cell line-derived neurotrophic factor in Parkinson's disease[J]. Brain, 2019,142(3):512-525.
[21] Souweidane MM, Kim K, Neeta PT , et al. Convection-enhanced delivery for diffuse intrinsic pontine glioma: a single-centre, dose-escalation, phase 1 trial[J]. Lancet Oncol, 2018,19(8):1040-1050.
[22] Bishop NA, Lu T, Yankner BA . Neural mechanisms of ageing and cognitive decline[J]. Nature, 2010,464(7288):529-535.
[23] Aibo W, Rui W, Dehua C , et al. The drainage of interstitial fluid in the deep brain is controlled by the integrity of myelination[J]. Aging Dis, 2019,10(5):937-948.
[24] Syková E, Nicholson C . Diffusion in brain extracellular space[J]. Physiol Rev, 2008,88(4):1277-1340.
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ISSN 1671-167X
CN 11-4691/R
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