CONVECTION-ENHANCED DISTRIBUTION OF LARGE MOLECULES IN GRAY-MATTER DURING INTERSTITIAL DRUG INFUSION
CONVECTION-ENHANCED DISTRIBUTION OF LARGE MOLECULES IN GRAY-MATTER DURING INTERSTITIAL DRUG INFUSION
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DOI：
10.3171/jns.1995.82.6.1021
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发表时间：
1995-06-01
影响因子：
4.1
通讯作者：
OLDFIELD, EH
中科院分区：
文献类型：
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作者：
LIEBERMAN, DM;LASKE, DW;OLDFIELD, EH
许多新的实验性治疗剂，如神经营养因子、酶、生物修饰剂和遗传载体，不容易穿过血脑屏障。将这些化合物递送至中枢神经系统的有效策略是它们在体内应用所必需的。在正常生理条件下，脑间质液通过整体流动（对流）和扩散两者移动。最近已经表明，向白色物质中的间质输注可用于增加整体流动，产生间质对流，并有效且均匀地将药物递送到脑的大区域，而没有显著的功能或结构损伤。理论上，在灰质中可能会有更均匀的分布。在目前的研究中，进行了四个实验，以检查是否可以使用对流增强输送来实现大分子在灰质中的区域分布。首先，体积和一致性的解剖分布的20 μ l的菜豆-白细胞凝集素（PHA-L;分子量（MW）126 kD）连续高流量微输注到五只大鼠的纹状体超过200分钟后，使用免疫细胞化学和定量与图像分析。其次，使用定量放射自显影术在四个半球中测定在相同条件下输注的C-14白蛋白（MW 69 kD）的浓度分布。第三，对流增强输注250或500 μ l生物素化葡聚糖（b-葡聚糖，MW 10 kD）后的分布体积，通过一个（250 μ l）或两个（500 μ l）套管在310分钟内递送到恒河猴的尾状核和壳核中，使用免疫细胞化学测定并用图像分析定量。最后，在三个实验中，通过将27 μ l辣根过氧化物酶标记的麦胚凝集素（WGA-HRP）输注到纹状体中300分钟后，通过中脑的免疫组织化学分析，评估了通过灌注纹状体并随后进行逆行转运而靶向黑质纹状体束的所有多巴胺能神经元的能力。L在整个大鼠纹状体中（纹状体灌注的体积百分比，V-s为86% +/- 5%;平均值+/-标准差），并在灌注区域产生均匀的组织浓度（C-14-白蛋白浓度相对于输注液浓度为30% +/- 5%）。在猴中，使用一个套管（尾状核和壳核V-s = 76%和76%）或两个套管（V-s = 90%和71%）输注广泛分布在纹状体内的b-葡聚糖。灌流大鼠纹状体WGA-HRP有效地靶向神经元通过其传出连接的黑质纹状体pathway.Convection-enhanced输注到灰质广泛分布大分子在一个相对均匀的浓度。这种将大分子有效急性递送到灰质中的技术与单独的扩散相比具有几个优点，并且在实验室和临床神经科学中具有广泛的潜在应用。
Many novel experimental therapeutic agents, such as neurotrophic factors, enzymes, biological modifiers, and genetic vectors, do not readily cross the blood-brain barrier. An effective strategy to deliver these compounds to the central nervous system is required for their application in vivo. Under normal physiological conditions, brain interstitial fluid moves by both bulk flow (convection) and diffusion. It has recently been shown that interstitial infusion into the white matter can be used to increase bulk flow, produce interstitial convection, and efficiently and homogeneously deliver drugs to large regions of brain without significant functional or structural damage. In theory, even more uniform distribution is likely in gray matter.In the current study, four experiments were performed to examine if convection-enhanced delivery could be used to achieve regional distribution of large molecules in gray matter. First, the volume and consistency of anatomical distribution of 20 mu l of phaseolus valgaris-leukoagglutinin (PHA-L; molecular weight (MW) 126 kD) after continuous high-flow microinfusion into the striatum of five rats over 200 minutes were determined using immunocytochemistry and quantified with image analysis. Second, the concentration profile of C-14 albumin (MW 69 kD) infused under identical conditions was determined in four hemispheres using quantitative autoradiography. Third, the volume of distribution after convection-enhanced infusion of 250 or 500 mu l biotinylated dextran (b-dextran, MW 10 kD), delivered over 310 minutes into the caudate and putamen of a rhesus monkey from one (250 mu I) or two (500 mu l) cannulas, was determined using immunocytochemistry and quantified with image analysis. Finally, the ability to target all dopaminergic neurons of the nigrostriatal tract via perfusion of the striatum with subsequent retrograde transport was assessed in three experiments by immunohistochemical analysis of the mesencephalon following a 300-minute infusion of 27 mu l horseradish peroxidase-labeled wheat germ agglutinin (WGA-HRP) into the striatum.Convection-enhanced delivery reproducibly distributed the large-compound PHA-L throughout the rat striatum (the percent volume of the striatum perfused, V-s, was 86% +/- 5%; mean +/- standard deviation) and produced a homogeneous tissue concentration in the perfused region (concentration of C-14-albumin relative to infusate concentration 30% +/- 5%). In the monkey, the infusion widely distributed b-dextran within the striatum using one cannula (caudate and putamen V-s = 76% and 76%) or two cannulas (V-s = 90% and 71%). Perfusion of the rat striatum with WGA-HRP effectively targeted neurons throughout the pars compacta of the substantia nigra via their efferent connections in the nigrostriatal pathway.Convection-enhanced infusion into gray matter distributes large molecules extensively at a relatively homogeneous concentration. This technique for effective acute delivery of large molecules into the gray matter has several advantages over diffusion alone and has a wide spectrum of potential applications in laboratory and clinical neuroscience.