Lonser Russell R, Walbridge Stuart, Garmestani Kayhan, Butman John A, Walters Hugh A, Vortmeyer Alexander O, Morrison Paul F, Brechbiel Martin W, Oldfield Edward H
Surgical Neurology Branch and Biomedical Engineering and Instrumentation Program, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892, USA.
J Neurosurg. 2002 Oct;97(4):905-13. doi: 10.3171/jns.2002.97.4.0905.
Intrinsic disease processes of the brainstem (gliomas, neurodegenerative disease, and others) have remained difficult or impossible to treat effectively because of limited drug penetration across the blood-brainstem barrier with conventional delivery methods. The authors used convection-enhanced delivery (CED) of a macromolecular tracer visible on magnetic resonance (MR) imaging to examine the utility of CED for safe perfusion of the brainstem.
Three primates (Macaca mulatta) underwent CED of various volumes of infusion ([Vis]; 85, 110, and 120 microl) of Gd-bound albumin (72 kD) in the pontine region of the brainstem during serial MR imaging. Infusate volume of distribution (Vd), homogeneity, and anatomical distribution were visualized and quantified using MR imaging. Neurological function was observed and recorded up to 35 days postinfusion. Histological analysis was performed in all animals. Large regions of the pons and midbrain were successfully and safely perfused with the macromolecular protein. The Vd was linearly proportional to the Vi (R2 = 0.94), with a Vd/Vi ratio of 8.7 +/- 1.2 (mean +/- standard deviation). Furthermore, the concentration across the perfused region was homogeneous. The Vd increased slightly at 24 hours after completion of the infusion, and remained larger until the intensity of infusion faded (by Day 7). No animal exhibited a neurological deficit after infusion. Histological analysis revealed normal tissue architecture and minimal gliosis that was limited to the region immediately surrounding the cannula track.
First, CED can be used to perfuse the brainstem safely and effectively with macromolecules. Second, a large-molecular-weight imaging tracer can be used successfully to deliver, monitor in vivo, and control the distribution of small- and large-molecular-weight putative therapeutic agents for treatment of intrinsic brainstem processes.
由于传统给药方法中药物穿过血脑桥屏障的渗透率有限，脑干的内在疾病过程（胶质瘤、神经退行性疾病等）一直难以或无法得到有效治疗。作者使用磁共振（MR）成像可见的大分子示踪剂进行对流增强递送（CED），以研究CED用于脑干安全灌注的效用。
在连续MR成像过程中，对三只灵长类动物（恒河猴）在脑干脑桥区域进行不同输注体积（[Vis]；85、110和120微升）的钆结合白蛋白（72 kD）的CED。使用MR成像对注入物的分布体积（Vd）、均匀性和解剖分布进行可视化和量化。在输注后长达35天观察并记录神经功能。对所有动物进行组织学分析。脑桥和中脑的大片区域成功且安全地被大分子蛋白灌注。Vd与Vi呈线性比例（R2 = 0.94），Vd/Vi比值为8.7±1.2（平均值±标准差）。此外，灌注区域的浓度是均匀的。输注完成后24小时Vd略有增加，并在输注强度消退之前（到第7天）一直保持较大。没有动物在输注后出现神经功能缺损。组织学分析显示组织结构正常，胶质增生最小，仅限于套管轨迹紧邻区域。
第一，CED可用于将大分子安全有效地灌注到脑干。第二，大分子成像示踪剂可成功用于递送、体内监测和控制小分子和大分子假定治疗剂在治疗脑干内在疾病过程中的分布。
