Muldoon L L, Pagel M A, Kroll R A, Roman-Goldstein S, Jones R S, Neuwelt E A
Department of Cell and Developmental Biology, Oregon Health Sciences University, Portland, USA.
AJNR Am J Neuroradiol. 1999 Feb;20(2):217-22.
Osmotic disruption of the blood-brain barrier (BBB) provides a method for transvascular delivery of therapeutic agents to the brain. The apparent global delivery of viral-sized iron oxide particles to the rat brain after BBB opening as seen on MR images was compared with the cellular and subcellular location and distribution of the particles.
Two dextran-coated superparamagnetic monocrystalline iron oxide nanoparticle contrast agents, MION and Feridex, were administered intraarterially in rats at 10 mg Fe/kg immediately after osmotic opening of the BBB with hyperosmolar mannitol. After 2 to 24 hours, iron distribution in the brain was evaluated first with MR imaging then by histochemical analysis and electron microscopy to assess perivascular and intracellular distribution.
After BBB opening, MR images showed enhancement throughout the disrupted hemisphere for both Feridex and MION. Feridex histochemical staining was found in capillaries of the disrupted hemisphere. Electron microscopy showed that the Feridex particles passed the capillary endothelial cells but did not cross beyond the basement membrane. In contrast, after MION delivery, iron histochemistry was detected within cell bodies in the disrupted hemisphere, and the electron-dense MION core was detected intracellularly and extracellularly in the neuropil.
MR images showing homogeneous delivery to the brain at the macroscopic level did not indicate delivery at the microscopic level. These data support the presence of a physiological barrier at the basal lamina, analogous to the podocyte in the kidney, distal to the anatomic (tight junction) BBB, which may limit the distribution of some proteins and viral particles after transvascular delivery to the brain.
血脑屏障（BBB）的渗透性破坏为治疗药物经血管输送至脑提供了一种方法。将磁共振成像（MR）上所见的血脑屏障开放后病毒大小的氧化铁颗粒向大鼠脑内的表观整体输送情况，与颗粒的细胞及亚细胞定位和分布进行比较。
在用高渗甘露醇使血脑屏障渗透性开放后，立即以10mg铁/千克的剂量将两种葡聚糖包被的超顺磁性单晶氧化铁纳米颗粒造影剂，即MION和Feridex，经动脉注射到大鼠体内。2至24小时后，首先通过MR成像评估脑内铁的分布，然后通过组织化学分析和电子显微镜检查评估血管周围和细胞内的分布。
血脑屏障开放后，MR图像显示Feridex和MION在整个受破坏的半球均有强化。在受破坏半球的毛细血管中发现了Feridex组织化学染色。电子显微镜检查显示，Feridex颗粒穿过了毛细血管内皮细胞，但未越过基底膜。相比之下，注射MION后，在受破坏半球的细胞体内检测到铁组织化学，并且在神经毡的细胞内和细胞外均检测到电子致密的MION核心。
在宏观水平上显示向脑内均匀输送的MR图像，在微观水平上并未表明有输送。这些数据支持在基底膜处存在一种生理屏障，类似于肾脏中的足细胞，位于解剖学（紧密连接）血脑屏障的远端，这可能会限制某些蛋白质和病毒颗粒经血管输送至脑后的分布。
