Drug Delivery to the Brain Using Cell Adhesion Molecule

脊髓灰质炎病毒受体被认为是细胞粘附分子的一员，是脊髓灰质炎病毒中枢神经系统选择性感染的决定因素。在结直肠癌中，选择素配体sLe^ X被认为是肝转移的决定因素。在本研究中，我们试图通过阐明器官特异性病毒感染和肿瘤转移来寻找脑选择性递送的新策略。将脊髓灰质炎病毒静脉注射到表达脊髓灰质炎病毒受体基因（Tg21）及其原生型（ICR）的转基因小鼠体内。毒株Mahoney在Tg21中的血脑屏障（BBB）通透性清除率与疫苗株Sabin 1非常相似。这些血脑屏障通透性清除率约为1251-白蛋白的100倍。此外，在ICR研究中获得了非常相似的结果，表明脊髓灰质炎病毒显著的血脑屏障通透性可能有不同的决定因素。在转移的研究中，我们发现首过效应对癌细胞的初始分布起着重要的作用。不同sLe^x表达水平的细胞在肝脏中的初始分布无显著差异。有趣的是。sLe^x在细胞质膜中的表达程度被认为是初始分布后粘附和侵袭的决定因素。在本研究中，我们还发现几种外排转运蛋白对药物在大脑中的分布有明显的限制。综上所述，本研究提示，除了细胞粘附分子的差异表达外，与脑毛细血管初始关联的增强和脑毛细血管外排转运体的缺乏识别是脑选择性给药的重要因素。

Poliovirus receptor considered to be a member of cell adhesion molecule is known to be a determinant for the central nervous system selective infection of poliovirus. In colorectal cancer, sialyl lewice X (sLe^x), a ligand of selectin, is considered to be a determinant for the hepatic metastatis. In the present study, we have examined to find new strategies of brain selective delivery by elucidating the organ specific virus infection and tumor metastasis. Poliovirus was inoculated intravenously to the transgenic mouse expressing poliovirus receptor gene (Tg21) and its native type (ICR). The blood-brain barrier (BBB) permeability clearance of Mahoney, a toxic strain, in Tg21 was very similar to that of Sabin 1, a vaccine strain. These BBB permeability clearances were approximately 100-folds greater than that of 1251-albumin, Moreover, very similar results were obtained for the study of ICR,suggesting that there would be a different determinat factor for the significant BBB permeation of poliovirus. In the study of metastasis, we have found that the first-pass effect plays an important role for the initial distribution of cancer cells. No significant difference was observed for the initial distribution in the liver between cells expressing diferent level of sLe^x. Interestingly. the extent of sLe^x expression in the plasma membrane of cells was suggested to be a determinant for the adhesion and the invasion following an initial distribution. In the present study, we have also found that several efflux transporters are responsible for the significantly restricted distribution of drugsinthebrain.In conclusion, the present study suggest that, in addition to the differential expression of cell adhesion molecule, the enhancement of tinitial association to the brain capillary and the lack of recognition by the efflux transporters at the brain capilary are important for the brain selective drug delivery.