Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, P.O. Box 80082, 3508 TB, Utrecht, The Netherlands.
Pharm Res. 2010 Apr;27(4):673-82. doi: 10.1007/s11095-010-0053-6. Epub 2010 Feb 17.
Transport of drugs to the brain is limited by the blood-brain barrier. New, specific brain endothelium ligands can facilitate brain-specific delivery of drugs.
We used phage display in an in situ brain perfusion model to screen for new brain endothelium peptide ligands.
Two phage clones, displaying 15 amino acid-peptides (GLA and GYR) that were selected for brain binding in the mouse model, showed significant binding to human brain endothelium (hCMEC/D3), compared to a random control phage. This binding was not seen for other human endothelial cells (HUVEC). Binding to hCMEC/D3 cells was dose dependent. When phage GLA and GYR were individually perfused through the murine brain, their ability to bind to the brain was 6-fold (GLA) and 5-fold (GYR) higher than the control phage. When compared to lung perfusion, phage showed an 8.5-fold (GYR) and 48-fold (GLA) preference for brain over lung compared to the control.
These results indicate that two new peptide ligands have been identified that may be used for specific targeting of drugs to the blood-brain barrier.
药物向脑部的转运受到血脑屏障的限制。新的、特定的脑内皮层配体可以促进药物对大脑的特异性传递。
我们使用噬菌体展示技术在原位脑灌注模型中筛选新的脑内皮肽配体。
两种噬菌体克隆，展示了 15 个氨基酸的肽（GLA 和 GYR），在小鼠模型中被选择用于脑结合，与随机对照噬菌体相比，显示出与人脑内皮细胞（hCMEC/D3）的显著结合。这种结合在其他人类内皮细胞（HUVEC）中没有出现。与 hCMEC/D3 细胞的结合呈剂量依赖性。当噬菌体 GLA 和 GYR 分别通过鼠脑灌注时，它们与脑结合的能力比对照噬菌体高 6 倍（GLA）和 5 倍（GYR）。与肺灌注相比，与对照相比，噬菌体对脑的偏好性分别为 GYR 的 8.5 倍和 GLA 的 48 倍。
这些结果表明，已经鉴定出两种新的肽配体，它们可能用于将药物特异性靶向血脑屏障。
