Bickel U, Yoshikawa T, Landaw E M, Faull K F, Pardridge W M
Department of Medicine, University of California School of Medicine, Los Angeles 90024.
Proc Natl Acad Sci U S A. 1993 Apr 1;90(7):2618-22. doi: 10.1073/pnas.90.7.2618.
Pharmacologic effects in brain caused by systemic administration of neuropeptides are prevented by poor transport of the peptide through the brain vascular endothelium, which comprises the blood-brain barrier in vivo. In the present study, successful application of a chimeric peptide approach to enhance drug delivery through the blood-brain barrier for the purpose of achieving a central nervous system pharmacologic effect is described. The chimeric peptide was formed by linkage of a potent vasoactive intestinal peptide (VIP) analogue, which had been monobiotinylated, to a drug transport vector. The vector consisted of a covalent conjugate of avidin and the OX26 monoclonal antibody to the transferrin receptor. Owing to the high concentration of transferrin receptors on brain capillary endothelia, OX26 targets brain and undergoes receptor-mediated transcytosis through the blood-brain barrier. Systemic infusion of low doses (12 micrograms/kg) of the VIP chimeric peptide in rats resulted in an in vivo central nervous system pharmacologic effect: a 65% increase in cerebral blood flow. Biotinylated VIP analogue without the brain transport vector was ineffective.
体内构成血脑屏障的脑血管内皮对神经肽的转运能力较差，这阻碍了全身给药的神经肽在脑内产生药理作用。在本研究中，描述了一种嵌合肽方法的成功应用，该方法旨在通过血脑屏障增强药物递送，以实现中枢神经系统药理作用。嵌合肽由单生物素化的强效血管活性肠肽（VIP）类似物与药物转运载体连接而成。该载体由抗转铁蛋白受体的抗生物素蛋白与OX26单克隆抗体的共价缀合物组成。由于脑毛细血管内皮上转铁蛋白受体的高浓度，OX26靶向脑并通过血脑屏障进行受体介导的转胞吞作用。给大鼠全身输注低剂量（12微克/千克）的VIP嵌合肽可产生体内中枢神经系统药理作用：脑血流量增加65%。没有脑转运载体的生物素化VIP类似物则无效。
