Zlokovic B V
Department of Neurological Surgery, Children's Hospital Los Angeles, University of Southern California School of Medicine 90033, USA.
Pharm Res. 1995 Oct;12(10):1395-406. doi: 10.1023/a:1016254514167.
The study of peptide transport across the blood-brain barrier (BBB) is a field fraught with conflicting interpretations. This review presents a fairly strong case that peptides can be differentially transported at the BBB. However, minimal transport of peptides could have important impact on central nervous system (CNS) functions since only small amounts are needed for physiologic pharmacologic and/or pathologic effects. Several BBB peptide transport mechanisms (i.e., receptor-mediated, absorptive-mediated, carrier-mediated and non-specific passive diffusion), as well as non-transport processes (i.e., endocytosis without transcytosis, absorption and metabolism) are discussed. It is emphasized that peptide transport systems at the BBB could be important targets for both therapeutic delivery of peptides and the development of certain brain pathologies. Strategies to manipulate peptide BBB transport processes have been discussed including lipidization, chemical modifications of the N-terminal end, coupling of transport with post-BBB metabolism and formation of potent neuroactive peptides, up-regulation of putative peptide transporters, use of chimeric peptides in which non-transportable peptide is chemically linked to a transportable peptide, use of monoclonal antibodies against peptide receptors, and binding of circulating peptides to apolipoproteins. It is suggested that future directions should be directed towards development of molecular strategies to up-regulate specific BBB peptide transporters to enhance brain delivery of peptide neuropharmaceuticals, or to down-regulate transport of peptides with potential role in cerebral pathogenesis.
对肽类跨血脑屏障（BBB）转运的研究是一个充满相互矛盾解释的领域。本综述提出了一个相当有力的观点，即肽类在血脑屏障处可被差异性转运。然而，肽类的微量转运可能对中枢神经系统（CNS）功能产生重要影响，因为生理、药理和/或病理效应仅需少量肽类即可。本文讨论了几种血脑屏障肽转运机制（即受体介导、吸附介导、载体介导和非特异性被动扩散）以及非转运过程（即无转胞吞作用的内吞作用、吸收和代谢）。需要强调的是，血脑屏障处的肽转运系统可能是肽类治疗性递送和某些脑部疾病发展的重要靶点。本文还讨论了操纵肽类血脑屏障转运过程的策略，包括脂化、N末端化学修饰、转运与血脑屏障后代谢的偶联以及强效神经活性肽的形成、上调假定的肽转运体、使用将不可转运肽与可转运肽化学连接的嵌合肽、使用抗肽受体单克隆抗体以及循环肽与载脂蛋白的结合。建议未来的研究方向应致力于开发分子策略，以上调特定的血脑屏障肽转运体，增强肽类神经药物的脑内递送，或下调在脑发病机制中可能起作用的肽类的转运。
