Prokai-Tatrai Katalin, Prokai Laszlo
Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, TX, USA.
Methods Mol Biol. 2011;789:313-36. doi: 10.1007/978-1-61779-310-3_21.
The blood-brain barrier (BBB) represents multiple barriers for drug delivery from the circulation. Peptides potentially useful to treat maladies of the brain are especially limited in their ability to cross the BBB due to several shortcomings. Specific delivery strategies have been conceived to outwit the BBB to target neuropeptides into the brain. It should be noted, however, that no unified method is possible for true brain-targeting of these fascinating biomolecules due to their structural features, properties, and intricate interplays among factors governing their entrance into and retention within the brain. In most brain-targeting prodrug approaches, a lipophilic and bioreversible moiety(ies) is covalently attached to the peptide that results in the complete loss of the innate biological activity of the parent peptide (prodrugs are inactive per definition) but significantly improves brain uptake and metabolic stability in the plasma and the interstitial fluid. Once the peptide prodrug has crossed the BBB, specific enzymes liberate the parent agent from its prodrug in the brain. To illustrate the applicability of the prodrug strategy for brain delivery of small neuropeptides, pGlu-Glu-Pro-NH(2), [Glu(2)TRH], a thyrotropin-releasing hormone (TRH) analogue with a vast array of central activities, was chosen as an example. An ester prodrug provided significantly improved brain delivery compared to the unmodified parent peptide. The synthesis, in vitro and in vivo evaluations of this prodrug as specific examples are given for typical exploratory prodrug validation.
血脑屏障（BBB）对药物从循环系统进入大脑构成了多重阻碍。由于存在若干缺陷，潜在可用于治疗脑部疾病的肽类在穿越血脑屏障方面的能力尤其有限。人们已构思出特定的递送策略，以巧妙绕过血脑屏障，将神经肽靶向递送至大脑。然而，应当注意的是，由于这些迷人的生物分子的结构特征、性质以及决定其进入大脑并在脑内存留的因素之间复杂的相互作用，不可能存在一种统一的方法来真正实现对这些生物分子的脑靶向递送。在大多数脑靶向前药方法中，一个亲脂性且可生物逆转的部分共价连接到肽上，这导致母体肽的固有生物活性完全丧失（根据定义，前药是无活性的），但显著提高了其在血浆和组织液中的脑摄取和代谢稳定性。一旦肽前药穿越了血脑屏障，特定的酶会在大脑中将母体药物从其前药形式中释放出来。为了说明前药策略在将小神经肽递送至大脑方面的适用性，选择了pGlu-Glu-Pro-NH₂，[Glu₂TRH]，一种具有广泛中枢活性的促甲状腺激素释放激素（TRH）类似物作为示例。与未修饰的母体肽相比，一种酯前药显著改善了脑部递送。作为典型的探索性前药验证的具体示例，给出了该前药的合成、体外和体内评估。
