Beard Rhiannon, Gaboriau David C A, Gee Antony D, Tate Edward W
Department of Chemistry , Imperial College London , Wood Lane , London , W12 0BZ , UK . Email:
Facility for Imaging by Light Microscopy , Imperial College London , Exhibition Road , London SW7 2AZ , UK.
Chem Sci. 2019 Oct 8;10(46):10772-10778. doi: 10.1039/c9sc04024b. eCollection 2019 Dec 14.
Absorptive- and receptor-mediated transcytosis (AMT/RMT) are widely studied strategies to deliver therapeutics across the blood-brain barrier (BBB). However, an improved understanding of the mechanism surrounding trafficking is required that could promote delivery. Accordingly, we designed a flexible platform that merged AMT and RMT motifs on a single scaffold to probe various parameters (ligand, affinity, valency, position) in a screening campaign. During this process we adapted an BBB model to reliably rank transcytosis of the vehicle library. Our results demonstrate heightened uptake and trafficking for the shuttles, with a structure-activity relationship for transcytosis emerging. Notably, due to their small size, the majority of shuttles demonstrated increased permeation compared to transferrin, with the highest performing shuttle affording a 4.9-fold increase. Consequently, we have identified novel peptide conjugates that have the capacity to act as promising brain shuttles.
吸收介导和受体介导的转胞吞作用（AMT/RMT）是用于将治疗药物递送至血脑屏障（BBB）的广泛研究的策略。然而，需要对围绕转运的机制有更深入的了解，以促进药物递送。因此，我们设计了一个灵活的平台，该平台在单个支架上融合了AMT和RMT基序，以便在筛选过程中探究各种参数（配体、亲和力、价态、位置）。在此过程中，我们采用了一种血脑屏障模型来可靠地对载体文库的转胞吞作用进行排名。我们的结果表明，穿梭体的摄取和转运增强，出现了转胞吞作用的构效关系。值得注意的是，由于其尺寸小，与转铁蛋白相比，大多数穿梭体的渗透性增加，性能最佳的穿梭体的渗透性提高了4.9倍。因此，我们鉴定出了具有作为有前景的脑穿梭体潜力的新型肽缀合物。
