Endocytic delivery of vancomycin mediated by a synthetic cell surface receptor: Rescue of bacterially infected mammalian cells and tissue targeting in vivo
Endocytic delivery of vancomycin mediated by a synthetic cell surface receptor: Rescue of bacterially infected mammalian cells and tissue targeting in vivo
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DOI：
10.1021/ja067674f
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发表时间：
2007-01-17
影响因子：
15
通讯作者：
Peterson, Blake R.
中科院分区：
文献类型：
--
作者：
Boonyarattanakalin, Siwarutt;Hu, Jianfang;Peterson, Blake R.
内化细胞表面受体的细胞外结构域通常被靶向以使得能够通过受体介导的内吞作用机制进行药物递送。为了规避内吞药物递送所需的天然受体，我们构建了一种小的人工细胞表面受体，其包含与结合糖肽抗生素万古霉素的D-Phe-D-Ala基序连接的膜锚N-烷基-3 β-胆固醇胺。通过模拟胆固醇的膜缔合和运输特性，这种胆固醇衍生的合成受体作为辅分子发挥作用，插入哺乳动物细胞的质膜，并在细胞表面和细胞内内体之间快速循环。用这种受体处理的人HeLa细胞获得了通过内吞作用内化万古霉素的能力，使这种细胞不可渗透的抗生素能够根除致命的细胞内病原体单核细胞增生李斯特菌，并在体外保持宿主细胞的活力。此外，当与合成受体结合时，万古霉素穿透血脑屏障，在体内小鼠的脑和其他组织中积累。由于它们能够定义跨越生物膜屏障的新途径，小的合成细胞表面受体代表了有前途的药物递送工具。
Extracellular domains of internalizing cell surface receptors are often targeted to enable drug delivery through the mechanism of receptor-mediated endocytosis. To circumvent natural receptors required for endocytic drug delivery, we constructed a small artificial cell surface receptor comprising the membrane anchor N-alkyl-3 beta-cholesterylamine linked to a D-Phe-D-Ala motif that binds the glycopeptide antibiotic vancomycin. By mimicking membrane association and trafficking properties of cholesterol, this cholesterol-derived synthetic receptor functions as a prosthetic molecule, inserting into plasma membranes of mammalian cells, and rapidly cycling between the cell surface and intracellular endosomes. Human HeLa cells treated with this receptor gained the ability to internalize vancomycin by endocytosis, enabling this cell-impermeable antibiotic to eradicate the lethal intracellular pathogen Listeria monocytogenes and preserving the viability of the host cells in vitro. Moreover, when combined with the synthetic receptor, vancomycin penetrated the blood-brain barrier, accumulating in the brain and other tissues of mice in vivo. Because of their ability to define new pathways across biological membrane barriers, small synthetic cell surface receptors represent promising tools for drug delivery.