Brain delivery of nanoparticles and macromolecular drugs depends on blood-brain barrier (BBB)-permeable carriers. In this study, we searched for cyclic heptapeptides facilitating BBB permeation of M13 phages by phage library screening using a transcellular permeability assay with hCMEC/D3 cell monolayers, a human BBB model. The M13 phage, which is larger than macromolecular drugs and nanoparticles, served as a model macromolecule. The screen identified cyclic heptapeptide SLSHSPQ (SLS) as a human BBB-permeable peptide. The SLS-displaying phage (SLS-phage) exhibited improved permeation across the cell monolayer of monkey and rat BBB co-culture models. The SLS-phage internalized into hCMEC/D3 cells via macropinocytosis and externalized via the exosome excretion pathway. SLS-phage distribution into brain parenchyma was observed in mice after intravenous administration. Moreover, liposome permeated across the BBB as cyclic SLS peptide conjugates. In conclusion, the cyclic SLS heptapeptide is a novel carrier candidate for brain delivery of macromolecular drugs and nanoparticles.

中文翻译：

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新型环肽促进大分子在体外和体内的跨细胞血脑屏障运输。

纳米颗粒和大分子药物的大脑输送取决于血脑屏障（BBB）渗透性载体。在这项研究中，我们使用具有hCMEC / D3细胞单层的人BBB模型的跨细胞通透性测定，通过噬菌体文库筛选，搜索了促进M13噬菌体BBB渗透的环状七肽。M13噬菌体比大分子药物和纳米颗粒大，可作为模型大分子。该筛查将环状七肽SLSHSPQ（SLS）鉴定为人BBB渗透性肽。展示SLS的噬菌体（SLS噬菌体）在猴子和大鼠BBB共培养模型的整个细胞单层中表现出改善的渗透性。SLS噬菌体通过巨胞饮作用内化到hCMEC / D3细胞中，并通过外泌体排泄途径外化。静脉内给药后在小鼠中观察到SLS噬菌体分布到脑实质中。此外，脂质体作为环状SLS肽结合物透过BBB。总之，环状SLS七肽是大分子药物和纳米颗粒的脑部输送的新型载体候选物。