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Novel cyclic peptides facilitating transcellular blood-brain barrier transport of macromolecules in vitro and in vivo

Shunsuke Yamaguchi, Shingo Ito, Takeshi Masuda, Pierre-Olivier Couraud, Sumio Ohtsuki
Journal of controlled release 2020 v.321 pp. 744-755
DNA libraries, blood-brain barrier, brain, coculture, cyclic peptides, drugs, excretion, exosomes, humans, intravenous injection, mice, models, monkeys, nanoparticles, parenchyma (animal tissue), permeability, phages, rats, screening
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.