Novel cyclic peptides facilitating transcellular blood-brain barrier transport of macromolecules in vitro and in vivo
- Source:
- Journal of controlled release 2020 v.321 pp. 744-755
- ISSN:
- 0168-3659
- Subject:
- 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
- Abstract:
- 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.
- Agid:
- 6865203
- https://doi.org/10.1016/j.jconrel.2020.03.001