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

JOURNAL OF CONTROLLED RELEASE

卷:321

Article

Yamaguchi, Shunsuke^1,2  Ito, Shingo^1,3  Masuda, Takeshi^1,3  Couraud, Pierre-Olivier⁴  Ohtsuki, Sumio^1,3 

[1] Kumamoto Univ, Grad Sch Pharmaceut Sci, Dept Pharmaceut Microbiol, Chuo Ku, 5-1 Oe Honmachi, Kumamoto 8620973, Japan

[2] Japan Soc Promot Sci, Res Fellowship Young Scientists, Chiyoda Ku, Tokyo, Japan

[3] Kumamoto Univ, Fac Life Sci, Dept Pharmaceut Microbiol, Chuo Ku, 5-1 Oe Honmachi, Kumamoto 8620973, Japan

[4] Univ Paris 05, Inst Cochin, Sorbonne Paris Cite, CNRS,UMR8104,INSERM U1016, Paris, France

关键词: Cyclic peptide;    Phage display technology;    Brain delivery;    Macromolecule;   

DOI  :  10.1016/j.jconrel.2020.03.001

来源: Elsevier

【 摘 要 】

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.

【 授权许可】

Free