Lysosomes of brain capillary endothelial cells are implicated in nicotine acetylcholine receptor (nAChR)‐mediated transcytosis and act as an enzymatic barrier for the transport of peptide ligands to the brain. AD‐peptide ligand of nAChRs (termedDCDX), which binds to nAChRs with an IC50value of 84.5 nM, was developed by retro–inverso isomerization.DCDX displayed exceptional stability in lysosomal homogenate and serum, and demonstrated significantly higher transcytosis efficiency in an in vitro blood–brain barrier monolayer compared with the parentL‐peptide. When modified on liposomal surface,DCDX facilitated significant brain‐targeted delivery of liposomes. As a result, brain‐targeted delivery ofDCDX modified liposomes enhanced therapeutic efficiency of encapsulated doxorubicin for glioblastoma. This study illustrates the importance of ligand stability in nAChRs‐mediated transcytosis, and paves the way for developing stable brain‐targeted entities.
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Wei et al. (2015) studied this question.
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