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A D ‐Peptide Ligand of Nicotine Acetylcholine Receptors for Brain‐Targeted Drug Delivery
Author(s) -
Wei Xiaoli,
Zhan Changyou,
Shen Qing,
Fu Wei,
Xie Cao,
Gao Jie,
Peng Chunmei,
Zheng Ping,
Lu Weiyue
Publication year - 2015
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201411226
Subject(s) - transcytosis , chemistry , liposome , blood–brain barrier , peptide , receptor , pharmacology , drug delivery , ligand (biochemistry) , acetylcholine receptor , nicotine , biochemistry , biophysics , biology , endocytosis , endocrinology , neuroscience , central nervous system , organic chemistry
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. A D ‐peptide ligand of nAChRs (termed D CDX), which binds to nAChRs with an IC 50 value of 84.5 n M , was developed by retro–inverso isomerization. D CDX 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 parent L ‐peptide. When modified on liposomal surface, D CDX facilitated significant brain‐targeted delivery of liposomes. As a result, brain‐targeted delivery of D CDX 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.