A D-Peptide Ligand of Nicotine Acetylcholine Receptors for Brain-Targeted Drug Delivery

• Published in: Angewandte Chemie (International ed.) Vol. 54; no. 10; pp. 3023 - 3027
• Main Authors: Wei, Xiaoli, Zhan, Changyou, Shen, Qing, Fu, Wei, Xie, Cao, Gao, Jie, Peng, Chunmei, Zheng, Ping, Lu, Weiyue
• Format: Journal Article
• Language: English
• Published: Weinheim WILEY-VCH Verlag 02.03.2015; WILEY‐VCH Verlag; Wiley Subscription Services, Inc
• Edition: International ed. in English
• Subjects: blood-brain barrier; Brain; Brain - metabolism; D-peptide ligands; Drug Delivery Systems; glioblastoma; Ligands; Liposomes; Medical services; Nicotine; nicotine acetylcholine receptors; Peptides; Peptides - metabolism; Receptors; Receptors, Nicotinic - metabolism; Stability; T cell receptors; blood-brain barrier; D-peptide ligands; glioblastoma; nicotine acetylcholine receptors
• ISSN: 1433-7851; 1521-3773
• DOI: 10.1002/anie.201411226

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 DCDX), which binds to nAChRs with an IC50 value 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 parent L‐peptide. When modified on liposomal surface, DCDX facilitated significant brain‐targeted delivery of liposomes. As a result, brain‐targeted delivery of DCDX 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. A D‐peptide ligand of nicotine acetylcholine receptors (nAChRs), termed DCDX, was developed. The function of DCDX as a D‐peptide antagonist of nAChRs was experimentally and computationally validated. DCDX exhibits exceptional stability during nAChRs‐mediated transcytosis and in blood circulation, offering potential for brain‐targeted drug delivery in the treatment of central nervous system diseases.