title: A D-peptide ligand of nicotine acetylcholine receptors for brain-targeted drug delivery.
abstract: 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 IC50 value of 84.5 nM, 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.
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Fudan University & Key Laboratory of Smart Drug Delivery (Fudan University), Ministry of Education, Shanghai, 201203 (P.R. China); State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, 200032 (P.R. China).
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Wei
authors.forename: Changyou
authors.initials: C
authors.lastname: Zhan
authors.forename: Qing
authors.initials: Q
authors.lastname: Shen
authors.forename: Wei
authors.initials: W
authors.lastname: Fu
authors.forename: Cao
authors.initials: C
authors.lastname: Xie
authors.forename: Jie
authors.initials: J
authors.lastname: Gao
authors.forename: Chunmei
authors.initials: C
authors.lastname: Peng
authors.forename: Ping
authors.initials: P
authors.lastname: Zheng
authors.forename: Weiyue
authors.initials: W
authors.lastname: Lu
mesh_terms: D001921:Brain / Q000378:metabolism*; D016503:Drug Delivery Systems; D008024:Ligands; D010455:Peptides / Q000378:metabolism*; D011978:Receptors, Nicotinic / Q000378:metabolism*
chemical_list: D008024:Ligands; D010455:Peptides; D011978:Receptors, Nicotinic
keywords: D-peptide ligands; blood-brain barrier; glioblastoma; nicotine acetylcholine receptors