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

被引：155

作者：

Wei, Xiaoli ^{[1
,2
,3
]}

Zhan, Changyou ^{[1
,2
]}

Shen, Qing ^{[1
,2
]}

Fu, Wei ^{[1
,2
]}

Xie, Cao ^{[1
,2
]}

Gao, Jie ^{[1
,2
]}

Peng, Chunmei ^{[1
,2
]}

Zheng, Ping ^{[3
]}

Lu, Weiyue ^{[1
,2
,3
,4
]}

机构：

[1] Fudan Univ, Sch Pharm, Dept Pharmaceut, Shanghai 201203, Peoples R China

[2] Fudan Univ, Minist Educ, Key Lab Smart Drug Delivery, Shanghai 201203, Peoples R China

[3] Fudan Univ, State Key Lab Med Neurobiol, Shanghai 200032, Peoples R China

[4] Fudan Univ, State Key Lab Mol Engn Polymers, Shanghai 200433, Peoples R China

来源：

ANGEWANDTE CHEMIE-INTERNATIONAL EDITION | 2015年 / 54卷 / 10期

基金：

中国国家自然科学基金;

关键词：

blood-brain barrier; D-peptide ligands; glioblastoma; nicotine acetylcholine receptors; CRYSTAL-STRUCTURE; BARRIER; TRANSPORT; PERMEABILITY; TRANSCYTOSIS; PATHOLOGY; REVEALS; COMPLEX; SYSTEM; CELLS;

D O I：

10.1002/anie.201411226

中图分类号：

O6 [化学];

学科分类号：

0703 ;

摘要：

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 (CDX)-C-D), which binds to nAChRs with an IC50 value of 84.5nM, was developed by retro-inverso isomerization. (CDX)-C-D displayed exceptional stability in lysosomal homogenate and serum, and demonstrated significantly higher transcytosis efficiency in an invitro blood-brain barrier monolayer compared with the parent L-peptide. When modified on liposomal surface, (CDX)-C-D facilitated significant brain-targeted delivery of liposomes. As a result, brain-targeted delivery of (CDX)-C-D 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.

引用

页码：3023 / 3027

页数：5

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