RVGP修饰脑靶向脂质体合理构建的分子基础

doi:10.5246/jcps.2019.07.047

中国药学(英文版) ›› 2019, Vol. 28 ›› Issue (7): 484-501.DOI: 10.5246/jcps.2019.07.047

RVGP修饰脑靶向脂质体合理构建的分子基础

邓博¹, 崔巍², 马爽¹, 刘晓娜¹, 张展¹, 闫百艺¹, 陈坤¹, 谢英^1*

1. 北京大学医学部药学院药剂学系; 分子药剂学与新释药系统北京市重点实验室, 北京 100191
2. 中国科学院大学化学科学学院, 北京 100049

收稿日期:2019-03-28 修回日期:2019-04-11 出版日期:2019-07-31 发布日期:2019-05-10
通讯作者: Tel.: +86-010-82805351, E-mail: bmuxieying@bjmu.edu.cn
基金资助:
National Natural Science Foundation of China (Grant No. 81202469).

Molecular basis for rational construction of RVGP modified liposomal delivery system targeting to brain

Bo Deng¹, Wei Cui², Shuang Ma¹, Xiaona Liu¹, Zhan Zhang¹, Baiyi Yan¹, Kun Chen¹, Ying Xie^1*

1. Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191, China
2. School of Chemical Sciences, University of Chinese Academy of Sciences, Beijing 100049, China

Received:2019-03-28 Revised:2019-04-11 Online:2019-07-31 Published:2019-05-10
Contact: Tel.: +86-010-82805351, E-mail: bmuxieying@bjmu.edu.cn
Supported by:
National Natural Science Foundation of China (Grant No. 81202469).

摘要/Abstract

摘要：

主动靶向脂质体的合理化构建是高效发挥其脑靶向的重要基础。目前尚缺乏对主动靶向脂质体结构-活性关系的清晰认识。我们采用多尺度计算模拟和实验验证相结合,建立了RVGP修饰的PEG化脂质体(RVGP-PEG-L)的计算模型,研究了PEG的作用规律,探讨了载体-配体-受体的分子作用机制。结果表明单体数目为42,修饰密度在8%以上的PEG在磷脂表面形成复杂的网格构象是脂质体具有长循环特征的结构基础。RVGP肽发挥靶向能力最小偶联的PEG linker的单体数为42。但由于PEG链的限制,脂质体上RVGP与受体nAChR的作用位点发生了改变,结合自由能有所降低。进一步提高PEG链长或者提高聚合物的非极性,将有助于提高RVGP-PEG-L与靶细胞乙酰胆碱受体nAChR的结合能力。

关键词: 多尺度动力学模拟, 脂质体, 分子作用机制, 合理构建

Abstract:

The rational construction of active targeting liposomes will provide an important structural support for its effective brain targeting. However, there is no clear understanding of the structure-activity relationship of active targeting liposomes. Combining multiscale computational simulation and experimental verification, we established a computational model of RVGP modified PEGylated liposomes (RVGP-PEG-L) and investigated the role of PEG and molecular interaction mechanism of carrier-ligand-receptor. The result indicated that the complex network conformation formed by PEG with 42 monomers (42PEG) above the density of 8% was the molecular basis for PEG-L to achieve long-circulation function. The lowest monomer number of PEG linker to ensure the targeting ability of RVGP was 42. However, the pose of RVGP binding to nAChR changed after it was linked with PEG-L due to the restraint of PEG chain, leading to a decrease of binding free energy. Increasing the monomer number of PEG linker or improving the non-polarity of polymers was a potential strategy to enhance the combination of RVGP-PEG-L with nAChR on the targeting cell.

Key words: Multiscale dynamic simulation, Liposomes, Molecular interaction mechanism, Rational construction

中图分类号:

R943

Supporting:

邓博, 崔巍, 马爽, 刘晓娜, 张展, 闫百艺, 陈坤, 谢英. RVGP修饰脑靶向脂质体合理构建的分子基础[J]. 中国药学(英文版), 2019, 28(7): 484-501.

Bo Deng, Wei Cui, Shuang Ma, Xiaona Liu, Zhan Zhang, Baiyi Yan, Kun Chen, Ying Xie. Molecular basis for rational construction of RVGP modified liposomal delivery system targeting to brain[J]. Journal of Chinese Pharmaceutical Sciences, 2019, 28(7): 484-501.

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RVGP修饰脑靶向脂质体合理构建的分子基础

Molecular basis for rational construction of RVGP modified liposomal delivery system targeting to brain

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