用于肺部给药的布地奈德白蛋白纳米粒中的分子相互作用

doi:10.5246/jcps.2018.06.042

中国药学(英文版) ›› 2018, Vol. 27 ›› Issue (6): 415-428.DOI: 10.5246/jcps.2018.06.042

用于肺部给药的布地奈德白蛋白纳米粒中的分子相互作用

孟帅¹, 崔巍², 林少辉¹, 王桂玲¹, 黑玉¹, 邓博¹, 马爽¹, 张展¹, 刘迎春³, 谢英^1*

1. 北京大学医学部药学院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与化学工程学院, 北京 100049
3. 浙江大学化学系与软物质研究中心, 浙江杭州 310027

收稿日期:2018-04-13 修回日期:2018-05-18 出版日期:2018-06-30 发布日期:2018-05-23
通讯作者: Tel.: +86-010-82805351; Fax: +86-010-82802745, E-mail: bmuxieying@bjmu.edu.cn
基金资助:
The National Natural Science Foundation of China (Grant No. 81202469) and Founder of new drug research fund (Grant No. 20130527).

Modeling the molecular interactions of budesonide with bovine serum albumin guides the rational preparation of nanoparticles for pulmonary delivery

Shuai Meng¹, Wei Cui², Shaohui Lin¹, Guiling Wang¹, Yu Hei¹, Bo Deng¹, Shuang Ma¹, Zhan Zhang¹, Yingchun Liu³, 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 Chemistry and Chemical Engineering, University of Chinese Academy of Sciences, Beijing 100049, China
3. Soft Matter Research Center and Department of Chemistry, Zhejiang University, Hangzhou 310027, Zhejiang, China

Received:2018-04-13 Revised:2018-05-18 Online:2018-06-30 Published:2018-05-23
Contact: Tel.: +86-010-82805351; Fax: +86-010-82802745, E-mail: bmuxieying@bjmu.edu.cn
Supported by:
The National Natural Science Foundation of China (Grant No. 81202469) and Founder of new drug research fund (Grant No. 20130527).

摘要/Abstract

摘要：

基于白蛋白纳米粒的中空性纳米聚集颗粒(LHNAs)是一种用于治疗肺部疾病的新型药物递送系统(DDS), 其由于具有良好的空气动力学特性有望成为一种有前途的肺部干粉吸入剂(DPI)。深入理解DDS中的分子作用机制有利于制剂的合理制备。本研究利用计算和实验相结合的方法揭示了布地奈德(BUD)与牛血清白蛋白(BSA)在分子水平上相互作用的机制。分子动力学模拟结果显示, BUD和BSA有三个结合位点(P1, P2, P3), 作用方式主要为疏水相互作用和氢键。P1–P3处的残基能量分解结果表明BUD与BSA结合位点周围的非极性残基具有重要作用。载药率实验表明制剂中BUD与BSA摩尔比接近3, 进一步证实了计算模拟的结果。计算得到的关于BUD与BSA结合位点的细节为设计包载BUD的BSA纳米颗粒提供了指导, 并最终成功制备了纳米粒。分子动力学模拟和实验的结合揭示分子间相互作用机制, 为今后制备BSA-LHNAs干粉吸入剂提供了坚实的理论基础。

关键词: 分子动力学, 相互作用机制, 白蛋白纳米粒, 布地奈德, 合理制备

Abstract:

Large Hollow nanoparticulate aggregates (LHNAs) based on albumin nanoparticles is a promising technology for developing dry powder inhaler (DPI) with good aerodynamic properties in order to provide a new drug delivery system (DDS) for the treatment of lung disease. Improved understanding of molecular interactions could lead to prepare the DDS rationally. Therefore, this investigation utilized computations and experiments to reveal the mechanisms of budesonide (BUD) interactions with bovine serum albumin (BSA) at the molecular level. The molecular dynamics (MD) simulation revealed that there were three critical stable binding sites of BUD on BSA (P1, P2, P3) mainly by hydrophobic interaction and hydrogen bond. The energydecomposition of each residue to the whole BUD-BSA complex system in P1-P3 showed that nonpolar residues in or around the binding site played an important role in the binding of BUD to BSA. The molar ratio was close to 3 in preparations in drug-loading efficiency experiment, which was confirmed to the simulation results. The details of the binding sites from computation provided a guideline for the design of the BSA nanoparticles carrying BUD, which was prepared successfully at last. Combination of the MD simulation and experiment as well as the mechanism of the molecular interaction provided a solid theoretical basis for the preparation of BSA-LHNAs for DPI in the future.

Key words: Molecular dynamics, Interaction mechanism, BSA nanoparticles, Budesonide, Rational preparation

中图分类号:

R943

Supporting:

孟帅, 崔巍, 林少辉, 王桂玲, 黑玉, 邓博, 马爽, 张展, 刘迎春, 谢英. 用于肺部给药的布地奈德白蛋白纳米粒中的分子相互作用[J]. 中国药学(英文版), 2018, 27(6): 415-428.

Shuai Meng, Wei Cui, Shaohui Lin, Guiling Wang, Yu Hei, Bo Deng, Shuang Ma, Zhan Zhang, Yingchun Liu, Ying Xie. Modeling the molecular interactions of budesonide with bovine serum albumin guides the rational preparation of nanoparticles for pulmonary delivery[J]. Journal of Chinese Pharmaceutical Sciences, 2018, 27(6): 415-428.

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用于肺部给药的布地奈德白蛋白纳米粒中的分子相互作用

Modeling the molecular interactions of budesonide with bovine serum albumin guides the rational preparation of nanoparticles for pulmonary delivery

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