基于透明质酸的缺氧响应型胶束的制备及性能研究

doi:10.6023/A17070336

化学学报 ›› 2018, Vol. 76 ›› Issue (1): 35-42.DOI: 10.6023/A17070336 上一篇下一篇

研究论文

基于透明质酸的缺氧响应型胶束的制备及性能研究

张蓓^a, 常柏松^b, 孙涛垒^a,b

a 武汉理工大学化学化工与生命科学学院武汉 430070;
b 武汉理工大学材料复合新技术国家重点实验室武汉 430070

投稿日期:2017-07-25 发布日期:2017-11-10
通讯作者: 孙涛垒 E-mail:suntl@whut.edu.cn
基金资助:
项目受国家杰出青年基金（No.51325302）、国家自然科学基金（No.51533007）、国家重点基础研究发展规划项目（No.2013CB933002）、复旦大学聚合物分子工程国家重点实验室开放项目（No.K2017-10）和湖北省自然科学基金（No.2015CFB304）资助.

Synthesis and Study of Hypoxia-Responsive Micelles Based on Hyaluronic Acid

Zhang Bei^a, Chang Baisong^b, Sun Taolei^a,b

a School of Chemistry, Chemical Engineering and Life Sciences, Wuhan University of Technology, Wuhan 430070;
b State Key Laboratory of Advanced Technology for Materials Synthesis and Processing, Wuhan University of Technology, Wuhan 430070

Received:2017-07-25 Published:2017-11-10
Contact: 10.6023/A17070336 E-mail:suntl@whut.edu.cn
Supported by:
Project supported by the China National Funds for Distinguished Young Scientists (No. 51325302), the National Natural Science Foundation of China (No. 51533007), the Major State Basic Research Development Program of China (No. 2013CB933002), the Open Project Program of the State Key Lab of Molecular Engineering of Polymers, the Fudan University (No. K2017-10) and the Natural Science Foundation of Hubei Province (No. 2015CFB304).

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摘要/Abstract

以透明质酸（HA）及硝基咪唑（NI）衍生物为原料，通过酰胺反应合成了一种两亲性接枝聚合物（HA-NI）.该聚合物具有缺氧响应性和肿瘤靶向性.利用傅里叶红外光谱（FT-IR）和核磁共振（NMR）对接枝聚合物的结构进行了表征，同时基于¹H NMR计算出接枝聚合物中NI的取代度.HA-NI在水中自组装形成胶束，利用动态光散射仪（DLS）表征胶束大小并对胶束的稳定性进行了研究，利用原子力显微镜（AFM）和透射电镜（TEM）观察胶束形貌.载药胶束的载药率（DL）和包封率（EE）通过紫外-可见吸收光谱（UV）测试并计算得到.胶束的缺氧响应性利用DLS、AFM、TEM、UV等探究.实验证明，该聚合物胶束具有缺氧响应性并对药物表现出良好的控制释放能力，在常氧环境下，胶束稳定存在；而在缺氧环境下，胶束散开，药物快速且完全地释放.

关键词: 药物传输体系, 缺氧响应, 透明质酸, 硝基咪唑, 胶束

Hypoxia is a hallmark of tumor. Based on this feature, a hypoxia-responsive drug delivery system combined with tumor-targeting was developed. HA-NI conjugates were prepared by grafting the carboxyl group of hyaluronic acid (HA) with an amine group of nitroimidazole (NI) derivative in the presence of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC) and N-hydroxysuccinimide (NHS). The structure of HA-NI conjugates was confirmed by FT-IR and ¹H NMR, the degree of substitution (DS) of NI derivative was also calculated based on ¹H NMR. Amphiphilic HA-NI conjugates could self-assemble into micelles by ultrasonic method. The size and morphology of micelles were characterized by dynamic light scattering (DLS), atomic force microscope (AFM) and transmission electron microscopy (TEM), the stability of micelles was also investigated by DLS. It was found the size of micelles was in the range of 80~220 nm while the DS decreased from 6.5% to 3.6%. Doxorubicin (DOX) was encapsulated in micelles, and DOX-loaded micelles had smaller sizes compared with blank micelles. Drug-loading (DL) and entrapment efficiency (EE) were obtained by UV-Vis analysis and increased with the increasing DS. Under hypoxic condition, micelles became bigger and size distribution of micelles became wider, it was clear to observe the destruction of micelles by AFM and TEM. UV spectrum revealed the characteristic peak belonging to NI at 325 nm disappeared and Zeta potential increased from -30.6±0.4 mV to -24.9±0.5 mV 6 h later. In vitro drug release studies demonstrated that DOX was released from HA-NI micelles in a hypoxia-dependent manner:micelles were sufficiently stable at normoxic condition while accomplished a rapid drug release under hypoxic condition.

Key words: drug delivery system, hypoxia-responsive, hyaluronic acid, nitroimidazole, micelles

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张蓓, 常柏松, 孙涛垒. 基于透明质酸的缺氧响应型胶束的制备及性能研究[J]. 化学学报, 2018, 76(1): 35-42.

Zhang Bei, Chang Baisong, Sun Taolei. Synthesis and Study of Hypoxia-Responsive Micelles Based on Hyaluronic Acid[J]. Acta Chim. Sinica, 2018, 76(1): 35-42.

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基于透明质酸的缺氧响应型胶束的制备及性能研究

Synthesis and Study of Hypoxia-Responsive Micelles Based on Hyaluronic Acid

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