Citation: Zhang Bei, Chang Baisong, Sun Taolei. Synthesis and Study of Hypoxia-Responsive Micelles Based on Hyaluronic Acid[J]. Acta Chimica Sinica, ;2018, 76(1): 35-42. doi: 10.6023/A17070336 shu

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

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

Corresponding author: Sun Taolei, suntl@whut.edu.cn
Received Date: 25 July 2017
Available Online: 10 January 2017
Fund Project: 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)the China National Funds for Distinguished Young Scientists 51325302the National Natural Science Foundation of China 51533007the Major State Basic Research Development Program of China 2013CB933002the Open Project Program of the State Key Lab of Molecular Engineering of Polymers, the Fudan University K2017-10the Natural Science Foundation of Hubei Province 2015CFB304

Figures(11)

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.
- drug delivery system,
- hypoxia-responsive,
- hyaluronic acid,
- nitroimidazole,
- micelles
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