High oral bioavailability of 2-methoxyestradiol in PEG-PLGA micelles-microspheres for cancer therapy

【作者】 XinHong Guo, CaiPing Chen, Xin Liu, PanPan Hou, XiaoNan Guo, Fang Ding, ZhiHao Wang, YuRong Hu, Zhi Li* and ZhenZhong Zhang*  

【期刊名】 European Journal of pharmaceutics and biopharmaceutics

【影响因子】 2016年: 3.975

【作者单位】School of Pharmaceutical Sciences,Zhengzhou University,100 Kexue Avenue, Zhengzhou 450001, People’s Republic of China

【年，卷(期)：页码】2017, 117:116-122

【关键词】 2-methoxyewtradiol; Polymer micelles; pH-sensitive microspheres; Sustained release; Oral bioavailability; Anti-tumor effect

【摘要】 The development of effective oral preparations of 2-methoxyestradiol (2-ME) has been a worldwide problem. In this study, breakthrough progress has been made in oral delivery of 2-ME by encapsulating 2-ME micelles in pH-responsive microspheres. 2-ME micelles with small particle size (58 nm) and high drug loading (7.94±0.23%) were successfully prepared and showed slower release characteristics and 12.8 times higher cytotoxicity on 4T1 cells than free 2-ME. The pH-sensitive microspheres could slowly release 82% of 2-ME micelles for 10 h in PBS (7.4). After oral administration to rats, 2-ME-micelles-microspheres compared to 2-ME micelles could prolonged significantly blood retention time (MRT) of 2-ME by 12 times and enhanced oral absolute bioavailability from 49.99% to 121.68%. In vivo imaging of 4T1 tumor-bearing mice showed that retention time and intensity of the fluorescence signal in each 2-ME preparation group all were consistent with the pharmacokinetic results and intact 2-ME micelles in the microspheres could be absorbed in intestine to blood to target to tumor. Furthermore, after the 4T1 tumor-bearing mice were treated with oral 2-ME-micelles-microspheres for 21 days, the tumor growth inhibition rate achieved 94.93% and the mice weight gained significantly, indicating their high antitumor activity and low toxicity. While oral administration of 2-ME micelles and 2-ME microspheres all were ineffective under the same conditions. Therefore, micelles-microspheres might be a promising candidate for oral administration of 2-ME for cancer therapy.

【全文链接】http://www.sciencedirect.com/science/article/pii/S0939641117304393