title: High oral bioavailability of 2-methoxyestradiol in PEG-PLGA micelles-microspheres for cancer therapy.
abstract: 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 (58nm) 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 10h in PBS (7.4). After oral administration to rats, 2-ME-micelles-microspheres compared to 2-ME micelles could prolong significantly blood retention time (MRT) of 2-ME by 12 times and enhance 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 21days, 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.
authors.affiliation: School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou 450001, People's Republic of China.
authors.forename: XinHong
authors.initials: X
authors.lastname: Guo
authors.affiliation: School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou 450001, People's Republic of China.
authors.forename: CaiPing
authors.initials: C
authors.lastname: Chen
authors.affiliation: School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou 450001, People's Republic of China.
authors.forename: Xin
authors.initials: X
authors.lastname: Liu
authors.affiliation: School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou 450001, People's Republic of China.
authors.forename: PanPan
authors.initials: P
authors.lastname: Hou
authors.affiliation: School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou 450001, People's Republic of China.
authors.forename: XiaoNan
authors.initials: X
authors.lastname: Guo
authors.affiliation: School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou 450001, People's Republic of China.
authors.forename: Fang
authors.initials: F
authors.lastname: Ding
authors.affiliation: School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou 450001, People's Republic of China.
authors.forename: ZhiHao
authors.initials: Z
authors.lastname: Wang
authors.affiliation: School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou 450001, People's Republic of China.
authors.forename: YuRong
authors.initials: Y
authors.lastname: Hu
authors.affiliation: School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou 450001, People's Republic of China.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Li
authors.affiliation: School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou 450001, People's Republic of China. Electronic address: 15237155029@126.com.
authors.forename: ZhenZhong
authors.initials: Z
authors.lastname: Zhang
mesh_terms: D000077584:2-Methoxyestradiol; D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000378:metabolism*; D001682:Biological Availability; D004305:Dose-Response Relationship, Drug; D004958:Estradiol / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism; D005260:Female; D051379:Mice; D008807:Mice, Inbred BALB C; D008823:Micelles; D008863:Microspheres; D011091:Polyesters / Q000008:administration & dosage / Q000378:metabolism*; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000378:metabolism*; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D050257:Tubulin Modulators / Q000008:administration & dosage / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects / Q000502:physiology
chemical_list: D000970:Antineoplastic Agents; D008823:Micelles; D011091:Polyesters; D050257:Tubulin Modulators; C000589473:polyethylene glycol-poly(lactide-co-glycolide); D011092:Polyethylene Glycols; D004958:Estradiol; D000077584:2-Methoxyestradiol
keywords: 2-Methoxyestradiol; Anti-tumor effect; Oral bioavailability; Polymer micelles; Sustained release; pH-sensitive microspheres