Yabing Xing,1 Wentao Hu,2 Yuxin Li,2 Yuru Zhang,2 Yulu Zhang,2 Binghua Wang,2,3 Xinhong Guo2,3 

1Department of Pharmacy, Children’s Hospital Affiliated to Zhengzhou University, Zhengzhou, Henan, People’s Republic of China; 2School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan, People’s Republic of China; 3Henan Key Laboratory of Nanomedicine for Targeting Diagnosis and Treatment, Zhengzhou, Henan, People’s Republic of China

Correspondence: Xinhong Guo, School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue road, Zhengzhou, Henan, 450001, People’s Republic of China, Email gxh371@zzu.edu.cn Binghua Wang, School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue road, Zhengzhou, Henan, 450001, People’s Republic of China, Email wbh1005@zzu.edu.cn

Purpose: 2-Methoxyestradiol (2-ME) has been demonstrated to possess extensive antitumor effects; however, various challenges have impeded its clinical utilization. In this study, we aimed to design a novel oral delivery system for 2-ME using a dual-target modification strategy to address the inherent drawbacks associated with poor absorption and rapid elimination, as well as to enhance oral bioavailability and antitumor effects.
Methods: Mannose(M)-modified zein (MZ) and cysteine(C)-modified zein (CZ) were synthesized. Glucose transporter (GLUT)-targeted adhesive nanoparticles (NPs), designated as 2-ME-CMZ (1:1:9)-NPs, were prepared via a solvent evaporation method using MZ, CZ, and Zein at a mass ratio of 1:1:9. Their in vitro and in vivo properties, including in vitro release, adhesion, antitumor effects etc. were evaluated.
Results: Compared with 2-ME-NPs, 2-ME-CMZ (1:1:9)-NPs showed a 3.89-fold increase in mucin adsorption in simulated intestinal fluid (SIF), a 0.61-fold extension of mean residence time (MRT), and a 1.2-fold increase in Caco-2 cell uptake, thereby prolonging the maintenance time of effective concentration (MTEC) after single-dose administration by 2.53-fold and enhancing oral bioavailability by 3.7-fold and tumor growth inhibition rate by 1.06-fold. Interestingly, for 2-ME-CMZ (1:1:9)-NPs, their cellular uptake was related to the mediation of multiple subtypes of GLUT with relative specificity, and they significantly enhanced the original cellular uptake pathway of 2-ME-NPs and showed higher tumor distribution than 2-ME-NPs. However, merely modifying 2-ME-NPs with mannose only increased the oral bioavailability of 2-ME-NPs by 0.44-fold.
Conclusion: Compared with 2-ME-NPs, 2-ME-CMZ (1:1:9)-NPs significantly enhanced absorption through the mediation of multiple subtypes of GLUT, enhancing their original cellular uptake pathway and prolonging absorption time. These findings demonstrated that 2-ME-CMZ (1:1:9)-NPs are an extremely promising oral drug delivery system for 2-ME, and endowing GLUT-targeted drug-loaded nanoparticles with adhesion is an effective strategy for fully leveraging the role of GLUT in mediating oral absorption.

Keywords: 2-methoxyestradiol, GLUT, mannose, cysteine, zein, oral bioavailability