Xing Yabing, Hu Wentao, Li Yuxin, Zhang Yuru, Zhang Yulu, Wang Binghua, Guo Xinhong
Department of Pharmacy, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou, Henan, People's Republic of China.
School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan, People's Republic of China.
Int J Nanomedicine. 2025 Apr 14;20:4661-4675. doi: 10.2147/IJN.S506086. eCollection 2025.
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.
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 -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.
Compared with 2-ME-NPs, 2-ME-CMZ -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 -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.
Compared with 2-ME-NPs, 2-ME-CMZ -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 -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.
2-甲氧基雌二醇（2-ME）已被证明具有广泛的抗肿瘤作用；然而，各种挑战阻碍了其临床应用。在本研究中，我们旨在设计一种新型的2-ME口服给药系统，采用双靶点修饰策略来解决其吸收差和快速消除的固有缺点，同时提高口服生物利用度和抗肿瘤效果。
合成了甘露糖（M）修饰的玉米醇溶蛋白（MZ）和半胱氨酸（C）修饰的玉米醇溶蛋白（CZ）。以质量比为1:1:9的MZ、CZ和玉米醇溶蛋白通过溶剂蒸发法制备了葡萄糖转运蛋白（GLUT）靶向黏附纳米粒（NPs），即2-ME-CMZ-NPs。评估了它们的体外和体内性质，包括体外释放、黏附性、抗肿瘤效果等。
与2-ME-NPs相比，2-ME-CMZ-NPs在模拟肠液（SIF）中的黏蛋白吸附增加了3.89倍，平均驻留时间（MRT）延长了0.61倍，Caco-2细胞摄取增加了1.2倍，从而使单剂量给药后的有效浓度维持时间（MTEC）延长了2.53倍，口服生物利用度提高了3.7倍，肿瘤生长抑制率提高了1.06倍。有趣的是，对于2-ME-CMZ-NPs，其细胞摄取与多种GLUT亚型的介导有关，具有相对特异性，它们显著增强了2-ME-NPs原有的细胞摄取途径，并且显示出比2-ME-NPs更高的肿瘤分布。然而，仅用甘露糖修饰2-ME-NPs仅使2-ME-NPs的口服生物利用度提高了0.44倍。
与2-ME-NPs相比，2-ME-CMZ-NPs通过多种GLUT亚型的介导显著增强了吸收，增强了其原有的细胞摄取途径并延长了吸收时间。这些发现表明，2-ME-CMZ-NPs是一种极有前景的2-ME口服给药系统，赋予GLUT靶向载药纳米粒黏附性是充分发挥GLUT在介导口服吸收中作用的有效策略。
