Xiao Shangying, Rao Lei, Yan Canying, Nie Ling, Wang Leiqi, Zhao Yingyin, Zhang Shihao, Zhan WeiMao, Qin Dongyun, Zhuang Manjiao
Guangdong Provincial Key Laboratory of Research and Development of Natural Drugs, and School of Pharmacy, Guangdong Medical University, Dongguan, People's Republic of China.
Medical College, Shaoguan University, Shaoguan, People's Republic of China.
Int J Nanomedicine. 2025 Mar 17;20:3363-3378. doi: 10.2147/IJN.S510240. eCollection 2025.
Oxidative stress has been shown to disrupt β-cell function and promote the development of type 2 diabetes mellitus (T2DM). Exenatide-4 (Ext-4) is a widely used anti-glycemic drug but cannot restore pancreatic β-cells' structure and function. Coenzyme Q10 (CoQ10) has great antioxidant activities but shows suboptimal therapeutic effects because of its poor solubility and poor bioavailability. To further enhance the therapeutic efficacy of the drugs, a pancreas-targeting liposomal co-delivery system encapsulating Ext-4 and CoQ10 ((E+Q)-Lip-Apt) was designed, using the aptamers as the targeting ligands.
(E+Q)-Lip-Apt was prepared by thin film dispersion method and its optimal formulation was obtained through single-factor experiments and orthogonal experiments. The pancreatic β-cell protecting effect of (E+Q)-Lip-Apt was investigated both in vitro and in vivo.
(E+Q)-Lip-Apt exhibited uniform size, good dispersion, and high encapsulation efficiency (EE) for both Ext-4 and CoQ10. The in vitro results showed that (E+Q)-Lip-Apt manifested superior capacity in scavenging ROS, enhancing mitochondrial membrane potential, and reducing malondialdehyde (MDA) content compared to Ext-4 in MIN6 cells. In vivo investigations demonstrated that (E+Q)-Lip-Apt significantly improved glucose tolerance, insulin sensitivity, hepatic lipid metabolism, oxidative stress, and enhanced antioxidant enzyme activity in diabetic mice. Moreover, Hematoxylin-eosin staining (H&E) and Immunohistochemistry (IHC) results indicated that (E+Q)-Lip-Apt could improve liver and pancreatic lesions, restoring the structure and function of β-cells in diabetic mice.
(E+Q)-Lip-Apt could improve oxidative stress, thereby restoring pancreatic β-cell function, and alleviating diabetes.
氧化应激已被证明会破坏β细胞功能并促进2型糖尿病（T2DM）的发展。艾塞那肽-4（Ext-4）是一种广泛使用的抗血糖药物，但不能恢复胰腺β细胞的结构和功能。辅酶Q10（CoQ10）具有强大的抗氧化活性，但由于其溶解性差和生物利用度低，治疗效果欠佳。为进一步提高药物的治疗效果，设计了一种以适体为靶向配体、包裹Ext-4和CoQ10的胰腺靶向脂质体共递送系统（(E+Q)-Lip-Apt）。
采用薄膜分散法制备(E+Q)-Lip-Apt，并通过单因素实验和正交实验获得其最佳配方。在体外和体内研究了(E+Q)-Lip-Apt对胰腺β细胞的保护作用。
(E+Q)-Lip-Apt粒径均匀、分散性好，对Ext-4和CoQ10均具有较高的包封率（EE）。体外实验结果表明，与MIN6细胞中的Ext-4相比，(E+Q)-Lip-Apt在清除活性氧、增强线粒体膜电位和降低丙二醛（MDA）含量方面表现出更强的能力。体内研究表明，(E+Q)-Lip-Apt可显著改善糖尿病小鼠的糖耐量、胰岛素敏感性、肝脏脂质代谢、氧化应激，并增强抗氧化酶活性。此外，苏木精-伊红染色（H&E）和免疫组织化学（IHC）结果表明，(E+Q)-Lip-Apt可以改善肝脏和胰腺病变，恢复糖尿病小鼠β细胞的结构和功能。
(E+Q)-Lip-Apt可以改善氧化应激，从而恢复胰腺β细胞功能，减轻糖尿病症状。
