Aptamer Functionalized Liposomes Co-Loaded with Exenatide-4 and Coenzyme Q10 Ameliorate Type 2 Diabetes Mellitus by Improving Pancreatic β Cell Function

Shangying Xiao,1 Lei Rao,2 Canying Yan,1 Ling Nie,1 Leiqi Wang,1 Yingyin Zhao,1 Shihao Zhang,1 WeiMao Zhan,1 Dongyun Qin,1 Manjiao Zhuang1 1Guangdong Provincial Key Laboratory of Research and Development of Natural Drugs, and School of Pharmacy, Guangdong Medical University, Dongguan, People’s Republic of China; 2Medical College, Shaoguan University, Shaoguan, People’s Republic of ChinaCorrespondence: Dongyun Qin; Manjiao Zhuang, Guangdong Provincial Key Laboratory of Research and Development of Natural Drugs, and School of Pharmacy, Guangdong Medical University, Dongguan, People’s Republic of China, Tel +15692005207, Email [email protected]; [email protected]: 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.Methods: (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.Results: (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.Conclusion: (E+Q)-Lip-Apt could improve oxidative stress, thereby restoring pancreatic β-cell function, and alleviating diabetes. Keywords: liposomes, type 2 diabetes mellitus, oxidative stress, targeted therapy, reactive oxygen species