A polyphenol-metal nanoparticle platform for tunable release of liraglutide to improve blood glycemic control and reduce cardiovascular complications in a mouse model of type II diabetes

摘要

Liraglutide is a GLP-1 receptor agonist recently approved for Type-II diabetes (T2D) treatment with superior hypoglycemic effect while also improving cardiovascular function for the patients. However, its application has been limited by its short half-life (similar to 13 h), which requires daily injections to maintain effective drug concentrations in blood, thus increasing the risk of poor patient compliance and complications. In this study, we developed a ternary liraglutide/tannic acid (TA)/Al3+ nanoparticle system based on hydrogen bond formation between liraglutide and TA and stabilized by complex coordination interaction between TA and Al3+. This ternary nanoparticle formulation offers sustained release of liraglutide for > 8 days by optimizing the concentration of TA during nanoparticle assembly. A flash nanocomplexation (FNC) process was adopted to confer homogeneous mixing of the three components and control the assembly kinetics, thus enabling efficient encapsulation, a tunable drug release profile, improved nanoparticle size uniformity, and a high degree of colloidal stability. Upon a single intraperitoneal (i.p.) administration, the optimized formulation effectively lowered the high blood glucose level in a T2D db/db mice model to the normal range (8-10 mmol/L) within 6 h, maintained it for 60 more hours, and kept it lower than the original level for > 6 days. In a 30-day treatment study, the nanoparticle formulation with a dosage frequency of once every 5 days exhibited similar or better control of blood sugar level (20% reduction in HbAlc) and weight control than daily injection of free liraglutide at the same treatment dose. The extended glycemic control led to distinctive improvements on reducing cardiomyopathy, including inhibition in lipo-toxicity by decreasing 40% of triglyceride, 30% of diacylglycerol and 50% of PKC level in the heart, as well as ameliorating oxidative stress and cell apoptosis activities through positive regulation on superoxidase, malondialdehyde, caspase-3 and Bax. This nanoparticle system demonstrates improved therapeutic potential owing to its long-acing glycemic control with improved cardiovascular function and reduced tissue toxicity in multiple organs.