Prolonged melittin release from polyelectrolyte-based nanocomplexes decreases acute toxicity and improves blood glycemic control in a mouse model of type II diabetes.

Gating modifier toxins (GMTs) from animal venom have shown great potential in controlling blood glucose levels in type II diabetes (T2D), but their high acute toxicity and quick clearance in the body hamper their potential therapeutic use. Inspired by their highly positive charge, we have developed a nanocomplex system based on polyelectrolytes, in which strong interactions form between positively charged GMTs and negatively charged dextran sulfate (DS). Using melittin as a model GMT and adapting flash nanocomplexation (FNC) technology for complex preparation, uniform nanocomplexes (polydispersity index: ~0.1) with high melittin encapsulation efficiency (~100%), high payload capacity (~30%), and tunable release profiles were formulated. In contrast to the high acute liver toxicity and low survival rate (60% after 8 days) observed after a single intraperitoneal (i.p.) injection of 3 mg/kg free melittin, melittin-loaded nanocomplexes displayed improved safety (100% survival after 8 days) due to prolonged melittin release. In a mouse model of T2D, a single i.p. injection of nanocomplexes decreased the blood glucose level to 12 mmol/L within 12 h and maintained it within the therapeutic range (<15 mmol/L) for 48 h. In addition, body weight decreased following treatment. This GMT/DS binary system shows great promise due to its simple components, facile preparation method, and enhanced potential druggability, including a decreased dosing frequency, decreased acute toxicity, and improved pathological indicators.

Sustained release of exendin-4 from tannic acid/Fe (III) nanoparticles prolongs blood glycemic control in a mouse model of type II diabetes.

Exendin-4 has been clinically adopted as an effective drug for treating type 2 diabetes (T2D), but its short circulation half-life in the blood requires two injections per day to maintain effective glycemic control. This significantly limits its clinical application. In this study, we developed a tannic acid/exendin-4/Fe3+ ternary nanoparticle system to provide sustained release of exendin-4 in vivo. The formation of these nanoparticles relies on TA/exendin-4 complexation and stabilization through TA-Fe3+ coordination, where the rapid reaction kinetics can benefit from efficient mixing of all three components. Adapting our recently developed flash nanocomplexation (FNC) method, we formulated nanoparticles with high encapsulation efficiency (~ 100%) of exendin-4, high payload capacity, and high degrees of uniformity and stability because the rapid turbulent mixing facilitated a homogeneous distribution of all three components in the complexation process. Intraperitoneal injection in mice showed that exendin-4 released from the nanoparticles had an AUC 7.2-fold higher than the free exendin-4 injection. Efficacy study in a T2D mouse model showed that the optimized formulation achieved a rapid reduction of the blood glucose level to the normal range within <12 h and maintained the same level for 72 h following a single intraperitoneal dose. The blood glucose level was maintained to below the therapeutic level (< 15 mmol/L) for 6 days, and the treatment led to reduced body weight with pathological and functional improvements in the kidney and liver. This tannic acid/exendin-4/Fe3+ ternary nanoparticle system holds translational potential in treating T2D, due to its improved treatment outcomes in terms of extended release of exendin-4, prolonged control of blood glucose level, reduced dosing frequency, and improved pathological indicators.