On demand regulation of blood glucose level by biocompatible oxidized starch-Con A nanogels for glucose-responsive release of exenatide

Diabetes mellitus is a long-term chronic disease characterized by abnormal high level blood glucose (BG). An artificial closed-loop system that mimics pancreatic β-cells and releases insulin on demand has potential to improve the therapeutic efficiency of diabetes. Herein, a lectin Concanavalin A modified oxidized starch nanogel was designed to regulate glucose dynamically according to different glucose concentrations. The nanogels were formed by double cross-linking the Concanavalin A and glucose units on oxidized starch via specific binding and amide bonds to achieve the high drug loading and glucose responsiveness. The results showed that oxidized starch nanogels prolonged the half-life of antidiabetic peptide drug exenatide and released it in response to high BG concentrations. It could absorb BG at a high level and maintain glucose homeostasis. Besides, the oxidized starch nanogels performed well in recovering regular BG level from hyperglycemia state and maintaining in euglycemia state that fitted in a biological rhythm. In addition, the nanogels showed high biocompatibility in vivo and could improve plasma half-life and therapeutic efficacy of exenatide. Overall, the nanogels protected peptide drugs from degradation in plasma as a glucose-responsive platform showing a high potential for peptide drugs delivery and antidiabetic therapy. A lectin Concanavalin A (Con A) modified oxidized starch (OS) nanogels was developed through inverse-emulsion method by double cross-linking via Con A-glucose unit specific affinity binding and amide bonds between Con A and carboxyl groups on the TEMPO-oxidized starch. Peptide drug exenatide (EX) with extremely short half-life was effectively loaded into the nanogels due to its excellent swelling capacity. The EX-loaded nanogels showed a glucose-responsive controlled release property and could maintain glucose homeostasis. At low glucose concentration, the nanogels showed an interesting swelling and deswelling behavior as an “on-off” effect in response to adding glucose and removing glucose in the media. However, at high glucose concentration, glucose could competitively bind to Con A on nanogels, disrupting the nanogels and releasing the loaded EX to adjust the blood glucose level. The EX-loaded nanogels with a high biocompatibility showed a long-term therapeutic effect in diabetic mice. • OS-Con A Ngels were prepared by double cross-linking via affinity and amide bonds. • OS-Con A Ngels showed a high biocompatibility and glucose stimuli-responsive property. • OS-Con A Ngels could responsively release EX and regulate glucose hemostasis. • The Ngels prolonged the half-life of EX and improved the glucose regulating property. • Ngels-EX showed both short and long-term therapeutic efficacy in diabetes mice.