The conventional method for controlling blood glucose levels (BGLs) involves the repeated subcutaneous injection of insulin, which is challenging to achieve satisfied blood glucose regulation and could often lead to hypoglycemia. Therefore, the development of self-regulated, glucose-triggered insulin delivery systems has attracted considerable attentions these years. Herein, we describe a new glucose-responsive insulin delivery formulation with ultrafast response both in vitro and in vivo, dependent on a glucose-triggered charge switch of a cationic polymer. A polymer (designated as poly(EDAA0.4-FPBA0.6)) with pendant amine and 4-carboxy-3-fluorophenylboronic acid was synthesized. Next, a stable complex with high insulin loading capacity (50%) and slow basal insulin release rate was prepared from an equal weight of insulin and polymer in PBS at 7.4. The addition of F-insulin to glucose solution led to decrease of the glucose level by 10 and 30 mg/dL for 100 and 400 mg/dL glucose solution, respectively, within 10 min. Meanwhile, the ζ-potential of poly(EDAA0.4-FPBA0.6) nanoparticles was decreased from the original +40 mV in the absence of glucose, to +22 mV in 100 mg/dL glucose solution, and further decreased to less than +8 mV in 400 mg/dL glucose solution. As a consequence, the insulin release kinetic from the complexes was highly glucose dependent. The in vivo therapeutic efficacy of F-insulin was evaluated in type 1 diabetic mouse model induced by streptozotocin. The BGLs of F-insulin treated group decreased to below 200 mg/dL within 30 min, and further maintained BGLs within the normal range (< 200 mg/dL) for more than 8 hours.


Z. Gu: None.

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