Engineered insulin-polycation complexes for glucose-responsive delivery with high insulin loading.

Abstract Glucose-responsive insulin delivery systems have the potential to improve quality of life for individuals with diabetes by improving blood sugar control and limiting the risk of hypoglycemia. However, systems with desirable insulin release kinetics and high loading capacities have proven difficult to achieve. Here, we report the development of electrostatic complexes (ECs) comprised of insulin, a polycation, and glucose oxidase (GOx). Under normoglycemic physiological conditions, insulin carries a slight negative charge and forms a stable EC with the polycation. In hyperglycemia, the encapsulated glucose-sensing enzyme GOx converts glucose to gluconic acid and lowers the pH of the microenvironment, causing insulin to adopt a positive charge. Thus, the electrostatic interactions are disrupted, and insulin is released. Using a model polycation, we conducted molecular dynamics simulations to model these interactions, synthesized ECs with > 50% insulin loading capacity, and determined in vitro release kinetics. We further showed that a single dose of ECs can provide a glycemic profile in streptozotocin-induced diabetic mice that mimics healthy mice over a 9 h period with 2 glucose tolerance tests.