Lisa R. Volpatti
Diabetes mellitus is a class of diseases in which the body either does not produce or is insensitive to insulin. The lack of proper insulin regulation results in poorly controlled blood glucose levels, often leading to severe complications including heart disease, stroke, and kidney failure. Patient compliance is also a major challenge due to pain and discomfort as well as fear of needles when measuring blood glucose levels. An attractive diabetes therapy is therefore the self-regulated delivery of insulin to recapitulate deficient insulin production or signaling. In order for a self-regulated system to be therapeutically relevant, it must rapidly respond to changes in glucose concentration. To achieve this goal, acetal-functionalized dextran (Ac-dex) was synthesized with various degrees of modification and formulated into nanoparticles encapsulating insulin, glucose oxidase (GOx), and catalase. GOx converts glucose to gluconic acid and reduces the pH in the microenvironment of the nanoparticles. The acetal groups are subsequently cleaved from the polymer in an acid catalyzed reaction, solubilizing the native dextran and releasing the insulin on demand. We demonstrate that a mix of nanoparticles synthesized from Ac-dex with 55% or 71% of residues containing a cyclic acetal modification release 100% of encapsulated insulin within the first 2 hours of exposure to hyperglycemic conditions with prolonged release kinetics under lower concentrations of glucose. We next preconcentrate nanoparticles into alginate microgels with an average diameter of 400 µm without altering the insulin release kinetics. We demonstrate that when injected subcutaneously, the alginate microgels release minimal insulin in a healthy mouse model but rapidly correct the blood glucose levels in a diabetic mouse model even after multiple glucose injections. Therefore, alginate microgels encapsulating nanoparticles synthesized from a range of modified dextran polymers show promise in creating a fast-acting glucose-responsive insulin delivery system that has the potential to modulate glucose levels on a therapeutically relevant timescale.