(351b) Insulin Delivery Using Biomaterials with Integrated Diboronate Motifs

Diabetes presents a growing global healthcare challenge. Currently, the standard of care for type-1 diabetes is multiple insulin injections daily or use of an insulin pump. However, traditional insulin therapy often fails to provide sufficient glycemic control, leading to a number of short-term and long-term complications. Thus, there remains an urgent need for new insulin therapies that better control blood glucose. Recently, glucose-responsive biomaterials based on dynamic-covalent bonding between phenylboronic acids (PBA) and diol motifs have gained attention for their use toward self-regulated insulin delivery. However, common PBA–diol chemistries have two key drawbacks: 1) PBAs have significantly higher binding affinity for the synthetic diol motifs used in network crosslinking than for glucose, limiting glucose sensitivity and glucose-responsive function of the resulting material under physiological glucose levels; 2) PBAs bind to other common analytes, such as fructose and lactate, with higher binding affinity than to glucose, limiting specificity in glucose sensing and raising risks for undesired and non-specific insulin leakage under normoglycemia. Here, we report the use of diphenylboronate (DiPBA) glucose sensors integrated within biomaterials intended for insulin delivery. This DiPBA motif offers high affinity and specificity in binding to glucose, utilizing its rigid diboronate to simultaneously bind two sites on a single glucose molecule. This DiPBA was designed, synthesized, and compared to a commonly used 4-carboxyl-3-fluorophenylboronic acid (FPBA) motif. The new DiPBA motif afforded significantly higher affinity in binding glucose than did the FPBA; the DiPBA motif further afforded high selectivity for glucose binding relative to fructose and lactate, whereas the FPBA actually bound these other analytes with higher affinity than glucose. DiPBA- and FPBA-modified PEG macromers were next synthesized and combined with a diol-bearing PEG macromer to prepare hydrogels and explore glucose-responsive and glucose-specific function. Hydrogel materials prepared from DiPBA–diol crosslinks were more glucose-responsive than their FPBA counterparts, translating to enhanced glucose-sensitivity in insulin release. These glucose-specific DiPBA hydrogels were furthermore able to resist fructose and lactate for better glucose-specific insulin release in vitro and enhanced blood glucose control in vivo. The glucose-responsive and glucose-specific features of this DiPBA motif have furthermore enabled its versatile use as a glucose sensor in the context of other polymeric systems beyond these initial PBA–diol PEG hydrogels as well as in protein-polymer conjugates. In one recent example, a nanoaggregate platform utilizing DiPBA as a glucose-sensing solubility trigger was able to afford dramatic glucose-dependent insulin solubility and long-lasting, multi-day function in controlling blood glucose in a diabetic mouse model. Overall, this DiPBA motif offer a new sensing chemistry for integration into biomaterials intended for insulin delivery, proving a route to overcome the known limitations of commonly used PBA chemistries and affording more sensitive and specific biomaterials for glucose-responsive insulin delivery.