Project Summary/Abstract Type 1 diabetes accounts for approximately 10% of all diabetes cases, and is responsible for the growing number of children with the disease. Due to the destruction of insulin-releasing b-cells in the pancreas, insulin replacement therapy is the first-line treatment. Currently, most patients receive insulin by multiple daily subcutaneous injections. The treatment is dictated by manual monitoring of blood glucose levels (BGLs) and food intake, and can be categorized as an “open-loop” delivery system, as insulin injections and dosage are not a direct result of BGLs. The result is periods of insulin excess and deficiency, causing daily episodes of hypo- and hyperglycemia; these changes in BGLs can lead to serious complications. Instead, a “closed-loop” delivery system would trigger insulin release in response to an external stimulus, in this case, high BGLs. Much of the research towards a closed-loop insulin therapy has been focused on glucose-responsive polymeric materials or insulin conjugates. A general strategy is to immobilize or encapsulate a glucose-sensing moiety in a polymer matrix or particle that can swell or degrade in response to glucose concentration, thereby releasing encapsulated insulin. These materials most commonly incorporate glucose-specific enzymes, which can denature and suffer from sluggish response, sugar-binding proteins or “lectins,” which similarly exhibit poor stability and also immunogenicity, or glucose-complexing phenylboronic acids, which are easily synthesized and stable, but bind many other metabolites. The goal of this proposal is to develop a glucose-responsive insulin therapy for type 1 diabetes that circumvents the use of nonspecific, unstable, or toxic components. The Research Strategy details the development of a completely synthetic glucose-specific receptor or “lectin mimic,” the immobilization of this glucose-sensing moiety in insulin-containing hydrogels, and the application of the resulting glucose-responsive materials to regulate BGLs in vivo. Molecular dynamics simulations have been used to guide the design of chiral macrocycles containing functional groups that form strong non-covalent interactions specifically with the CH and OH groups of b-D-glucose. Modular syntheses of the proposed compounds will enable the efficient evaluation of binding affinities, and any modifications that need to be made to receptor design. The next aim of the proposal involves the covalent attachment of the lead compounds to a polymer matrix; the responsiveness of these hydrogels to glucose concentration will be initially evaluated in a series of glucose solutions. Glucose-responsive hydrogels will then be utilized in aim 3 for the regulation of BGLs in an in vivo mouse model of diabetes. If successful, the proposed research will allow for the generation of glucose-responsive materials that are more accessible, stable, glucose-specific, and less toxic than previously developed closed-loop systems....