428840 Engineering Insulin Therapy

Thursday, November 12, 2015: 10:00 AM
251A (Salt Palace Convention Center)
Matthew Webber, Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA, Robert Langer, Massachusetts Institute of Technology, Cambridge, MA and Daniel G. Anderson, Koch Institue for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA

Introduction: Since its discovery and isolation, exogenous insulin has dramatically changed the outlook for patients with diabetes. However, even when patients strictly follow an insulin regimen, serious complications can result as both hyperglycemic and hypoglycemic states are routinely experienced. Several chemically or genetically modified insulins have been developed that tune the pharmacokinetics of insulin activity for personalized therapy. A goal in the area of insulin therapeutics is to engineer glucose-responsiveness, which envisions a “closed-loop” approach to insulin therapy. In this scenario, insulin bioavailability would be controlled as a function of blood glucose levels, and insulin would only be functional when it was needed. Here, we demonstrate a strategy for the covalent modification of insulin intended to promote both long-lasting and glucose-responsive activity through the use of aliphatic molecular recognition moieties for glucose detection.

Materials and Methods: Covalent modification of insulin with small molecule aliphatic phenylboronic acids was achieved through site-specific amide bond formation at the B29 lysine side-chain. Insulin conjugates were evaluated in a chemically induced diabetic mouse model across a range of doses. Meals were simulated by a intraperitoneal glucose tolerance test, and blood glucose was monitored to assess insulin responsiveness and activity as a function of blood glucose levels.

Results and Discussion: Four covalently modified insulins were synthesized, each bearing an alkyl domain attached to a different phenylboronic acid intended to vary the pKa of the boronic acid group to tune molecular recognition of glucose within a physiologic range. The synthetized insulin derivatives enabled rapid reversal of blood glucose in a diabetic mouse model upon initial administration. Three hours following insulin administration, an intraperitoneal glucose tolerance test was performed. The best-performing insulin derivative provided glucose control that was superior to native insulin, with responsiveness to glucose challenge improved over a clinically used long-acting insulin derivative. Some of the modified insulin derivatives responded to repeated glucose challenges over a thirteen-hour period following a single administration. Moreover, continuous glucose monitoring revealed responsiveness matching that of a healthy pancreas. When evaluated in a dose escalation study in normoglycemic mice, synthetically modified insulins exhibited less hypoglycemia, further supporting glucose-dependent potency of these modified insulins. This described approach to insulin modification demonstrates both long-lasting and glucose-mediated insulin activity, which could reduce the frequency of administration and improve the fidelity of glycemic control for insulin therapy.

Conclusions: We believe this to be the first demonstration of glucose-responsive behavior with a modified insulin derivative in a diabetic model. Covalent modification of insulin with conjugates containing an aliphatic domain and a PBA afforded long-lasting insulin with glucose-mediated activity. The lead candidate demonstrated enhanced responsiveness to glucose challenge in diabetic mice, but a reduction in hypoglycemia in healthy mice. It is possible that these modified insulins could interface with insulin pumps, infusion devices, or controlled release materials to further improve performance.

Extended Abstract: File Not Uploaded
See more of this Session: Biomaterials for Drug Delivery
See more of this Group/Topical: Materials Engineering and Sciences Division