An official website of the United States government
This study investigates the development of a supramolecular peptide amphiphile (PA) material functionalized with phenylboronic acid (PBA) for glucose-responsive glucagon delivery. The PA-PBA system self-assembles into nanofibrillar hydrogels in the presence of physiological glucose levels, resulting in stable hydrogels capable of releasing glucagon under hypoglycemic conditions. Glucose responsiveness is driven by reversible binding between PBA and glucose, which modulates the electrostatic interactions necessary for hydrogel formation and dissolution. Through comprehensive in vitro characterization, including circular dichroism, zeta potential measurements, and rheological assessments, the PA-PBA system is found to exhibit glucose-dependent assembly, enabling controlled glucagon release that is inversely related to glucose concentration. Glucagon release is accelerated under low glucose conditions, simulating a hypoglycemic state, with a reduced rate seen at higher glucose levels. Evaluation of the platform in vivo using a type 1 diabetic mouse model demonstrates efficacy in protecting against insulin-induced hypoglycemia by restoring blood glucose levels following an insulin overdose. The ability to tailor glucagon release in response to fluctuating glucose concentrations underscores the potential of this platform for improving glycemic control. These findings suggest that glucose-stabilized supramolecular peptide hydrogels hold significant promise for responsive drug delivery applications, offering an approach to manage glucose levels in diabetes and other metabolic disorders.
more »
« less
Managing Diabetes with Hydrogel Drug Delivery
Abstract Diabetes is one of the most pressing healthcare challenges facing society. Dysfunctional insulin signaling causes diabetes, leading to blood glucose instability and many associated complications. While the administration of exogenous insulin is then essential for achieving glucose control, issues with dosing accuracy and timing remain. Hydrogel‐based drug delivery systems have been broadly explored for controlled protein release, including for applications in long‐lasting and oral insulin delivery. More recently, efforts have focused on injectable hydrogels with glucose‐directed controlled release of insulin and glucagon, aiming for more autonomous and biomimetic approaches to blood glucose control. These materials typically use protein‐based sensing mechanisms or glucose binding by synthetic aryl boronates for glucose‐directed release. Despite advancements in this area, there remains a need for more precise timing of therapeutic availability to afford healthy blood glucose homeostasis, providing an opportunity for further research and innovation. This review summarizes the current state of hydrogel‐based delivery of insulin and glucagon, with insights into the potential benefits, future directions, and challenges that must be overcome to achieve clinical impact.
more »
« less
- Award ID(s):
- 1944875
- PAR ID:
- 10424565
- Publisher / Repository:
- Wiley Blackwell (John Wiley & Sons)
- Date Published:
- Journal Name:
- Advanced Therapeutics
- Volume:
- 7
- Issue:
- 1
- ISSN:
- 2366-3987
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
More Like this
-
-
Abstract The management of diabetes in a manner offering autonomous insulin therapy responsive to glucose‐directed need, and moreover with a dosing schedule amenable to facile administration, remains an ongoing goal to improve the standard of care. While basal insulins with reduced dosing frequency, even once‐weekly administration, are on the horizon, there is still no approved therapy that offers glucose‐responsive insulin function. Herein, a nanoscale complex combining both electrostatic‐ and dynamic‐covalent interactions between a synthetic dendrimer carrier and an insulin analogue modified with a high‐affinity glucose‐binding motif yields an injectable insulin depot affording both glucose‐directed and long‐lasting insulin availability. Following a single injection, it is even possible to control blood glucose for at least one week in diabetic swine subjected to daily oral glucose challenges. Measurements of serum insulin concentration in response to challenge show increases in insulin corresponding to elevated blood glucose levels, an uncommon finding even in preclinical work on glucose‐responsive insulin. Accordingly, the subcutaneous nanocomplex that results from combining electrostatic‐ and dynamic‐covalent interactions between a modified insulin and a synthetic dendrimer carrier affords a glucose‐responsive insulin depot for week‐long control following a single routine injection.more » « less
-
Abstract The global cost of diabetes care exceeds $1 trillion each year with more than $327 billion being spent in the United States alone. Despite some of the advances in diabetes care including continuous glucose monitoring systems and insulin pumps, the technology associated with managing diabetes has largely remained unchanged over the past several decades. With the rise of wearable electronics and novel functional materials, the field is well‐poised for the next generation of closed‐loop diabetes care. Wearable glucose sensors implanted within diverse platforms including skin or on‐tooth tattoos, skin‐mounted patches, eyeglasses, contact lenses, fabrics, mouthguards, and pacifiers have enabled noninvasive, unobtrusive, and real‐time analysis of glucose excursions in ambulatory care settings. These wearable glucose sensors can be integrated with implantable drug delivery systems, including an insulin pump, glucose responsive insulin release implant, and islets transplantation, to form self‐regulating closed‐loop systems. This review article encompasses the emerging trends and latest innovations of wearable glucose monitoring and implantable insulin delivery technologies for diabetes management with a focus on their advanced materials and construction. Perspectives on the current unmet challenges of these strategies are also discussed to motivate future technological development toward improved patient care in diabetes management.more » « less
-
Abstract Type 1 and advanced type 2 diabetes treatment involves daily injections or continuous infusion of exogenous insulin aimed at regulating blood glucose levels in the normoglycemic range. However, current options for insulin therapy are limited by the risk of hypoglycemia and are associated with suboptimal glycemic control outcomes. Therefore, a range of glucose‐responsive components that can undergo changes in conformation or show alterations in intermolecular binding capability in response to glucose stimulation has been studied for ultimate integration into closed‐loop insulin delivery or “smart insulin” systems. Here, an overview of the evolution and recent progress in the development of molecular approaches for glucose‐responsive insulin delivery systems, a rapidly growing subfield of precision medicine, is presented. Three central glucose‐responsive moieties, including glucose oxidase, phenylboronic acid, and glucose‐binding molecules are examined in detail. Future opportunities and challenges regarding translation are also discussed.more » « less
-
Glucose-responsive hydrogel systems are increasingly explored for insulin delivery, with dynamic-covalent crosslinking interactions between phenylboronic acids (PBA) and diols forming a key glucose-sensing mechanism. However, commonly used PBA and diol chemistries often have limited responsiveness to glucose under physiological concentrations. This is due, in part, to the binding of PBA to the commonly used diol chemistries having higher affinity than for PBA to glucose. The present study addresses this challenge by redesigning the diol chemistry in an effort to reduce its binding affinity to PBA, thereby enhancing the ability of glucose to compete with these redesigned PBA–diol crosslinks at its physiological concentration, thus improving responsiveness of the hydrogel network. Rheological analyses support enhanced sensitivity of these PBA–diol networks to glucose, while insulin release likewise improves from networks with reduced crosslink affinities. This work thus offers a new molecular design approach to improve glucose-responsive hydrogels for insulin delivery in diabetes management.more » « less
