An Engineered Nanosugar Enables Rapid and Sustained Glucose‐Responsive Insulin Delivery in Diabetic Mice (Adv. Mater. 21/2023)
Rong XuSukhvir Kaur BhanguKarly C. SourrisDomitilla VanniMarc‐Antoine SaniJohn A. KarasKaren AltBe’eri NiegoAnukreity AleQuinn A. BesfordBrendan DyettJoshua PatrickIrena CarmichaelJonathan E. ShawFrank CarusoMark E. CooperChristoph E. HagemeyerFrancesca Cavalieri
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Insulin Delivery In article number 2210392, Christoph E. Hagemeyer, Francesca Cavalieri, and co-workers report how biodegradable and charge-switchable phytoglycogen nanoparticles with glucose-sensitive phenylboronic acid groups and amine moieties can be engineered to form nanocomplexes with insulin for its rapid and efficient glucose-responsive delivery. Subcutaneous injection of nanocomplexes in two distinct diabetic mouse models helps to maintain normal glucose levels for up to 13 h.Keywords:
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A new 'intelligent' polymer system was developed utilizing the binding and exchange of phenylboronic acid (PBA) with polyols and/or glucose. In this improved system, an amine component was incorporated into the polymer chain along with PBA, to enhance binding between PBA and glucose under physiological conditions. The PBA-based polymer was formed by free-radical copolymerization of 3-methacrylamidophenylboronic acid (MAPB) with comonomers, N,N-dimethylaminopropylacrylamide (DMAPAA) and acrylamide (AAm) in the presence of N,N'-methylenebis(acrylamide) (Bis-AAm) as a cross-linker. The proportion of the amount of PBA groups complexed with glucose vs total amount of PBA groups was determined by the batch method. Compared to PBA copolymers synthesized without amine component, the proportion increased as a function of the amine content as well as the pH of the buffer. These results confirm that the interaction of neighboring amines (unprotonated) to PBA strengthens the binding with glucose, especially at pH 7.4 and above. This new PBA-amine copolymer is promising as a material useful for polyol separation, protection of polyols, and possibly, as an insulin delivery device.
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Here described is a phenylboronic acid (PBA) based glucose-responsive hydrogel operating under physiological pH and temperature, a material potentially applicable to a totally synthetic smart insulin delivery system to treat diabetes.
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Until now, phenylboronic acid (PBA)-based glucose-responsive materials in the forms of bulk gels, nanogels (microgels), micelles, vesicles, and silica nanoparticles have been synthesized and used for drug delivery. This chapter discusses the recent advances in the synthesis of PBA-containing glucose-responsive polymer materials and the application of them in drug (especially insulin) delivery. Though PBA-containing bulk gels could be synthesized and used as implantable carrier for insulin delivery, more desirable PBA-based glucose-responsive materials were suggested to be in the nanoscale forms such as nanogels (microgels), which may meet different needs such as prompt drug release, oral administration, and intravenous injection. Most drug delivery studies based on PBA-containing polymer materials, now, focused on insulin aiming at the treatment of diabetes mellitus.
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This chapter contains sections titled: Introduction Diabetes Management and the Need for Insulin Engineering Insulin Structure Prolonged-acting Insulin Solids Prolonged-acting Insulin Solutions Fast-acting Insulins Glucose-sensitive Insulin Preparations Alternative Insulin Delivery Insulin Mimetics Pushing the Limits of Insulin Engineering Conclusion References
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Glucose-sensitive drug platforms are highly attractive in the field of self-regulated drug delivery. Drug carriers based on boronic acid (BA), especially phenylboronic acid (PBA), have been designed for glucose-sensitive self-regulated insulin delivery. The PBA-functionalized gels have attracted more interest in recent years. The cross-linked three-dimensional (3D) structure endows the glucose-sensitive gels with great physicochemical properties. The PBA-based platforms with cross-linked structures have found promising applications in self-regulated drug delivery systems. This article summarizes some recent attempts at the developments of PBA-mediated glucose-sensitive gels for self-regulated drug delivery. The PBA-based glucose-sensitive gels, including hydrogels, microgels, and nanogels, are expected to significantly promote the development of smart self-regulated drug delivery systems for diabetes therapy.
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In past few years, phenylboronic acids (PBAs) have attracted researcher's attention due to their unique responsiveness towards diol-containing molecules such as glucose. This property allows hydrogel-bearing PBAs potentially to serve as an alternative for glucose-sensing and insulin-delivery systems. This review provides an outlook on the binding mechanism of PBA moieties with diols and the approaches to increase their binding selectivity and response for glucose molecules. The preparation methods and strategies of hydrogel-bearing PBA moieties along with their properties are discussed. In the last section, their applications in glucose-sensing and insulin-regulatory systems are described.
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Insulin delivery in a self-regulated and painless way to tightly control the glycemic level is highly demanded for diabetes treatment. Phenylboronic acid (PBA) has gained great research interests due to its synthetic nature and reversible binding capability with glucose. A totally synthetic smart PBA hydrogel exhibiting efficient glucose sensitivity at physiological pH and temperature has been previously developed. However, its clinical applications may be hampered by the temperature-dependent release profile. Herein, we report a glucose-responsive, temperature-stable, boronate-containing hydrogel with optimized formulation and its fabrication into a microneedle (MN) patch to provide on-demand and convenient insulin delivery. The resulting MN patch displayed temperature-independent and glucose-responsive insulin release in a rapid and sustained manner through the regulation by the "skin layer" formed on the surface. This MNs patch can effectively penetrate the skin and was highly biocompatible. Compared to the majority of the glucose-responsive MN patches capitalizing on glucose oxidase and nanoparticles, this totally synthetic, protein-free, and nanoparticle-free MN patch could eliminate the safety concerns and provide the sustainability and advantage for large-scale production.
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Abstract Diabetes is one of the most devastating global diseases with an ever-increasing number of patients. Achieving persistent glycemic control in a painless and convenient way is an unmet goal for diabetes management. Insulin therapy is commonly utilized for diabetes treatment and usually relies on patient self-injection. This not only impairs a patient’s quality of life and fails to precisely control the blood glucose level but also brings the risk of life-threatening hypoglycemia. “closed-loop” insulin delivery systems could avoid these issues by providing on-demand insulin delivery. However, safety concerns limit the application of currently developed electronics-derived or enzyme-based systems. Phenylboronic acid (PBA), with the ability to reversibly bind glucose and a chemically tailored binding specificity, has attracted substantial attention in recent years. This focus review provides an overview of PBA-based versatile insulin delivery platforms developed in our group, including new PBA derivatives, glucose-responsive gels, and gel-combined medical devices, with a unique “skin layer” controlled diffusion feature.
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