Glucose-responsive Insulin Release Research Articles

Glucose-Responsive Microneedle Patch with High Insulin Loading Capacity for Prolonged Glycemic Control in Mice and Minipigs.

Transdermal microneedle-mediated glucose-responsive insulin delivery systems can modulate insulin release based on fluctuations in blood glucose levels, thus maintaining normoglycemia effectively in a continuous, convenient, and minimally invasive manner. However, conventional microneedles are limited by the low drug loading capacity, making it challenging to be applied on human skin at a reasonable size for a lasting glucose-controlling effect, thus hindering their clinical translation. Here, we design a microneedle patch with a solid insulin powder core to achieve a high loading capacity of insulin (>70 wt %) as well as a glucose-sensitive polymeric shell to realize glucose-responsive insulin release. Once exposed to hyperglycemia, the formation of negatively charged glucose-boronate complexes increases the charge density of the shell matrix, leading to swelling of the shell and accelerating insulin release from the core. We have demonstrated that this glucose-responsive microneedle patch could achieve long-term regulation of blood glucose levels in both type 1 diabetic mice and minipigs (up to 48 h with patches of ∼3.5 cm2 for minipigs >25 kg).

Synthesis of multi-responsive poly(NIPA-co-DMAEMA)-PBA hydrogel nanoparticles in aqueous solution for application as glucose-sensitive insulin-releasing nanoparticles.

This study aimed to present an innovative method for synthesizing pH-thermo-glucose responsive poly(NIPA-co-DMAEMA)-PBA hydrogel nanoparticles via single-step aqueous free radical polymerization. The synthesis process involved free radical polymerization in an aqueous solution, and the resulting nanoparticles were characterized for their physical and chemical properties by 1H NMR, Dynamic Light Scattering (DLS) and Scanning Electron Microscopy (SEM). Insulin-loaded poly(NIPA-co-DMAEMA)-PBA hydrogel nanoparticles were prepared and evaluated for their insulin capture and release properties at different pH and temperature, in addition to different glucose concentrations, with the release profile of insulin quantitatively evaluated using the Bradford method. 1H NMR results confirmed successful PBA incorporation, and DLS outcomes consistently indicated a transition to a more hydrophobic state above the Lower Critical Solution Temperature (LCST) of NIPA and DMAEMA. While pH responsiveness exhibited variation, insulin release generally increased with rising pH from acidic to neutral conditions, aligning with the anticipated augmentation of anionic PBA moieties and increased hydrogel hydrophilicity. Increased insulin release in the presence of glucose, particularly for formulations with the lowest mol % PBA, along with a slight increase for the highest mol % PBA formulation when increasing glucose from 1 to 4mg/mL, supported the potential of this approach for nanoparticle synthesis tailored for glucose-responsive insulin release. This work successfully demonstrates a novel method for synthesizing responsive hydrogel nanoparticles and underscores their potential for controlled insulin release in response to glucose concentrations. The observed pH-dependent insulin release patterns and the influence of PBA content on responsiveness highlight the versatility and promise of this nanoparticle synthesis approach for applications in glucose-responsive drug delivery systems. Poly(NIPA) nanoparticles containing PBA moieties are normally synthesized in two or more steps in the presence of organic solvents. Here we propose a new method for the synthesis of multiresponsive hydrogel poly(NIPA-co-DMAEMA)-PBA nanoparticles in aqueous medium in a single reaction to provide a fast and effective strategy for the production of glucose-responsive multi-systems in aqueous media from free radical polymerization.

Dually crosslinked degradable polyionic micelles for sustained glucose-responsive insulin release.

Glucose -sensitive delivery systems hold great promise as a therapeutic approach for high-incidence diabetes owing to their ability to release insulin whenever elevated glycemia is detected. However, they are unstable in a hyperglycemic environment, which leads to short-term sustained insulin release. Herein, we designed dually crosslinked insulin polyionic micelles (DCM@insulin) based on triblock polymers of o-glycol and phenylboronic acid-functionalized poly(ethylene glycol)-poly(dimethylamino carbonate)-poly(dimethylamino-trimethylene carbonate) (mPEG-P(AC-co-MPD)-PDMAC and mPEG-P(AC-co-MAPBA)-PDMATC, respectively) for sustained glucose-responsive insulin release. DCM@insulin with a phenylboronic acid ester structure (first crosslinking structure) enhanced glycemic responsiveness by regulating insulin release in a hyperglycemic environment. Additionally, the UV-crosslinking structure (second crosslinking structure) formed by the residual double bonds in AC units endowed DCM@insulin with the ability to effectively protect the loaded insulin against protease degradation and avoid burst release under multiple insulin release. The in vivo findings demonstrated that DCM@insulin effectively maintained glycemic levels (BGLs) within the normal range for 6 h in comparison to single-crosslinked micelles (SCM@insulin). Therefore, the glucose-responsive and dually crosslinked polyionic micelle system exhibits potential as a viable option for the treatment of diabetes.

Preparation of phenylboronic acid‐based glucose-responsive hydrogels and microneedles for regulated delivery of insulin

Phenylboronic acid (PBA)-based glucose-responsive microneedles that can painlessly deliver insulin and self-regulate the release of insulin according to the blood glucose levels (BGLs) have been considered promising in the treatment of diabetes. However, the reported PBA-based glucose-responsive microneedles are still faced with the challenges of complicated insulin loading process or insulin denaturation. Herein, we report a novel kind of PBA‐based glucose-responsive microneedles derived from PBA‐based glucose-responsive hydrogels. 3-fluoro-4-carboxy-phenylboronic acid-grafted polylysine (PLL-PBA) were synthesized and combined with natural guar gum (GG) to produce PLL-PBA/GG hydrogels via the phenylboronate ester bonds formed between the FCPBA groups on PLL-PBA and the diols on GG. The resulting hydrogels could regulate the release amount of insulin according to the glucose concentrations based on the glucose-induced disintegration mechanism. The PLL-PBA/GG microneedles were prepared via micro-mold casting method using the hydrogels as the precursors. Due to the simple and mild preparation conditions of the microneedles, the bioactivity of insulin was greatly preserved. The microneedles had uniform morphology, moderate skin penetration ability as well as good glucose-responsive insulin release capability. In animal experiments, the PLL-PBA/GG microneedles demonstrated BGLs lowering and maintain performance via glucose-responsive transdermal insulin delivery.

In Situ-Forming Protein-Polymer Hydrogel for Glucose-Responsive Insulin Release.

Phenylboronic acid (PBA)-containing hydrogels (HGs), capable of glucose-responsive insulin release, have shown promise in diabetes management in preclinical studies. However, sustainable material usage and attaining an optimum insulin release profile pose a significant challenge in such HG design. Herein, we present the development of a straightforward fabrication strategy for glucose-responsive protein-polymer hybrid HGs (PPHGs). We prepare PPHGs by crosslinking polyvinyl alcohol (PVA) with various nature-abundant proteins, such as bovine serum albumin (BSA), egg albumin, casein, whey protein, and so forth, using formylphenylboronic acid (FPBA)-based crosslinkers. We showcase PPHGs with diverse bulk rheological properties that are appropriately modulated by the positions of aldehyde, boronic acid, and fluorine substitutions in the FPBA-crosslinker. The orthogonal imine and boronate ester bonds formed by FPBAs are susceptible to the acidic pH environment and glucose concentrations, leading to the glucose-responsive dissolution of the PPHGs. We further demonstrate that by an appropriate selection of FPBAs, glucose-responsive insulin release profiles of the PPHGs can be precisely engineered at the molecular level. Importantly, PPHGs are injectable, incur no cytotoxicity, and, therefore, hold great potential as smart insulin for in vivo applications in the near future.

Microneedle Patches Loaded with Nanovesicles for Glucose Transporter-Mediated Insulin Delivery.

Glucose-responsive insulin delivery systems that mimic insulin secretion activity in the pancreas show great potential to improve clinical therapeutic outcomes for people with type 1 and advanced type 2 diabetes. Here, we report a glucose-responsive insulin delivery microneedle (MN) array patch that is loaded with red blood cell (RBC) vesicles or liposome nanoparticles containing glucose transporters (GLUTs) bound with glucosamine-modified insulin (Glu-Insulin). In hyperglycemic conditions, high concentrations of glucose in interstitial fluid can replace Glu-Insulin via a competitive interaction with GLUT, leading to a quick release of Glu-Insulin and subsequent regulation of blood glucose (BG) levels in vivo. To prolong the effective glucose-responsive insulin release from MNs, additional free Glu-Insulin, which serves as "stored insulin", is loaded after RBC vesicles or liposome nanoparticles bound with Glu-Insulin. In the streptozotocin (STZ)-induced type 1 diabetic mouse model, this smart GLUT-based insulin patch can effectively control BG levels without causing hypoglycemia.

Diboronate crosslinking: Introducing glucose specificity in glucose-responsive dynamic-covalent networks.

Dynamic-covalent motifs are increasingly used for hydrogel crosslinking, leveraging equilibrium-governed reversible bonds to prepare viscoelastic materials with dynamic properties and self-healing character. The bonding between aryl boronates and diols is one dynamic-covalent chemistry of interest. The extent of network crosslinking using this motif may be subject to competition from ambient diols such as glucose; this approach has long been explored for glucose-directed release of insulin to control diabetes. However, the majority of such work has used phenylboronic acids (PBAs) that suffer from low-affinity glucose binding, limiting material responsiveness. Moreover, many PBA chemistries also bind with higher affinity to certain non-glucose analytes like fructose and lactate than they do to glucose, limiting their specificity of sensing and therapeutic deployment. Here, dynamic-covalent hydrogels are prepared that, for the first time, use a new diboronate motif with enhanced glucose binding-and importantly improved glucose specificity-leveraging the ability of rigid diboronates to simultaneously bind two sites on a single glucose molecule. Compared to long-used PBA-based approaches, diboronate hydrogels offer more glucose-responsive insulin release that is minimally impacted by non-glucose analytes. Improved responsiveness translates to more rapid blood glucose correction in a rodent diabetes model. Accordingly, this new dynamic-covalent crosslinking chemistry is useful in realizing more sensitive and specific glucose-responsive materials.

Materials and Carriers Development for Glucose-Responsive Insulin

ConspectusInsulin replacement therapy is an essential and effective treatment strategy for controlling the blood glucose level (BGL) of people without sufficient endogenous insulin production. However, insulin therapy faces challenges such as daily multiple injections and hypoglycemia risk arising from its narrow therapeutic index, which together leads to poor BGL control. Thus, glucose-responsive insulin delivery systems that can mimic β-cell function are developed to improve BGL control and reduce injection frequency. Glucose-responsive materials-based insulin delivery systems are competent in tightly controlling the BGL with an additional benefit of reducing the hypoglycemia risk. Glucose-responsive materials generally work together with three major glucose-sensing elements: glucose oxidase (GOx), phenylboronic acid (PBA), and glucose-binding molecules. Based on glucose-sensing elements, glucose-responsive materials are rationally designed to sense the change in glucose concentration or indirect signals associated with glucose fluctuation, such as pH, H2O2 concentration, and O2 level, and adjust their physical or chemical characteristics accordingly. Many advanced glucose-responsive materials have been developed along this line, aiming to achieve robust glucose-responsive insulin release performance and elevate their therapeutic outcome. These advanced materials mainly include organic materials such as biomacromolecules, synthetic polymers, polypeptides, liposomes, and inorganic materials such as calcium phosphate (Ca3(PO4)2) and metal organic frameworks (MOFs). Built on these glucose-responsive materials, other groups and we have developed various carriers such as hydrogels, micro/nanoparticles, liposomes, complexes, cell–drug conjugates, and microneedle (MN) array patches. These delivery systems can release insulin via glucose-stimulated swelling/contraction, dissolution, pore size change, charge reversal, and polymer deterioration. Also, these carriers are continuously under development to accelerate responsive rate, increase response index, and improve biocompatibility. Our group focuses on the synthesis of glucose-responsive materials and the design of glucose-responsive MN array patches, hydrogels, insulin complexes, and cell–drug conjugates for the treatment of diabetes in a dose-, spatial-, and temporal-controlled fashion. These closed-loop insulin delivery systems can respond to BGL alternation and secrete the correct amount of insulin accordingly. Also, MN array patches have the additional merits of reducing pain and easy administration.In this Account, we briefly introduce the glucose-responsive mechanisms and the relevant requirements of materials that can work cooperatively with these mechanisms. Then, we highlight our group’s work in preparing various materials for constructing glucose-responsive carriers. We are mainly aiming to improve glucose-responsive properties, administration feasibility, and in vivo biocompatibility. The challenges and perspectives associated with glucose-responsive materials for clinical translation are also discussed. We envision that our glucose-responsive MN array patch for insulin release will facilitate the clinical use of glucose-responsive materials.

RECENT APPROACHES IN GLUCOSE RESPONSIVE INSULIN DELIVERY SYSTEM

Diabetes mellitus is a chronic medical condition currently affecting 382 million people across the globe, caused due to increased blood glucose levels due to less insulin production or insulin resistance. Subcutaneous insulin administration for diabetes is the only most accepted therapy for maintaining blood glucose levels in diabetic patients. Many patients with advanced type II diabetes mellitus need to regularly monitor their blood glucose level to keep their blood glucose level in the target range. However long-term insulin therapy through an invasive route of administration causes problems with patient compliance and a sudden decrease in blood glucose levels. An artificial closed-loop insulin release system that mimics the glucose-responsive insulin secretion by β-cells of pancreas is one of the ways to overcome the problem faced with the conventional method of insulin administration. Many polymeric formulations showed an improved glucose-responsive release of insulin when incorporated with glucose-responsive catalysts such as glucose oxidase, phenylboronic acid, and glucose binding proteins, the release rate can be controlled by optimizing the concentration of glucose-responsive catalysts. This article is been focused on different mechanisms of glucose-responsive release by incorporation with glucose-responsive catalysts.

Responsive hydrogel-based microneedle dressing for diabetic wound healing.

Wound healing is a critical challenge in diabetic patients, mainly due to long-term dysglycemia and its related pathological complications. Subcutaneous insulin injection represents a typical clinical solution, while the low controllability of insulin administration commonly leads to a result far from the optimal therapeutic effect. In this work, we developed a glucose-responsive insulin-releasing hydrogel for microneedle dressing fabrication and then investigated its effects on diabetic wound healing. The hydrogel system was composed of biocompatible gelatin methacrylate (GelMa), glucose-responsive monomer 4-(2-acrylamidoethylcarbamoyl)-3-fluorophenylboronic acid (AFPBA) and gluconic insulin (G-insulin), and the Gel-AFPBA-ins hydrogel-based microneedle dressing was developed by replicating PDMS molds. The resultant hydrogel microneedle dressing exhibited adequate mechanical properties, high biocompatibility, glucose-responsive insulin release behavior upon exposure to different glucose solutions, and potent adhesion to the skin compared to hydrogels without microstructures. The microneedle dressing could accelerate the diabetic wound healing process with decreased inflammatory reaction, enhanced collagen deposition on the regenerated tissue sites, and improved blood glucose control in animals. Therefore, the glucose-responsive insulin-releasing hydrogel microneedle dressing is effective in diabetic wound management and has potential for treatment of other chronic skin injuries.

Glucose-responsive oral insulin delivery platform for one treatment a day in diabetes

Glucose-responsive oral insulin delivery platform for one treatment a day in diabetes

Synthesis and testing of polymer grafted mesoporous silica as glucose-responsive insulin release drug delivery systems

Stimuli-responsive materials based on mesoporous silica have been widely studied for the controlled release of drugs. Glucose-responsive systems play a vital role in the controlled release of insulin because they can smartly adjust the amount of released insulin in response to the fluctuational blood glucose concentration. Here, the mesoporous silica (MS) was modified with 3-fluoro-4-carboxyphenylboronic acid (FCPBA) to prepare phenylboronic acid-modified mesoporous silica (MS-FCPBA). N-acryloyl glucosamine (AGA) was copolymerized with N-isopropyl acrylamide (NIPAM) and acrylic acid (AAc) respectively to synthesize two polymers with diol groups, noted as P(NIPAM-co-AGA) and P(AAc-co-AGA) respectively. Since the phenylboronic acid group can form a borate ester bond with the diol group, the polymers were coated on the surface of insulin-loaded MS-FCPBA to obtain the insulin release systems. The results showed that the loading capacity and encapsulation efficiency of insulin could reach 14.7% and 85.9%, respectively. The two systems exhibited different glucose-responsive performance.

Wearable Glucose Monitoring and Implantable Drug Delivery Systems for Diabetes Management.

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.

Microgel encapsulated nanoparticles for glucose-responsive insulin delivery

An insulin delivery system that self-regulates blood glucose levels has the potential to limit hypoglycemic events and improve glycemic control. Glucose-responsive insulin delivery systems have been developed by coupling glucose oxidase with a stimuli-responsive biomaterial. However, the challenge of achieving desirable release kinetics (i.e., insulin release within minutes after glucose elevation and duration of release on the order of weeks) still remains. Here, we develop a glucose-responsive delivery system using encapsulated glucose-responsive, acetalated-dextran nanoparticles in porous alginate microgels. The nanoparticles respond rapidly to changes in glucose concentrations while the microgels provide them with protection and stability, allowing for extended glucose-responsive insulin release. This system reduces blood sugar in a diabetic mouse model at a rate similar to naked insulin and responds to a glucose challenge 3 days after administration similarly to a healthy animal. With 2 doses of microgels containing 60 IU/kg insulin each, we are able to achieve extended glycemic control in diabetic mice for 22 days.

Prevascularization-free Primary Subcutaneous Transplantation of Xenogeneic Islets Coencapsulated With Hepatocyte Growth Factor.

In vitro experiments examined slow release of HGF from the chitosan gel and islet-protection effect of HGF against hypoxia. In the latter, rat islets with/without HGF (200 ng/mL) was cultured in 1% oxygen. In in vivo experiment, fabricated device with/without HGF (10 μg/device) containing rat islets was primarily transplanted to streptozotocin-induced diabetic mice subcutaneously. In vitro experiments showed sustained release of HGF for 28 d and alleviating effect of HGF on cell death and glucose-responsive insulin release after hypoxic culture. Islet + HGF mice, but not islet-alone mice, showed decreased nonfasting blood glucose and regained body weight after transplantation. In intraperitoneal glucose tolerance test, islet + HGF mice exhibited decreased fasting blood glucose (200 ± 55 mg/dL) and good blood glucose disappearance rate (K value) (0.817 ± 0.101) comparing to normal mice (123 ± 28 mg/dL and 1.074 ± 0.374, respectively). However, in islet-alone mice, fasting blood glucose was high (365 ± 172 mg/dL) and K value was indeterminable. Serum insulin in islet + HGF mice (1.58 ± 0.94 μg/L) was close to normal mice (1.66 ± 0.55 μg/L), whereas those in islet-alone mice (0.279 ± 0.076 μg/L) and diabetic mice (0.165 ± 0.079 μg/L) were low. Immunohistochemical examination showed intact insulin- and glucagon-positive islets in retrieved devices with HGF, but no intact islet was found in the device without HGF. HGF could enhance islet survival in hypoxia and enhance in vivo function of encapsulated islets after primary subcutaneous transplantation.

Synthetic enzyme-based nanoparticles act as smart catalyst for glucose responsive release of insulin

BackgroundEarlier studies have attempted to create electronic free insulin delivery systems using different glucose sensing mechanism, no successful clinical translation as hitherto been made. This study aimed to assess the faster responsiveness of the insulin release from this enzyme based nanoparticles which is a self-regulated insulin delivery system constructed by loading with insulin, enzyme glucose oxidase into hyaluronic acid and 2-nitroimidazole forming enzyme-based nanoparticles which works in accordance to the blood glucose level. Materials and methodEnzyme-based nanoparticles were prepared by ionic gelation method. Insulin content in the nanoparticles kept for stability study was estimated by human insulin enzyme based immunosorbent assay. In in-vitro studies; different concentrations of glucose were taken and the release study of insulin was recorded. ResultsThis enzyme-based nanoparticles were having average diameter of around 193 nm and stability studies showed that nanoparticles were stable upto 30 days at 4 °C. In-vitro studies showed the release of insulin from nanoparticle conjugates which was effectively correlated with the external glucose concentration created where different concentrations of glucose taken thus facilitating the stabilization of blood glucose levels in the hyperglycemia state which was achieved within 10 min. (400 mg/dL) wherein drug release rate remarkably increased in hyperglycemia state and no specific changes or small amount of release was observed in normoglycemia state (100 mg/dL). ConclusionOverall, this preliminary study of this enzyme-based nanoparticles formulation showed excellent rapid responsiveness towards hyperglycemia which might act as a potential biomimetic system in triggering the release of insulin in sustained manner.

Assisted 3D printing of microneedle patches for minimally invasive glucose control in diabetes.

Recently, microneedle systems have become an attractive solution for drug delivery. Traditionally, microneedle systems were fabricated via template molding methods. In this study, we present a novel method for the fabrication of a microneedle patch system. We used extrusion-based 3D printing and post stretching to fabricate a microneedle patch system for minimally invasive and glucose-responsive insulin delivery for diabetes treatment. First, we investigated the printability of various bioinks composed of alginate with hydroxyapatite as an additive. After printing the substrate and a cylindrical array of the patch, we stretched the top surface of the cylindrical array to form needle-like tips. The prepared microneedle patch contained 6×6 microneedles, and only the microneedles performed glucose-responsive release of insulin. Each microneedle was conical in shape, with a base diameter of 601μm, a tip diameter of 24μm, and a height of 643μm. The fabricated microneedles exhibited sufficient mechanical strength to penetrate the skin of mice and responsively released insulin according to the glucose levels both in glucose solution and in type 1 diabetic mice. When transdermal application was performed only once on the skin of mice, the microneedle patches regulated the blood glucose levels of diabetic mice in normoglycemic ranges for up to 40h and alleviated the diabetic symptoms of the mice. Our study proposed a method for the fabrication of microneedle patch systems, which can be potentially applied for transdermal drug delivery.

Development of glucose oxidase-immobilized alginate nanoparticles for enhanced glucose-triggered insulin delivery in diabetic mice

In this work, we successfully developed poly(acrylamido phenylboronic acid)/sodium alginate nanoparticles (NPs) via formation of cycloborates (glucose- and H2O2-responsive functional groups), as an improved glucose-mediated insulin delivery system loaded with glucose oxidase (GOx). Dynamic light scattering revealed that the GOx-loaded NPs showed better glucose-sensitivity than the GOx-unloaded NPs. In addition, compared to insulin-loaded NPs, the insulin/GOx-loaded NPs displayed faster glucose-responsive insulin release. Importantly, there was a significant hypoglycemic effect on diabetic mice following the subcutaneous injection of insulin/GOx-loaded NPs. Furthermore, the NPs exhibited favorable biocompatibility as demonstrated by cytotoxicity assay, hemolysis study, and histopathological examination. The NPs have the advantages of easy preparation, enhanced glucose-responsiveness, and good biocompatibility, making them as potential candidates for subcutaneous insulin delivery.

Glucose and H2O2 Dual-Responsive Polymeric Micelles for the Self-Regulated Release of Insulin.

In the past decades, insulin delivery systems have been widely developed for diabetes treatment. Though a few works have investigated polymeric micelles with glucose and H2O2 dual-responsiveness for the delivery of insulin, great efforts should still be devoted to enhancing the therapeutic efficacy. Herein, glucose/H2O2 dual-responsive polymeric micelles were fabricated for the self-regulated insulin delivery. The polymeric micelles were self-assembled by poly(ethylene glycol)-block-poly(amino phenylboronic ester) (PEG-b-PAPBE), where the hydrophilic PEG offered the shell and the hydrophobic PAPBE endowed the polymeric micelles with the dual-sensibility to glucose and H2O2. The built-in phenylboronic ester (PBE) could be not only broken by glucose but also hydrolyzed by H2O2, thus resulting in the disintegration of the polymeric micelles. The glucose-responsive release of insulin was achieved and could be further facilitated by the coencapsulation of glucose oxidase (GOx) in the micelles, which would produce H2O2 by catalytic oxidation of glucose and thus lead to the hydrolysis of the phenylboronic ester by H2O2. Compared with free insulin or micelles that carried insulin alone, a subcutaneous injection of the insulin/GOx-coloaded polymeric micelles to the diabetic mice presented a superior hypoglycemic effect in vivo. This kind of polymeric micelle with glucose and H2O2 dual-responsiveness provides a promising approach for diabetes therapy.

Stimuli-responsive self-assembled dendrimers for oral protein delivery

Oral delivery of protein is very challenging for therapeutic applications due to protein instability and degradability. Herein we synthesized benzoboroxole-containing multi-armed poly(ethylene glycol) amphiphilic dendrimers sensitive to both pH and glucose. The multi-branched structure of dendrimer facilitated its self-assembly into micelles in aqueous solution and exhibited good encapsulation of insulin just by simply mixing with insulin solution. The insulin loaded micelles were stable under strong acidic condition and showed glucose-responsive insulin release at physiological pH. The reversible binding between benzoboroxole and glucose can effectively regulate the disassembly of micelles and insulin release rate, which in turn stabilizes blood sugar fluctuations. Utilizing a mouse model of type 1 diabetes, it was demonstrated that these insulin loaded micelles could successfully control the blood glucose levels under a normoglycemic state and avoid the risk of hypoglycemia. Therefore, this smart delivery system shows great potential to significantly improve the effect of oral protein therapy.