Controlled Release Of Insulin Research Articles

Arrestin-independent internalization of the GLP-1 receptoris facilitated by a GRK, clathrin, and caveolae-dependent mechanism.

The glucagon-like peptide-1 receptor (GLP-1R) plays an important role in regulating insulin secretion and reducing body weight, making it a prominent target in the treatment of type 2 diabetes and obesity. Extensive research on GLP-1R signaling has provided insights into the connection between receptor function and physiological outcomes, such as the correlation between Gs signaling and insulin secretion, yet the exact mechanisms regulating signaling remain unclear. Here, we explore the internalization pathway of GLP-1R, which is crucial for controlling insulin release and maintaining pancreatic beta-cell function. Utilizing a reliable and sensitive time-resolved fluorescence resonance energy transfer (TR-FRET) internalization assay, combined with HEK293-derived knockout cell lines, we were able to directly compare the involvement of different endocytic machinery in GLP-1R internalization. Our findings indicate that the receptor internalizes independently of arrestin and is dependent on Gs and Gi/o activation and G protein-coupled receptor kinase phosphorylation. Mechanistically, we observed that the receptor undergoes distinct clathrin- and caveolae-mediated internalization in HEK293 cells. This study also investigated the role of arrestins in GLP-1R function and regulation. These insights into key endocytic components that are involved in the GLP-1R internalization pathway could enhance the rational design of GLP-1R therapeutics for type 2 diabetes and other GLP-1R-related diseases.

An environment-responsive platform based on acid-resistant metal organic framework for efficient oral insulin delivery

Oral insulin delivery is considered a revolutionary alternative to daily subcutaneous injections in terms of compliance and convenience. However, significant challenges remain in terms of inactivation in gastrointestinal environment and limited permeation across the intestinal epithelium. Herein, we used acid-resistant metal-organic framework (PCN-222) to load insulin and modified the exterior with sodium dodecyl sulfate (SDS) to achieve efficient oral insulin delivery. The PCN-222 nanocarrier with ordered mesoporous cage structure and suitable pore size achieved a high insulin loading of 75%. The SDS on the surface of nanocarrier reduces its hydrophilicity while reversibly altering cell morphology and increasing epithelial cell permeability, thereby promoting intestinal epithelial absorption. The constructed particle (I@P@S) was encapsulated in sodium alginate (SA) microspheres to protect it from gastric acid degradation and releases it upon entry into the intestinal tract. Through an uptake pathway dominated by clathrin-mediated endocytosis, the released I@P@S realized efficient intestinal permeability and controlled insulin release under physiological conditions due to the phosphate sensitivity of PCN-222, leading to an in vivo bioavailability of 12.9%. This work provides a valuable reference for the design of oral insulin delivery systems.

Colonic targeting insulin-loaded trimethyl chitosan nanoparticles coated pectin for oral delivery: In vitro and In vivo studies

Colon-targeted delivery offers several benefits for oral protein delivery, such as low proteolytic enzyme activity, a natural pH environment, and extended residence time, which improve the bioavailability of the encapsulated protein. Therefore, we hypothesize that developing a novel colonic nanocarrier system, featuring modified chitosan that is soluble at physiological pH and coated with a colon-degradable polymer, will provide an effective delivery system for oral insulin. This study aims to synthesize insulin-loaded pectin-trimethyl chitosan nanoparticles (Ins-P-TMC-NPs) as an oral insulin delivery system and to evaluate its efficacy both in vitro and in vivo. N-trimethyl chitosan (TMC), synthesized via a methylation method, was used to prepare insulin-TMC nanoparticles coated with pectin via the ionic gelation method. The nanoparticles were characterized for their physicochemical properties, cumulative release profile, and surface morphology. The in vitro biological cytotoxicity and cellular uptake of the nanoparticles were evaluated against HT-29 cells. The in vivo blood glucose-lowering effect and histological toxicity were assessed in diabetic male Sprague-Dawley rats. The results showed that Ins-P-TMC-NPs were spherical, with an average size of 379.40±40.26nm, a polydispersity index of 24.10±1.03%, a zeta potential of +17.20±0.52mV, and a loading efficiency of 83.21±1.23%. Compared to uncoated TMC nanoparticles, Ins-P-TMC-NPs reduced insulin loss in simulated gastrointestinal fluid by approximately 67.23±0.97% and provided controlled insulin release in simulated colonic fluid. In vitro bioactivity studies revealed that Ins-P-TMC-NPs were non-toxic, with cell viability of 91.12±0.91% after 24 h of treatment, and exhibited high cellular uptake in the HT-29 cell line with a fluorescence intensity of 37.80±2.40 after 4 h of incubation. Furthermore, the in vivo study demonstrated a sustained reduction in blood glucose levels after oral administration of Ins-P-TMC-NPs, peaking after 8h with a blood glucose reduction of 87±1.03%. Histological sections showed no signs of toxicity when compared to those of healthy rats. Overall, the developed colon-targeted oral insulin delivery system exhibits strong potential as a candidate for effective oral insulin administration.

Preparation and biological evaluation of a glucose-responsive block copolymer nanoparticle with the ability to ameliorate diabetic kidney damage

Preparation and biological evaluation of a glucose-responsive block copolymer nanoparticle with the ability to ameliorate diabetic kidney damage

Glucose-Operated Widget (GLOW) for Closed-Loop Optogenetic Glycemic Control.

Closed-loop control systems for precise control of therapeutic gene expression are promising candidates for personalized treatment of chronic ailments such as diabetes. Pancreatic iβ-cells are engineered with blue-light-inducible melanopsin to drive rapid insulin release by vesicular secretion from intracellular stores. In this work, a glucose-operated widget (GLOW) is designed as a component of a closed-loop control system for diabetes treatment by employing a probe that emits blue fluorescence in a glucose-concentration-dependent manner as a real-time glucose sensor to precisely control insulin release from these iβ-cells. As proof-of-concept of the complete control system, the probe is encapsulated together with iβ-cells in alginate-poly-(L-lysine) hydrogel-microbeads(400µm in diameter and containing about 500 cells) called GLOWiβ (GLOW with iβ-cells), are subcutaneously implanted into type-1-diabetic (T1D) mice. Illumination by UV-A light at 390nm results in glucose-concentration-dependent blue-light emission from the probe at 445nm that in turn induces glucose-concentration-dependent insulin release from the iβ-cells in a fully reversible manner. Activation of the injected GLOWiβ at 390nm for 15 min effectively restores normoglycemia within 60-120 min in a closed-loop manner in these diabetic mice. The system is robust, as normoglycemia is well maintained by daily activation for at least 7 days.

Anti-inflammatory PEGylated bilirubin microneedle patch for diabetes treatment

Anti-inflammatory PEGylated bilirubin microneedle patch for diabetes treatment

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.

Glucose-Responsive Self-Regulated Injectable Silk Fibroin Hydrogel for Controlled Insulin Delivery.

Stimuli-responsive drug delivery systems are gaining importance in personalized medicine to deliver therapeutic doses in response to disease-specific stimulation. Pancreas-mimicking glucose-responsive insulin delivery systems offer improved therapeutic outcomes in the treatment of type 1 and advanced stage of type 2 diabetic conditions. Herein, we present a glucose-responsive smart hydrogel platform based on phenylboronic acid-functionalized natural silk fibroin protein for regulated insulin delivery. The modified protein was synergistically self-assembled and cross-linked through β-sheet and phenylboronate ester formation. The dynamic nature of the bonding confers smooth injectability through the needle. The cross-linked hydrogel structures firmly hold the glucose-sensing element and insulin in its pores and contribute to long-term sensing and drug storage. Under hyperglycemic conditions, the hydrogen peroxide generated from the sensing element induces hydrogel matrix degradation by oxidative cleavage, enabling insulin release. In vivo studies in a type 1 diabetic Wistar rat model revealed that the controlled insulin release from the hydrogel restored diabetic glucose level to physiological conditions for 36 h. This work establishes the functional modification of silk fibroin into a glucose-responsive hydrogel platform for regulated and functional insulin delivery application.

A Closed Loop Stimuli-Responsive Concanavalin A-Loaded Chitosan-Pluronic Hydrogel for Glucose-Responsive Delivery of Short-Acting Insulin Prototyped in RIN-5F Pancreatic Cells.

The optimal treatment of diabetes (in particular, type 1 diabetes-T1D) remains a challenge. Closed-loop systems (implants/inserts) provide significant advantages for glucose responsivity and providing real-time sustained release of rapid-acting insulin. Concanavalin A (ConA), a glucose affinity agent, has been used to design closed-loop insulin delivery systems but not without significant risk of leakage of ConA from the matrices and poor mechanical strength of the hydrogels impacting longevity and control of insulin release. Therefore, this work focused on employing a thermoresponsive co-forming matrix between Pluronic F-127 (PL) and structurally robust chitosan (CHT) via EDC/NHS coupling (i.e., covalent linkage of -NH2 from CHT and ConA to the -COOH of PL). The system was characterized for its chemical structure stability and integrity (FTIR, XRD and TGA), injectability, rheological parameters and hydrogel morphology (Texture Analysis, Elastosens TM Bio2 and SEM). The prepared hydrogels demonstrated shear-thinning for injectability with a maximum force of 4.9 ± 8.3 N in a 26G needle with sol-gel transitioning from 25 to 38 °C. The apparent yield stress value of the hydrogel was determined to be 67.47 Pa. The insulin loading efficiency within the hydrogel matrix was calculated to be 46.8%. Insulin release studies revealed glucose responsiveness in simulated glycemic media (4 and 10 mg/mL) over 7 days (97%) (305 nm via fluorescence spectrophotometry). The MTT studies were performed over 72 h on RIN-5F pancreatic cells with viability results >80%. Results revealed that the thermoresponsive hydrogel is a promising alternative to current closed-loop insulin delivery systems.

Visually controlled pulsatile release of insulin from chitosan poly-acrylic acid nanobubbles triggered by focused ultrasound

Insulin therapy is the most effective way to control the blood glucose value of diabetic patients. The most effective administration route for insulin is subcutaneous injection because bioavailability for non-injection administration is low and unstable. However, patients often need a multiple daily insulin injection regimen to control basal and postprandial blood glucose, which causes various complications. Controlled pulsatile drug release technology using ultrasound as an external stimulus source is a very promising method to avoid multiple injections of insulin. However, most of the drug-loaded microbubbles used for ultrasound-mediated treatment have a short half-life, which limits their use in controlled pulsatile drug release. More importantly, how to control insulin release is still a challenge. In this paper, chitosan poly-acrylic acid nanobubbles as drug carriers of insulin were prepared to achieve a visually controlled pulsatile release of insulin triggered by focused ultrasound. The experimental results in vivo demonstrated that nanobubbles were stable enough to achieve long-term visualization for 7 days after intramuscular injection in rats. Under the guidance of ultrasound imaging, it is visible to find the position and observe the gray values change of nanobubbles. Thus, when triggered by focused ultrasound, the amount of insulin could be accurately pulsatile released from nanobubbles. In vivo experiments in rats showed that the visually controlled pulsatile release of insulin could be achieved for a long time, up to 3 consecutive days. The blood glucose level could be repeatedly reduced by focused ultrasound irradiation with just one injection. Our research provided a promising way for visually controlled pulsatile release of insulin, which would significantly reduce the injection frequency of insulin.

Managing Diabetes with Hydrogel Drug Delivery

AbstractDiabetes 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.

Glucose‐Responsive Microneedle Patch With Variable Crosslinking Density and Flexible Core–Shell Structure for Insulin Delivery

AbstractDeveloping glucose‐responsive microneedle patches with features of simple preparation, high insulin loading, and safety has a great contribution to the treatment of diabetic patients. In this work, a novel glucose‐responsive core–shell microneedle patch is prepared from biocompatible materials by a facile process. The exterior glucose‐responsive shell is composed of polyvinyl alcohol (PVA) and ɛ‐polylysine modified with phenylboronic acid , and the inner flexible core is prepared by pure PVA loaded with insulin. The shell shows superior glucose‐induced swelling and controlled insulin release ability due to the decomposition of borate ester bonds under the synergistic effect of glucose and water. The microneedle patch also features flexibility and high insulin loading capacity (36 IU cm−2). It shows high puncture efficiency (92%) and maintains a relatively complete morphology after being removed, enabling to reduce material residues in the skin. Moreover, the microneedle patch reveals a good hypoglycemic effect in diabetic rats, achieves a hypoglycemic rate similar to that of direct injection after swelling, and works effectively to prevent excess insulin transmission. The high glucose‐responsive ability, simple preparation, high loading capacity, rapid hypoglycemic speed, high conformability to skin, and low component dissolution make this microneedle patch a suitable candidate for diabetic treatment.

Neuroscience: Moving thoughts control insulin release

Insulin release has mostly been studied in the context of metabolic signals. An electrophysiology approach inDrosophila now reveals regulation of insulin-producing cell activity by neuronal circuits controlling locomotion. Even without actual movement, activating these circuits is sufficient to inhibit neuropeptide release.

Controlled release of silica-coated insulin-loaded chitosan nanoparticles as a promising oral administration system

BackgroundOral insulin administration has recently become one of the most exciting research subjects. Different approaches have been carried out to get an effective oral insulin delivery system using nanotechnology. The development of a delivery system that overcomes the difficulties of oral insulin administration, achieving high stability and minimal side effects, is still an urgent need. Therefore, this study is considered one of the efforts to design a new prospective drug delivery nano-composite (silica-coated chitosan-dextran sulfate nanoparticles).MethodsChitosan-dextran sulfate nanoparticles (CS-DS NPs) were prepared via a complex coacervation method and then coated with silica. Uncoated and silica-coated CS-DS NPs were physically characterized via different techniques. Transmission electron microscopy (TEM), scanning electron microscopy (SEM), energy-dispersive X-ray (EDX) analysis, and atomic force microscopy (AFM) have been used to investigate the chemical elements, size, morphology, and surface properties of the prepared formulations. Differential scanning calorimetry (DSC) to assess the thermal properties of formed nano-formulations. Fourier transform infrared (FT-IR) spectroscopy investigated the silica coat and chitosan interaction. The encapsulation efficiency was evaluated using high-performance liquid chromatography (HPLC) analysis. The insulin release profile of nano-formulations was performed with and without silica coat at two different pHs (5.5,7), nearly simulating the environment of the gastrointestinal tract (GIT).ResultsThe silica-coated CS-DS NPs revealed interesting physicochemical properties exemplified by suitable core particle size obtained by TEM images (145.31 ± 33.15 nm), hydrodynamic diameter (210 ± 21 nm), high stability indicated by their zeta potential value (-32 ± 3.2 mV), and adequate surface roughness assessed by AFM. The encapsulation efficiency of insulin-loaded chitosan nanoparticles (ICN) was (66.5%) higher than that of insulin-chitosan complex nanoparticles (ICCN). The silica-coated ICN demonstrated a controlled insulin release profile at pHs (5.5 and 7) compared with uncoated ICN.ConclusionThe silica-coated ICN can be an efficient candidate as a desired oral delivery system, overcoming the common obstacles of peptides and proteins delivery and achieving high stability and controlled release for further applications.

Functionalized zein nanoparticles targeting neonatal Fc receptor to enhance lung absorption of peptides

Peptides have a distinguished therapeutic potential for several chronic conditions, and more than 80 peptides exist in the global market. However, most of these marketed peptide drugs are currently delivered intravenously or subcutaneously due to their fast degradation and limited absorption through non-invasive routes. The pulmonary route is favored as a non-invasive route. Neonatal Fc receptor (FcRn) is expressed in adult human lungs and has a role in enhancing the pulmonary absorption of monoclonal antibodies. In this work, we developed and characterized candidate protein delivery systems for the pulmonary administration of peptides. The prepared bare and loaded zein nanoparticles (ZNPs), targeted, physically, and covalently PEGylated ZNPs showed hydrodynamic diameters between 137 and 155 nm and a narrow distribution index. Insulin, which was used as a protein model, showed an association efficiency of 72%, while the FcRn-targeted peptide conjugation efficiency was approximately 68%. The physically adsorbed poloxamer 407 on insulin-loaded ZNPs showed slower and controlled insulin release. The in vitro cell culture model consists of the NCI-H441 epithelial cell line, which confirmed its expression of the targeted receptor, FcRn. The safety of ZNPs was verified after incubation with both cell lines of the in vitro pulmonary model, namely NCI-H441 and HPMEC-ST1.6R, for 24 h. It was observed that targeted ZNPs enhanced insulin permeability by showing a higher apparent permeation coefficient than non-targeted ZNPs. Overall, both targeted PEGylated ZNPs showed to be suitable peptide carriers and adequately fit the demands of delivery systems designed for pulmonary administration.Graphical

Glucose-responsive nanogate of poly(methacrylic acid) brush-glucosamine network capping on the holes of chips for controlled insulin release

• A well-defined 500-nm hole array is fabricated on a silicon wafer as an insulin container. • Glucosamine (GA) is grafted to poly(methacrylic acid) (PMAA) brushes as the nanogate of the container. • Biphenyl-4,4′-diboronic acid (DBA) is employed to lock the nanogate and cap the container. • The locked nanogate can be opened with glucose to release the insulin from the container. • The nanogate can be opened and closed reversibly to control insulin release over ten days. • The glucose-triggered insulin release system provides a novel strategy on a subcutaneous implant chip. Diabetes mellitus is a disease caused by deficient glycemic control by the pancreas that has caused serious health issues globally. Patients must inject insulin manually to stabilize their blood glucose levels (BGLs). A hole array was fabricated on a silicon wafer to graft poly(methacrylic acid) (PMAA) brushes from the silicon surface via atom transfer radical polymerization. Glucosamine (GA) was sequentially immobilized on the PMAA chains to obtain a P(MAA-GA) brush surrounding the hole edges on the silicon surface. After loading insulin inside the holes, biphenyl-4,4′-diboronic acid (DBA) was used to cross-link the P(MAA-GA) chains through the formation of boronate esters to cap the hole and block the release of insulin. The boronate esters were disassociated with glucose solution to open of the holes and the release of insulin, thus indicating a reversible association. The total amount of drug inside the chip was approximately 32.4 ± 1.8 g cm −2 , which could be released at a rate of approximately 107 ± 5.7 ng h −1 cm −2 at a glucose concentration of 1 g L −1 for 270 h. Drug release was not significantly influenced by the presence of GA and amino acids, indicating excellent stability and selectivity of the chip.

A Closed-Loop Autologous Erythrocyte-Mediated Delivery Platform for Diabetic Nephropathy Therapy.

Failure to control blood glucose level (BGL) may aggravate oxidative stress and contribute to the development of diabetic nephropathy (DN). Using erythrocytes (ERs) as the carriers, a smart self-regulatory insulin (INS) release system was constructed to release INS according to changes in BGLs to improve patients’ compliance and health. To overcome the limited sources of ERs and decrease the risk of transmitting infections, we developed an in vitro, closed-loop autologous ER-mediated delivery (CAER) platform, based on a commercial hemodialysis instrument modified with a glucose-responsive ER-based INS delivery system (GOx-INS@ER). After the blood was drained via a jugular vein cannula, some of the blood was pumped into the CAER platform. The INS was packed inside the autologous ERs in the INS reactor, and then their surface was modified with glucose oxidase (GOx), which acts as a glucose-activated switch. In vivo, the CAER platform showed that the BGL responsively controlled INS release in order to control hyperglycemia and maintain the BGL in the normal range for up to 3 days; plus, there was good glycemic control without the added burden of hemodialysis in DN rabbits. These results demonstrate that this closed-loop extracorporeal hemodialysis platform provides a practical approach for improving diabetes management in DN patients.

Oral Glucose-Responsive Nanocarrier System for Management of Diabetes

Background: The regulation of postprandial blood glucose concentration in a diabetic person is a toilsome task by the conventional approaches. The continuous monitoring and subcutaneous injection of insulin are always imperative for diabetes management. To overcome the hurdle associated with the conventional system, a glucose-responsive nanoparticle (NP)-based approach was developed for oral insulin administration. The objective of the work is the formulation and characterization of a nanocarrier-based bio-responsive, self-regulated oral insulin drug delivery system. Methods: The mannose ligand-conjugated NPs were prepared by the inotropic gelation method in which insulin and glucose oxidase enclosed alginate nanocarrier cross-linked by tripolyphosphate. The prepared NPs were filled into the enteric-coated capsule and their release profile was determined at different pH and glucose concentrations. NPs were characterized by size distribution, % drug entrapment, enzyme activity, and in vivo and in vitro drug release studies. Results: The average size, surface potential, % drug entrapment of optimized NPs were 245.52 ± 3.37 nm, 22.12 ± 2.13, and 76.15±1.3%, respectively. The release of insulin from optimized NPs (GOx-ALG-MCNPs) (98.56±0.06%) occurs only at higher sugar concentrations (? 400 mg/dL) and prevents the release at low sugar concentrations (< 100 mg/dL). The enteric capsule shell protected the formulation to the gastric environment upon oral administration and directed them into the intestine. Mucoadhesion characteristics of NPs prolonged intestinal retention to make them available for cellular uptake. Glucose sensitivity and glucose-dependent effect on different pH environments study revealed that NPs released the drug only at higher concentrations of sugar solution while inhibiting the release at normal and lower sugar concentrations. Besides, compared to other prepared formulations, the GOx-ALG-MCNPs displayed controlled insulin release in response to glucose concentration. Conclusions: An important finding of GOx-ALG-MCNPs is auto-regulating, glucose-responsive behavior imparting a significantly controlled lowering of blood glucose in an animal model. The findings reveal that the developed glucose-responsive NPs may prove to be a potential strategy for oral insulin delivery. J Endocrinol Metab. 2022;12(4-5):146-160 doi: https://doi.org/10.14740/jem747

Synthesis and characterization of 4-formylphenylboronic acid cross-linked chitosan hydrogel with dual action: Glucose-sensitivity and controlled insulin release

The number of people affected by diabetes mellitus is increasing globally in each year. A cause of elevated blood glucose levels can result from a lack of insulin or insufficient utilization of produced insulin. However, diabetes, a metabolic disorder is a serious chronic disease and an acute public health problem. Glucose-sensitive hydrogels that have 3D network structure can act in response to glucose and garners immense attention in biomedical appliance especially for drug delivery. Herein, a novel, glucose- and pH-responsive intelligent hydrogel encompassing chitosan cross-linked to 4-formylphenylboronic acid is prepared via dynamical reversible chemical bonds (imine) between chitosan and 4-formylphenylboronic acid with potential of controlled release of insulin. The characteristic features of such hydrogels are confirmed by Fourier transformed infrared (FT-IR), scanning electron microscopy (SEM), differential scanning calorimetry (DSC) and swelling ratio. Of these, the glucose-sensitive polymeric carrier (hydrogel) based on 4-formylphenylboronic acid has the advantages of enhanced stability, long-term storage, reversible response to glucose with high entrapment efficiency and controlled drug release into the physiological condition. In this paper, chitosan cross-linked with 4-formylphenylboronic acid, comprising the realization of Schiff base bearing (–C=N–) linkage, leads to the generation of a hydrogel which works better than normal phenylboronic acid (PBA) under physiological setting. The ensuing outcome implies that the glucose-susceptible hydrogel has prospective appliance as a glucose-receptive matter for insulin transport.

Electrical signals regulate the release of insulin from electrodeposited chitosan composite hydrogel: An in vitro and in vivo study.

Electrical signal controlled drug release from polymeric drug delivery system provides an efficient way for accurate and demandable drug release. In this work, insulin was loaded on inorganic nanoplates (layered double hydroxides, LDHs) and coated on a copper wire by co-electrodeposition with chitosan. The formed structure in chitosan composite hydrogel entrapped insulin efficiently, which were proved by various techniques. In addition, the drug loaded chitosan composite hydrogel demonstrated good biocompatibility as suggested by cell attachment. In vitro drug release experiment showed fast responsive pulsed release of insulin by biasing electrical signals. The in vivo experiment in diabetic rats revealed controllable insulin release in plasma and stable decrease of blood glucose can be achieved by using appropriate electrical signal. In addition, HE staining suggested negligible effect to the tissue by electrical signals. This work suggests that the electrical signal controlled insulin release from chitosan composited hydrogel may be a promising administration route for insulin.