Glucose- and H₂O₂-Responsive Polymeric Vesicles Integrated with Microneedle Patches for Glucose-Sensitive Transcutaneous Delivery of Insulin in Diabetic Rats

Abstract

Herein, a dual-responsive insulin delivery device by integrating glucose- and HO-responsive polymeric vesicles (PVs) with transcutaneous microneedles (MNs) has been designed. This novel microneedle delivery device achieves a goal of fast response, excellent biocompatibility, and painless administration. The PVs are self-assembled from a triblock copolymer including poly(ethylene glycol), poly(phenylboronic acid) (glucose-sensitive block), and poly(phenylboronic acid pinacol ester) (HO-sensitive block). After loading with insulin and glucose oxidase (GO ), the drug-loaded PVs display a basal insulin release as well as a promoted insulin release in response to hyperglycemic states. The insulin release rate responds quickly to elevated glucose and can be further promoted by the incorporated GO , which will generate the HO at high glucose levels and further break the chemical links of phenylboronic acid pinacol ester group. Finally, the transdermal delivery of insulin to the diabetic rats ((insulin + GO )-loaded MNs) presents an effective hypoglycemic effect compared to that of subcutaneous injection or only insulin-loaded MNs, which indicates the as-prepared MNs insulin delivery system could be of great importance for the applications in the therapy of diabetes.

Interplay of Solvation and Size Effects Induced by the Counterions in Ionic Block Copolymers on the Basis of Hofmeister Series

“…The self‐assembly of amphiphilic block copolymers (BCPs) in selective solvents is increasingly attracting the attention of researchers in the past decades due to their potential applications in biological drug delivery, microreactor chemistry, and in novel nanostructural templating . In selective solvents, neutral BCPs can form various morphologies such as spheres, cylinders, vesicles, and lamellae, which can be regulated by many factors, such as block length, solvent composition, pH, and inorganic salt .…”

Glucose‐Responsive Composite Microneedle Patch for Hypoglycemia‐Triggered Delivery of Native Glucagon

“…Even when ready‐to‐use glucagon rescue pens become available in the future, proper glucagon administration is challenging for patients who suffer from hypoglycemia‐unawareness, nocturnal hypoglycemia, or rely on caregivers/parents for treatment . In recent years, extensive research efforts have been made to develop glucose‐responsive insulin delivery systems, including a glucose‐responsive MN patch that utilizes glucose oxidase‐catalyzed bioreactions to trigger insulin release . Nevertheless, the application of these devices is still accompanied with the risk of hypoglycemia.…”

Biologically Inspired and Chemically Derived Methods for Glucose‐Responsive Insulin Therapy

“…This approach can be accomplished through the inclusion of both subunits as pendant groups on the same polymer or by functional attachments to separate polymers that are then mixed . Phenylboronic esters, a class of PBA derivatives, are known to demonstrate peroxide‐sensitive degradation behavior, and have been exploited in some systems to drive insulin release dependent on the H 2 O 2 generated from GOx activity or from other sources . Efforts have also been undertaken to integrate diagnostic and therapeutic elements within the same system, as has been demonstrated in studies where a glucose‐responsive polymeric PBA‐modified shell was integrated with silver or silica nanoparticles for fluorescent signaling of glucose concentrations and proportionate insulin release …”