Glucose-Responsive Chitosan Nanoparticle/Poly(vinyl alcohol) Hydrogels for Sustained Insulin Release In Vivo

Stimuli-responsivehydrogels (HGs) with a controlled drug releaseprofile are the current challenge for advanced therapeutic applications.Specifically, antidiabetic drug-loaded glucose-responsive HGs arebeing investigated for closed-loop insulin delivery in insulin-dependentdiabetes patients. In this direction, new design principles must beexploited to create inexpensive, naturally occurring, biocompatibleglucose-responsive HG materials for the future. In this work, we developedchitosan nanoparticle/poly(vinyl alcohol) (PVA) hybrid HGs (CPHGs)for controlled insulin delivery for diabetes management. In this design,PVA and chitosan nanoparticles (CNPs) are cross-linked with a glucose-responsiveformylphenylboronic acid (FPBA)-based cross-linker in situ. Leveraging the structural diversity of FPBA and its pinacol ester-basedcross-linkers, we fabricate six CPHGs (CPHG1-6) with more than80% water content. Using dynamic rheological measurements, we demonstrateelastic solid-like properties of CPHG1-6, which are dramaticallyreduced under low-pH and high-glucose environments. An invitro drug release assay reveals size-dependent glucose-responsivedrug release from the CPHGs under physiological conditions. It isimportant to note that the CPHGs show appreciable self-healing andnoncytotoxic properties. Promisingly, we observe a significantly slowerinsulin release profile from the CPHG matrix in the type-1 diabetes(T1D) rat model. We are actively pursuing scaling up of CPHGs andthe in vivo safety studies for clinical trial inthe near future.

Automated summary

In this study, chitosan nanoparticle/poly(vinyl alcohol) hybrid hydrogels (CPHGs) were developed for controlled insulin delivery for diabetes management. CPHGs exhibited reduced solid-like properties under low pH and high glucose environments. They also showed good self-healing and noncytotoxic properties.