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

Stimuli-responsive hydrogels (HGs) with a controlled drug release profile are the current challenge for advanced therapeutic applications. Specifically, antidiabetic drug-loaded glucose-responsive HGs are being investigated for closed-loop insulin delivery in insulin-dependent diabetes patients. In this direction, new design principles must be exploited to create inexpensive, naturally occurring, biocompatible glucose-responsive HG materials for the future. In this work, we developed chitosan 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-responsive formylphenylboronic acid (FPBA)-based cross-linker in situ. Leveraging the structural diversity of FPBA and its pinacol ester-based cross-linkers, we fabricate six CPHGs (CPHG1-6) with more than 80% water content. Using dynamic rheological measurements, we demonstrate elastic solid-like properties of CPHG1-6, which are dramatically reduced under low-pH and high-glucose environments. An in vitro drug release assay reveals size-dependent glucose-responsive drug release from the CPHGs under physiological conditions. It is important to note that the CPHGs show appreciable self-healing and noncytotoxic properties. Promisingly, we observe a significantly slower insulin release profile from the CPHG matrix in the type-1 diabetes (T1D) rat model. We are actively pursuing scaling up of CPHGs and the in vivo safety studies for clinical trial in the near future.