Surface-Functionalized Nanoceria: Dual Action in Diabetes Management via Glucose-Responsive Insulin Delivery and Oxidative Stress Mitigation.

Abstract

Nanoceria (NC) is gaining scientific attention due to its widespread drug delivery efficacy and modulation of oxidative stress. Herein, we developed dextran (Dex) capped insulin (INS)-loaded phenylboronic acid (PBA)-functionalized nanoceria (NC-PBA-INS-Dex) for glucose-responsive insulin delivery and mitigating excessive ROS production to regulate both hyperglycemia and oxidative stress in diabetes mellitus (DM). The prepared nanoparticle showed favorable loading capacity and excellent encapsulation efficiency of insulin. Glucose-responsive insulin release from NC-PBA-INS-Dex was observed initially in the cell-free mode when subjected to varying glucose concentrations (5.5, 11, and 25 mM). Interestingly, under in vitro setting, promising insulin release from NC-PBA-INS-Dex was found in muscle cells (major glucose storage cells) compared to lung cells against exposure to different glucose concentration suggesting a glucose-sensitive intracellular insulin delivery. NC-PBA-INS-Dex treatment further upregulated GLUT4 translocation and glucose uptake/utilization in sodium palmitate-exposed muscle cells, and results were significantly higher compared to NC or INS alone treated cells. Studies in diabetic animals demonstrated the maintenance of normoglycemia for up to 12 h upon gavaging a single dose of NC-PBA-INS-Dex compared to INS alone treatment (subcutaneous/oral). Oral administration of NC-PBA-INS-Dex also increased insulin bioavailability (in both serum and muscle tissue) compared with either subcutaneous or oral insulin administration. NC-PBA-INS-Dex further exhibited ROS scavenging (superoxide radical) potential in cell-free, in vitro, and in vivo systems, and results were comparable to treatment with NC alone. NC-PBA-INS-Dex could effectively regulate the expression of occludin and induce the reversible opening of a tight junction in intestinal epithelial cells, allowing the particle transport through the intestinal mucosa. Treatment with NC-PBA-INS-Dex did not exhibit any toxicity to in vitro and in vivo models. The NC-based drug delivery system will mimic the physiological regulation of insulin secretion in a noninvasive manner, offering improved patient compliance, reduced risk of hyperglycemia, and enhanced overall management of DM.