1237-P: Generation of Targeted Nanoparticles for ß-Cell-Selective Delivery of Antioxidant Drugs

Abstract

β-cells are highly metabolic and vulnerable to a variety of exogenous stressors, many of which elicit the generation of reactive oxygen species (ROS). Endogenous adaptive responses can restore homeostasis after excessive ROS elevation. If the endogenous adaptive response fails, ROS accumulation can cause damage to DNA, proteins, and organelles, ultimately leading to apoptosis. A wealth of evidence supports that ROS accumulation contributes to β-cell dysfunction and destruction during diabetes development. These findings suggest that stimulating the antioxidant response could prevent or treat diabetes. However, limitations exist in that persistent systemic activation of the antioxidant response can perturb the normal second messenger function of ROS, and that exogenous antioxidants have poor bioavailability and lack specificity. To overcome these obstacles, we developed β-cell targeted nanoparticles to selectively deliver antioxidants to β-cells. We conjugated modified Exendin-4 (Ex4) to an amphiphilic polymer, allowing us to generate lipid nanoparticles to deliver small hydrophobic compounds to GLP-1R expressing cells. We assessed β-cell targeting of our nanoparticles using isolated islets from mice expressing tdTomato selectively in the β-cell. Isolated islets were treated with nanoparticles containing a lipid intercalating dye, DiO, and we observed selective DiO accumulation in tdTomato positive cells. We also performed in vivo imaging of live mice injected with targeted or non-targeted nanoparticles containing a near-IR lipid intercalating dye. These experiments demonstrated selective retention of targeted nanoparticles both systemically and in the pancreata of animals 1 hour after tail vein injection. Collectively, we provide evidence that Ex4 coated micelles are selective to β-cells. Future experiments will explore this targeted approach to deliver drugs to stimulate the antioxidant response and reduce β-cell apoptosis under diabetogenic conditions. Disclosure A. Novak: None. T. Nallan chakravarthula: None. J. Crowder: None. N. J. Alves: None. J. Broichhagen: None. D. Hodson: None. A. Bedwell: None. A. K. Linnemann: None.