Empagliflozin-loaded nanomicelles responsive to reactive oxygen species for renal ischemia/reperfusion injury protection

Abstract

Abstract The brain, heart, liver, kidney, and other organs are susceptible to the harmful effects of ischemia-reperfusion injury (IRI), where the excessive production of reactive oxygen species (ROS) following IRI contributes to tissue damage and ensuing inflammation. In recent years, researchers have designed various nanoparticles that are responsive to ROS for the treatment of IRI. Empagliflozin (EMPA), an inhibitor of the sodium-glucose cotransporter-2 commonly used in type 2 diabetes mellitus, shows promise in mitigating IRI. However, its water-insolubility and low bioavailability present challenges in fully realizing its therapeutic efficacy. To tackle this issue, we formulated EMPA-loaded nanomicelles designed to respond to ROS, aiming to prevent renal damage caused by ischemia-reperfusion. Extensive characterization confirmed the effectiveness of the formulated nanomicelles. Through simulations and release studies, we observed structural modifications in the micelles leading to the release of EMPA upon encountering ROS (H2O2). In animal studies, rats treated with EMPA-loaded micelles showed normal renal tissue architecture, with only some remaining tubular swelling. Molecular assessments revealed that IRI triggered cell apoptosis through mechanisms involving hypoxia, metabolic stress, ROS, and TNF-α elevation. EMPA treatment reversed this process by upregulating B-cell lymphoma protein 2 and reducing levels of associated X (BAX) protein, Caspase 3, and Caspase 8. These results indicate that ROS-responsive micelles could act as a spatially targeted delivery system, effectively transporting EMPA directly to the ischemic kidney. This offers a promising therapeutic strategy for alleviating the impact of renal IRI.