Robust micelles formulation to improve systemic corticosteroid therapy in sepsis in multiple healthcare systems

Abstract

Sepsis is a life-threatening condition resulting from an imbalanced immune response to an infection that causes over 10 million deaths annually, particularly in low and middle-income countries. Current clinical management of sepsis relies on infection control, homeostasis restoration, and systemic corticosteroid therapy. Unfortunately, while beneficial, corticosteroid regimens, including dexamethasone, can lead to adverse effects such as neurological and metabolic complications, limiting their use. In this work, we decided to develop a scalable production method using only approved and cost-effective materials. We also conceived our formulation to be freeze-drying friendly to allow its use within various healthcare systems. Following those concepts, we designed DSPE-PEG(2000)-based micelles to encapsulate dexamethasone, and improve its in vivo efficacy by extending blood circulation time and targeting innate blood immune cells. First, the physicochemical properties, stability, in vitro release kinetics, and efficacy of dexamethasone-loaded micelles were comprehensively measured to demonstrate the platform's robustness. The therapeutic in vivo efficacy of dexamethasone-loaded micelles and their ability to increase animal survival was exhibited in two murine sepsis models, an endotoxemia model, and the cecal ligation and puncture model. Various biodistribution and ex vivo fluorescence imaging assays revealed that using micelles led to an improved blood circulation time and a preferential accumulation within immune cells that could explain the enhanced efficacy of dexamethasone-loaded micelles compared to the soluble form of the drug used clinically. Altogether, our results indicate that this robust micellar delivery system can potentially improve the anti-inflammatory therapy of dexamethasone, offering a safer and more effective alternative to conventional corticosteroid regimens in sepsis.