PEGylation Improves the Therapeutic Index of Dexamethasone To Treat Acute Respiratory Distress Syndrome with Obesity Background in Mouse

Abstract

With increasing prevalence globally, obesity presents unique challenges to the clinical management of other diseases. In the case of acute respiratory distress syndrome (ARDS), glucocorticoid therapy (e.g., dexamethasone (DEX)) represents one of the few pharmacological treatment options, but it comes with severe adverse effects, especially when long-term usage (>1 week) is required. One important reason for the adverse effects of DEX is its nonspecific accumulation in healthy tissues upon systemic administration. Therefore, we hypothesize that refining its pharmacokinetics (PK) and in vivo biodistribution may improve its therapeutic index (higher efficacy, lower toxicity) and thus make it safer for obese populations. To achieve this goal, DEX was conjugated with polyethylene glycol (PEG) with three different molecular weights (M_w, 2K, 5K, and 10K) via a reactive oxygen species (ROS)-cleavable linker. Their anti-inflammatory efficacy and long-term adverse effects were evaluated in a murine obesity-ARDS model. Strikingly, DEX-PEG-2K (conjugates with 2K PEG M_w) provided the optimal therapeutic index compared to free DEX and to the other two conjugates with longer PEGs (M_w of 5K and 10K): While retaining the comparable therapeutic efficacy to DEX, DEX-PEG-2K significantly reduced the accumulation of free DEX in the liver and spleen, which led to a 51% reduction of fatty area in liver and a 32% reduction of blood triglycerides concentration. DEX-induced apoptosis of the thymus was also rescued by DEX-PEG-2K under normal conditions. The PK and biodistribution were also investigated to elicit the underlying mechanism. In summary, we provided here a chemical modification strategy to improve the therapeutic index of dexamethasone and possibly other glucocorticoid drugs for ARDS treatment with an obesity background.