Abstract
Acute respiratory distress syndrome (ARDS), a catastrophic illness of multifactorial etiology, involves a rapid upsurge in inflammatory cytokines that leads to hypoxemic respiratory failure. Dexamethasone, a synthetic corticosteroid, mitigates the glucocorticoid-receptor-mediated inflammation and accelerates tissue homeostasis towards disease resolution. To minimize non-target organ side effects arising from frequent and chronic use of dexamethasone, we designed biodegradable, lung-targeted microspheres with sustained release profiles. Dexamethasone-loaded lipopolymeric microspheres of PLGA (Poly Lactic-co-Glycolic Acid) and DPPC (Dipalmitoylphosphatidylcholine) stabilized with vitamin E TPGS (D-α-tocopheryl polyethylene glycol succinate) were prepared by a single emulsion technique that had a mean diameter of 8.83 ± 0.32 μm and were spherical in shape as revealed from electron microscopy imaging. Pharmacokinetic and biodistribution patterns studied in the lungs, liver, and spleen of Wistar rats showed high selectivity and targeting efficiency for the lung tissue (re 13.98). As a proof-of-concept, in vivo efficacy of the microspheres was tested in the lipopolysaccharide-induced ARDS model in rats. Inflammation markers such as IL-1β, IL-6, and TNF-α, quantified in the bronchoalveolar lavage fluid indicated major improvement in rats treated with dexamethasone microspheres by intravenous route. Additionally, the microspheres substantially inhibited the protein infiltration, neutrophil accumulation and lipid peroxidation in the lungs of ARDS bearing rats, suggesting a reduction in oxidative stress. Histopathology showed decreased damage to the pulmonary tissue upon treatment with the dexamethasone-loaded microspheres. The multipronged formulation technology approach can thus serve as a potential treatment modality for reducing lung inflammation in ARDS. An improved therapeutic profile would help to reduce the dose, dosing frequency and, eventually, the toxicity.
Highlights
In the current situation of the COVID-19 pandemic, the world has witnessed a huge loss of life due to respiratory complications worldwide
High oxidative stress reduces the functionality of lung surfactants eventually leading to acute respiratory distress syndrome (ARDS)
The anatomy of the respiratory tract, presence of alveolar edema and atelectasis make the reach and effectiveness of administered drug therapies challenging. These obstacles encountered during treatment have directed the attention of researchers towards the development of targeted delivery systems achieving sufficiently high doses directly to the infection site [38]
Summary
In the current situation of the COVID-19 pandemic, the world has witnessed a huge loss of life due to respiratory complications worldwide. The COVID-19 pandemic has once again reinforced the fact that respiratory illness often accelerates morbidity making the health conditions difficult to manage [1,2]. A multitude of respiratory diseases, such as pulmonary hypertension, acute respiratory distress syndrome (ARDS), Pharmaceutics 2021, 13, 1347. ARDS is typically observed in critically ill or patients with sepsis, severe pneumonia, coronavirus disease, or significant head or chest injuries [4]. Severe shortness of breath is the main symptom of ARDS which usually develops within a few hours and lasts for several days, precipitating the injury that eventually necessitates mechanical ventilation. Administration of dexamethasone could reduce the duration of mechanical ventilation and mortality in patients with moderate-to-severe ARDS [6,7,8]. Dexamethasone, a synthetic corticosteroid, downregulates glucocorticoid-receptor-mediated inflammatory cascade, mitigating inflammation and accelerating tissue homeostasis towards disease resolution [9]
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