Mitigation of Hydrochloric Acid (HCl)-Induced Lung Injury in Mice by Aerosol Therapy of Surface-Active Nanovesicles Containing Antioxidant and Anti-inflammatory Drugs.

Acute lung injury leading to alveolar inflammation and surfactant dysfunction remains a medical challenge. Surface-active lipid nanovesicles of 200-250 nm size with antioxidant D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) and anti-inflammatory drug dexamethasone disodium phosphate (DXP) dual combination (Dual-NV) were developed for delivery as aerosols by nebulization in acid lung injury models. Drug deposition studies showed Dual-NV deposited ∼2.5 times more DXP compared to equivalent DXP solution. Nanovesicles are actively internalized by A549 cells through ATP- and clathrin-dependent pathways. The nanovesicles could be phagocytosed by RAW 264.7 macrophages and were nonimmunogenic and did not elicit overproduction of TNF-α, IL-1β, and IL-6. Dual-NV aerosol therapy at 200 mg/kg body weight, in HCl acid-induced lung injury in mice, markedly reduced pulmonary hemorrhage and protein leakage and improved capillary (airway) patency to ∼96%. Dual-NV aerosol therapy also significantly lowered production of inflammatory cytokine IL-1β, IL-6, and TNF-α and reduced oxidative stress by ∼95% in the injured group. Surface-active Dual-NV aerosol therapy is promising for replenishing the dysfunctional surfactant pool and mitigating inflammation and oxidative stress in lung injuries.