This study aimed to develop and evaluate reactive oxygen species (ROS)-responsive (Thioketal-grafted DSPE-PEG2000, DTP) liposomes loaded with dexamethasone (DTP@DEX-LP) for aerosol inhalation to achieve targeted drug delivery and controlled release in the pulmonary fibrosis microenvironment. DTP@DEX-LP was prepared and optimized. The liposomes were characterized for particle size, zeta potential, encapsulation efficiency (EE), and morphology. Their aerosol performance, ROS-responsive drug release, and cellular uptake were assessed in vitro. In vivo pulmonary deposition, pharmacokinetics, and antifibrotic efficacy were evaluated in a bleomycin-induced mouse model, alongside safety profiling. The optimized DTP@DEX-LP exhibited a uniform particle size of ∼ 115 nm, a high EE of >82%, and desirable aerosol properties (FPF ∼ 50%, MMAD ∼ 4.9 μm). The formulation demonstrated ROS-triggered drug release and enhanced cellular uptake in vitro. Following inhalation, DTP@DEX-LP significantly prolonged lung retention and reduced systemic exposure of DEX compared to controls. In the fibrosis model, DTP@DEX-LP treatment yielded superior therapeutic outcomes, markedly improving survival, and reducing collagen deposition. It also showed a notably improved safety profile, with reduced hepatotoxicity compared to intravenous DEX. The ROS-responsive liposomal system represents a promising inhaled platform for the precise treatment of pulmonary fibrosis, effectively enhancing the therapeutic index of dexamethasone by simultaneously improving its efficacy and mitigating systemic toxicity.
Sun et al. (Wed,) studied this question.