Inhalable PLGA microspheres: Tunable lung retention and systemic exposure via polyethylene glycol modification

Polyethylene glycol (PEG) modification is one of the promising approaches to overcome both mucus and alveolar macrophage uptake barriers in the deep lung for sustained therapy of pulmonary diseases such as asthma. To investigate the feasibility of using PEG-modified microspheres to bypass both barriers, we prepared a collection of polyethylene glycol-distearoyl glycero-phosphoethanolamine (PEG-DSPE)-modified poly (lactide-co-glycolide) (PLGA) microspheres bearing specific PEG molecular weights (0.75, 2, 5, and 10 kDa) and PEG-DSPE/PLGA molar ratios (0.25:1 and 1:1). Drug release, mucus penetration, and macrophage uptake were evaluated in vitro, and the corresponding in vivo activities of microspheres in rats were investigated. It was found that the PEG₂₀₀₀-DSPE/PLGA 1:1 group showed enhanced mucus permeability and reduced macrophage uptake in vitro compared to the PEG₂₀₀₀-DSPE/PLGA 0.25:1 group. At high PEG molar ratios, only the PEG 2000-based group showed significantly prolonged lung retention in vivo compared to the control group. The systemic exposure of the PEG₂₀₀₀-DSPE/PLGA 1:1 group was significantly lower than that of the PEG₂₀₀₀-DSPE/PLGA 0.25:1 group (39% of AUC reduction). Additionally, when using the same molar ratio of 1:1, the PEG 2000 group significantly lowered the systemic drug exposure compared to that of the PEG 5000 and 10000 groups (48% and 33% of AUC reduction, respectively), thus making it a promising sustained lung delivery candidate for pulmonary disease treatment.