Resveratrol-Loaded Dipalmitoylphosphatidylcholine Liposomal Large Porous Microparticle Inhalations for the Treatment of Bacterial Pneumonia Caused by Acinetobacter baumannii.

Background: Acinetobacter baumannii-mediated bacterial pneumonia is a common disease that is harmful to human health. Dipalmitoylphosphatidylcholine (DPPC) is the major lipid component of the pulmonary surfactant (PS) found in the alveolar space; the PS helps to keep surface tension low, which allows for improved oxygen delivery. Resveratrol (RE) is a phytoalexin found in plants that is released in response to injury or infection. The therapeutic effect of Re is limited due to its low solubility and bioavailability. In this study, we report pulmonary delivery of Re-loaded DPPC liposomal large porous microparticles (RDLPMs) for treatment of A. baumannii-induced pneumonia. Methods: Novel RDLPMs were prepared by rotary evaporation and a freeze-drying method in this study. RDLPMs were evaluated by the particle size, electric potential, in vitro release, and particle size distribution. A rat model of A. baumannii-mediated pneumonia was established and used for pharmacodynamic evaluations. Results: The Re-loaded DPPC liposomes (RDLs) consisted of Re/DPPC (1:3, mol/mol) and DPPC/cholesterol (3:1, w/w), with a hydration time of 15 minutes. The RDLs had a high encapsulation efficiency of 69.8% ± 1.6%, a mean size of 191.5 ± 4.5 nm, and a high zeta potential of 12.4 ± 1.5 mV. The RDLPMs were composed of mannitol/large porous microparticles/RDLs (1:4:2, w/w/w) and had a loading efficiency of 2.20% ± 0.24%. The RDLPMs had an aerodynamic diameter (2.73 ± 0.65 μm), a good fluidity (28.30° ± 6.13°), and demonstrated high lung deposition (fine particle fraction = 43.33%). Surprisingly, while penicillin showed better microbial inhibition than the RDLPMs and Re groups in vitro, the RDLPMs were more effective in vivo. Conclusion: The RDLPMs showed good powder properties for pulmonary delivery. The RDLPMs may inhibit the nuclear factor kappa-B pathway and downregulate the expression of cytokines downstream of tumor necrosis factor-α and interleukin-1β. As well as, RDLPMs demonstrated some antibacterial properties against A. baumannii bacteria. Re, when delivered in RDLPMs as a dry powder inhaler, is a promising substitute for antibiotics in the treatment of A. baumannii pneumonia.