Spray freeze-dried doxycycline nanoparticles for macrophage-targeted lung delivery

Developing inhalable drug delivery systems offers transformative potential for treating lung diseases by enabling localized, efficient, and sustained therapeutic effects. In this study, doxycycline was encapsulated into lipid nanoparticles (LNPs) composed of different percentage molar ratios of L-α-egg phosphatidylglycerol (EPG) or 1,2-di(cis-9-octadecenoyl)-sn-glycerol 3-phosphate sodium salt (DOPA) with L-α-hydrogenated soybean phosphatidylcholine (HSPC), and cholesterol (CHO), using a microfluidics method to enhance its bioavailability and therapeutic efficacy. LNPs were characterized for particle size, polydispersity index (PDI), zeta potential (ZP), drug content, and in-vitro drug release. LNPs containing DOPA, HSPC, and CHO in a percentage molar ratio of 60:20:20 exhibited a smaller PDI, and the highest drug content (∼95 %), and were subsequently processed into a dry powder inhalation (DPI) formulation via spray freeze-drying (SFD) using mannitol, mannose, and leucine, exhibiting suitability for pulmonary administration. Next-generation impactor (NGI) aerosol dispersions studies confirmed suitable aerosolization properties for lung targeting with a mass median aerodynamic diameter (MMAD) adequate for deposition in the lower respiratory tract. The DPI formulation also exhibited efficient cellular uptake and targeting of J774.A1 macrophage cells, resulting in superior antimicrobial efficacy within macrophages. This formulation provides a promising inhalable drug delivery system for doxycycline loaded LNPs for targeting alveolar macrophages to boost antimicrobial activity against critical lung infection.