Development of hydrolytically stable γ-cyclodextrin-based microparticles derived from MOFs for sustained pulmonary drug delivery

Abstract

Chronic lung diseases remain challenging to treat due to inefficient drug delivery and rapid clearance from the respiratory tract. In this study, covalently crosslinked γ-cyclodextrin particles (CDPs) were synthesized from γ-cyclodextrin metal–organic frameworks (MOFs) via esterification with diphenyl carbonate. The obtained CDPs exhibited a uniform particle size (D₅₀ = 1.19 μm) and a crosslinking degree of approximately 4. Structural and physicochemical characterizations indicated the successful covalent transformation, preserved internal cavities, and enhanced aqueous stability. Dexamethasone (DEX) was encapsulated within CDPs to form DEX@CDP complexes. Next generation impactor testing revealed superior aerosolization with fine particle fractions of 85.36 % (CDP) and 67.01 % (DEX), ensuring efficient deposition in the deep lung region. In vitro release studies showed sustained release, with less than 31 % of DEX released over 24 h. In vivo pharmacokinetic analysis demonstrated that DEX@CDP doubled mean residence time (MRT) and elimination half-life (t_1/2) compared to inhaled DEX@MOF and intragastric DEX. Furthermore, CDPs exhibited excellent cytocompatibility toward A549 and J774A.1 cells (20–500 μg/mL) and favorable in vivo biocompatibility. These results indicate that the hydrolytically stable, cavity-retaining CDPs derived from MOFs are promising inhalable carriers for efficient and sustained pulmonary drug delivery.