Paeonol loaded cyclodextrin metal-organic framework particles for treatment of acute lung injury via inhalation

Administration of drugs via inhalation can overcome issues related to poor water solubility, low absorption or bioavailability associated with oral administration. In the current study we used gamma-cyclodextrin metal organic frameworks (CD-MOFs) of inhalable particle sizes, with cubic morphologies and favorable aerodynamic properties to achieve targeted pulmonary drug delivery via dry powder inhalers. The active natural compound, paeonol (PAE), was chosen as a model drug for treatment of acute lung injury (ALI). After loading of PAE into CD-MOF particles of inhalable sizes, PAE was rapidly released in phosphate buffer (pH = 7.4; 90% within 30 min) and in vivo experiments. After mixing with coarse and fine lactose (Inhalac (R) 230: Inhalac (R) 400: PAE-CD-MOF = 40:10:50, w/w/w), paeonol had a high fine particle fraction (FPF) (28.59%). Atom force microscopy was used to assess surface roughness and adhesive force. In vivo inhalation of PAE-CD-MOF dry powder inhaler by rat demonstrated rapid absorption (tmax of 4.0 min) and high absolute bioavailability (71%) of PAE, highlighting significant improvements in absorption and bioavailability of PAE when compared with oral administration (C-max and absolute bioavailability increased 6.5 and 9.3 folds, respectively). Results of in vivo experiments were consistent with cellular permeability studies (after loading into CD-MOF, the permeability of PAE improved about 5 folds in comparison to the pure PAE). Finally, the efficacy of inhaled PAE for ALI was validated by histopathological examination and via reduced levels of inflammatory factors observed in rat plasma. Overall, targeted pulmonary delivery of paeonol by inhaled PAE-CD-MOF particles appears to be promising method of delivery for treatment of ALI.