Use of cilomilast-loaded phosphatiosomes to suppress neutrophilic inflammation for attenuating acute lung injury: the effect of nanovesicular surface charge

Abstract

BackgroundCilomilast is a phosphodiesterase 4 (PDE4) inhibitor for treating inflammatory lung diseases. This agent has a narrow therapeutic index with significant adverse effects on the nervous system. This study was conducted to entrap cilomilast into PEGylated phosphatidylcholine-rich niosomes (phosphatiosomes) to improve pulmonary delivery via the strong affinity to pulmonary surfactant film. Neutrophils were used as a cell model to test the anti-inflammatory activity of phosphatiosomes. In an in vivo approach, mice were given lipopolysaccharide to produce acute lung injury. The surface charge in phosphatiosomes that influenced the anti-inflammatory potency is discussed in this study.ResultsThe average diameter of the phosphatiosomes was about 100 nm. The zeta potential of anionic and cationic nanovesicles was − 35 and 32 mV, respectively. Cilomilast in both its free and nanocapsulated forms inhibited superoxide anion production but not elastase release in activated neutrophils. Cationic phosphatiosomes mitigated calcium mobilization far more effectively than the free drug. In vivo biodistribution evaluated by organ imaging demonstrated a 2-fold ameliorated lung uptake after dye encapsulation into the phosphatiosomes. The lung/brain distribution ratio increased from 3 to 11 after nanocarrier loading. The intravenous nanocarriers deactivated the neutrophils in ALI, resulting in the elimination of hemorrhage and alveolar wall damage. Only cationic phosphatiosomes could significantly suppress IL-1β and TNF-α in the inflamed lung tissue.ConclusionsThese results suggest that phosphatiosomes should further be investigated as a potential nanocarrier for the treatment of pulmonary inflammation.

Metabolomic Analysis of the Effects of Adipose-Derived Mesenchymal Stem Cell Treatment on Rats With Sepsis-Induced Acute Lung Injury

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Mathematical Models as Tools to Predict the Release Kinetic of Fluorescein from Lyotropic Colloidal Liquid Crystals

“…This is used to synthesize other different colloidal nanoparticles made up of organic or hybrid materials. These colloidal nanoparticles have a negative Z-potential, as has been previously reported [ 41 , 42 , 43 , 44 , 45 , 46 ], and the value of the negative charge depends on the medium in which the colloidal nanoparticles are diluted/dispersed, before the analysis, as well as other components of the pharmaceutical formulations [ 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 ].…”

Therapeutic targeting of 3′,5′-cyclic nucleotide phosphodiesterases: inhibition and beyond

“…For example, agents that show remarkable selectivity for subfamilies of PDE4 are showing promising results in mouse models of learning and memory and translation to human disease would be a game changing advance (135). Additionally, novel delivery systems are being developed that can transport PDE inhibitors to precise tissues or cell types, thereby abrogating complications associated with systemic distribution (e.g., (293,294)). In the future, novel delivery systems such as these could be employed to deliver agents that specifically disrupt the anchoring of single isoforms.…”