Oleic acid as the active agent and lipid matrix in cilomilast-loaded nanocarriers to assist PDE4 inhibition of activated neutrophils for mitigating psoriasis-like lesions

Abstract Both phosphodiesterase (PDE4) inhibitors and omega-9 fatty acids show anti-inflammatory activity for treating inflamed skin diseases, but their efficacy remains low. Combinatorial agents are anticipated to offer an advanced strategy for efficient therapy. We prepared cilomilast-loaded oleic acid (OA) nanocarriers to test the inhibitory capability against human neutrophil stimulation and a murine psoriasis model. OA played dual roles in the nanocarriers as both the active ingredient and lipid matrix in the nanoparticulate core. OA nanoparticles but not free OA could restrain calcium mobilization in activated neutrophils. The inhibition level of superoxide anion and elastase by cilomilast-loaded OA nanocarriers approximated that of free forms. In the mouse model, the intradermal nanosystems reduced imiquimod-induced epidermal thickening from 230.4 to 63.1 μm. Transepidermal water loss was decreased from 30.2 to 11.3 g/m 2 /h by integrated nanocarriers. The nanosystems mitigated neutrophil infiltration and hyperproliferation in the psoriasiform lesion via decreased expression of cytokines and chemokines. Statement of Significance The long-term therapy for psoriasis is unsatisfactory due to the possible adverse effects and inefficiency after prolonged use. Both phosphodiesterase (PDE4) inhibitors and omega-9 fatty acids such as oleic acid (OA) show anti-inflammatory activity for treating inflamed skin diseases. Combinatorial agents are anticipated to offer an advanced strategy for efficient therapy. OA is also ideal for incorporation into nanoparticles to enhance particulate emulsification, drug entrapment, and biocompatibility. We prepared cilomilast-loaded oleic acid (OA) nanocarriers to test the inhibitory capability against human neutrophil stimulation and a murine psoriasis lesion. OA nanocarriers are indigenous to prevent neutrophil activation and the deterioration of psoriatic lesion. Cilomilast incorporation in OA nanocarriers could further mitigate the clinical score and suppressing proinflammatory mediators.