Nimp-R14 Antibody-Conjugated Lipid Nanocarriers Mediate Neutrophil Targeting for Ameliorating the Anti-Psoriatic Activity of Pde4 Inhibitor

Psoriasis is a chronic autoimmune disease mainly affecting skin. About 2~3% population in the world is involved in psoriasis. The current drug therapy for treating psoriasis includes steroids and anti-inflammatory drugs. GlaxoSmithKline had developed cilomilast which is a phosphodiesterase 4 (PDE4) inhibitor. This drug can be utilized to treat asthma, chronic obstructive pulmonary disease, and psoriasis. However, the clinical trial had failed due to that the patients couldn’t accept the nausea, vomiting and other side effects. Our proposal aims to encapsulate cilomilast by ligand-conjugated nanostructured lipid carriers (NLCs) for efficiently treating psoriasis via nutrophil targeting. The application of nanomedicine on anti-inflammatory therapy demonstrates some benefits, including the tiny and controllable particle size for formulation optimization, very high total surface area/volume ratio for close contact with immune cells, high affinity with the cells after formulation modulation, and specific interaction to cellular membrane. NLCs act as potential nanosystems for controlled drug delivery with nontoxicity, excellent stability, and ease of production. Moreover, NLCs are facile to scale-up in the industrial pharmacy. We will prepare the NLCs by using cetyl palmitate and oleic acid as the lipid phases. The active targeting ability of the NLCs is come from the conjugation of NIMP-R14 antibody on the shell of NLCs for showing affinity with the activated neutrophils. The targeting strategy may result in a high cilomilast concentration inside the neutrophils, leading to an efficient inhibition of psoriatic inflammation. The preliminary results showed a successful preparation of passive-targeting NLCs with sufficient stability. Our results show that the cilomilast-loaded NLCs significantly inhibited neutrophil superoxide generation and elastase release. The confocal microscopy demonstrated a high uptake of fluorescence dye-loaded NLCs by the activated neutrophils. We had developed a psoriasis-like animal model in mouse by topical application of imiquimod (IMQ). The same with the results of cell study, cilomilast-loaded NLCs could inhibit the oxidative burst in psoriatic inflammation, leading to the suppression of cytokines and chemokines. These included TNF, IL-1, IL-6, CXCL1, CXCL2, CXCL8. Nevertheless, the elevated cytokines and chemokines by IMQ could not be reversed to normal level by the treatment of NLCs. The further formulation design is needed to achieve a better therapy. We will continuously modify the nanosystems and conjugate the antibody to NLCs for promoting the anti-psoriatic activity. The mechanisms about nanoparticle targeting to psoriasis are still unclear. We will also try to elucidate the mechanisms via cellular, in vitro, and in vivo experimental platforms.

Project ID:PC10901-0506
External Project ID:MOST107-2320-B182-016-MY3