Therapeutic effect of cell permeable peptide-conjugated methotrexate on mouse model of psoriasis induced by imiquimod

Abstract

Oral methotrexate (MTX) is an effective treatment for psoriasis being used over 50 years. However, common drug-related toxicities such as myelosuppresion, gastrointestinal irritation, nephrotoxicity, hepatotoxicity, and pulmonary fibrosis deter physicians from a prolonged prescription of MTX. These adverse effects may be minimized by administering MTX topically, using an effective drug delivery system. The aim of this work is to evaluate efficacy and safety of a cell permeable, protein transduction domain (PTD)-conjugated, MTX on imiquimod (IQM)-induced psoriasis-like skin inflammation in BALB/c mice. Topical application of cell permeable-MTX alleviated IQM-induced psoriasiform skin inflammation in mice. The cumulative PASI score of 1% PTD-MTX-applied mice was the lowest (5.350.29) followed by intraperitoneal (IP) MTX-injected (6.151.22), 0.1% PTD-MTX-applied (7.050.57), and IQM alone applied groups (8.150.58) in ascending order. Increased number of immune cells in the skin including epidermal MHC-II+ cells and dermal MHC-II+, CD11c+, CD4+ and IL-17A producing δ TCR+ cells in IQM-applied mice were normalized by both IP-MTX and cell permeable MTX. In addition, increased levels of IL-23, IL-17A and IL-22 in the skin were reduced by both IP-MTX and cell permeable MTX as well. However, altered composition of spleen cells induced by IQM was only affected by IP injection of MTX but not by cell permeable MTX. Besides, cell permeable MTX had no toxic effect on the liver, kidney and myeloid cells, unlike IP-MTX. In conclusion, topically applied, cell permeable MTX ameliorated IQM-induced psoriasiform skin inflammation without systemic immune suppressive nor toxic effects.