Nanoparticle-Coupled Topical Methotrexate Can Normalize Immune Responses and Induce Tissue Remodeling in Psoriasis

Abstract

Methotrexate (MTX) is an antiproliferative drug used for treating inflammatory diseases, including psoriasis. Nevertheless, its use in localized therapy is hindered because of poor transdermal penetration. We show that MTX coupled with gold nanoparticles (GNPs) demonstrates superior antiinflammatory efficacy than MTX alone in an imiquimod-induced mouse model, significantly reducing gd T cells, CD4 þ T cells, and neutrophils. Furthermore, it was well tolerated upon systemic and topical administration. In an AGR129 human xenograft mouse model, two-week topical treatment with MTX-GNPs inhibited skin hyperplasia significantly better than topical calcipotriol-betamethasone and led to profound tissue remodeling, involving the upregulation of extracellular matrix reorganization and the downregulation of cornification and keratinization processes. The number of resident T cells in the grafts, as well as interleukin-17 production, drastically decreased upon MTX-GNP treatment. While both MTX and MTX-GNPs directly prevented the proliferation and induced apoptosis of T cells, the suppression of cytokine production was a shared mechanism of GNP and MTX-GNPs. In conclusion, MTX-GNPs influence immune and stromal components of the skin, leading to the potent inhibition of pathogenesis in preclinical psoriasis. MTX-GNPs surpass the efficacy of conventional MTX and standard of care, emerging as a non-steroidal, topical alternative for psoriasis treatment.

Dihydroartemisinin ameliorates psoriatic skin inflammation and its relapse by diminishing CD8+ T-cell memory in wild-type and humanized mice

“…On the other hand, we revealed that DHA decreased the frequency of CLA + , CD69 + or CD103 + T RM cells within CD8 + T-cell subset in the skin of psoriatic mice while MTX failed to do so, indicating that DHA is also more effective in suppressing CD8 + T RM cells than MTX. Ozcan et al found that nanoparticle-coupled topical MTX normalized immune responses and ameliorated psoriasis in mice 52 . They found that the coupled MTX mainly reduced CD4 + T cell number in the skin, with CD8 + T cells less affected.…”

Non-invasive transdermal delivery of chemotherapeutic molecules in vivo using superparamagnetic iron oxide nanoparticles

“…There has been a limited number of reports investigating the permeability of inorganic nanoparticles through the skin, with or without conjugated drugs (Baroli et al 2007;Nose et al 2012;Anandhakumar and Raichur 2013;Fernandes et al 2015;Santini et al 2015;Hsiao et al 2016;Ozcan et al 2020). Most previous transdermal nanoparticle studies focused on gold nanoparticles, with studies investigating Fe 3 O 4 magnetic nanoparticles for topical application rare (Baroli et al 2007;Rao et al 2015;Santini et al 2015).…”

The interaction between nanoparticles and immune system: application in the treatment of inflammatory diseases

“…It can inhibit cell proliferation and impair the activation and migration of leukocytes, such as T cells, macrophages, and neutrophils [ 120 ]. Özcan et al showed that gold nanoparticles combined with MTX demonstrated superior antiinflammatory efficacy than MTX alone in an imiquimod-induced psoriasis mouse model [ 121 ]. The γδ T and CD4 + T cell count was significantly reduced and skin hyperplasia was inhibited compared with calcipotriol-betamethasone treatment group, accompanied by profound tissue remodeling [ 121 ] (Fig.…”