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Nanoparticle-coupled topical methotrexate can normalize immune responses and induce tissue remodeling in psoriasis


Özcan, Alaz; Sahin, Dilara; Impellizzieri, Daniela; Nguyen, Tuan T; Hafner, Jürg; Yawalkar, Nikhil; Kurzbach, Dennis; Tan, Ge; Akdis, Cezmi A; Nilsson, Jakob; Boyman, Onur; Kolios, Antonios G A (2019). Nanoparticle-coupled topical methotrexate can normalize immune responses and induce tissue remodeling in psoriasis. Journal of Investigative Dermatology:Epub ahead of print.

Abstract

Methotrexate (MTX) is an anti-proliferative drug used for treating inflammatory diseases including psoriasis. Nevertheless, its use in localized therapy is impeded due to poor transdermal penetration. We show that MTX coupled with gold-nanoparticles (GNPs) demonstrates superior anti-inflammatory efficacy compared to MTX-alone in an imiquimod (IMQ)-induced mouse model, significantly reducing γδ T cells, CD4+ 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 (TCB) and led to profound tissue remodeling, involving upregulation of extracellular matrix reorganization and downregulation of cornification and keratinization processes. The number of resident T cells in the grafts as well as IL-17 production drastically decreased upon MTX-GNP treatment. While both MTX and MTX-GNPs directly prevented proliferation and induced apoptosis of T cells, 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 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.

Abstract

Methotrexate (MTX) is an anti-proliferative drug used for treating inflammatory diseases including psoriasis. Nevertheless, its use in localized therapy is impeded due to poor transdermal penetration. We show that MTX coupled with gold-nanoparticles (GNPs) demonstrates superior anti-inflammatory efficacy compared to MTX-alone in an imiquimod (IMQ)-induced mouse model, significantly reducing γδ T cells, CD4+ 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 (TCB) and led to profound tissue remodeling, involving upregulation of extracellular matrix reorganization and downregulation of cornification and keratinization processes. The number of resident T cells in the grafts as well as IL-17 production drastically decreased upon MTX-GNP treatment. While both MTX and MTX-GNPs directly prevented proliferation and induced apoptosis of T cells, 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 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.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Clinic for Immunology
04 Faculty of Medicine > University Hospital Zurich > Dermatology Clinic
04 Faculty of Medicine > Swiss Institute of Allergy and Asthma Research
Dewey Decimal Classification:610 Medicine & health
Uncontrolled Keywords:Cell Biology, Biochemistry, Molecular Biology, Dermatology
Language:English
Date:1 October 2019
Deposited On:17 Dec 2019 16:01
Last Modified:29 Feb 2020 08:24
Publisher:Elsevier
ISSN:0022-202X
OA Status:Closed
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1016/j.jid.2019.09.018
PubMed ID:31678057

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