061 Dextran-based mycophenolic acid nanoparticle ameliorates imiquimod-induced psoriasis-like skin inflammation

Abstract

Mycophenolate mofetil(MMF), the prodrug of mycophenolic acid(MPA), is an immune suppressive drug that is widely used in various autoimmune diseases including psoriasis. MMF causes less side effects but it requires daily dosing and usually takes several months to take effect. Herein, we developed the Dextran-based MPA nanoparticles(DMNPs) and proved significant effect in ameliorating imiquimod-induced murine psoriasis. Dextran and MPA molecules were linked by ester bonds to form a spherical nanostructure, and extra free MPA molecules were encapsulated. When injected in vivo, free MPA will be soon released while the linked MPA will be dissociated slowly to keep an effective blood concentration for a long time. We treated the psoriasis mice with DMNPs by intraperitoneal injection for 9 days, then we evaluated the skin lesion by Psoriasis Area and Severity Index(PASI) scoring, H&E staining and immunohistochemical staining. We also detected the dendritic cells(DCs) and IL-17a producing T cells(Th17) in spleen and draining lymph nodes. Furthermore we identified the in vitro effect of DMNPs in murine Bone Marrow-Derived Dendritic Cells(BMDCs). Our results in vivo showed a significant reduction of PASI score and epidermal thickness after DMNPs treatment, Ki-67 expressing in keratinocytes also decreased(P<0.01). Compared to control groups, DMNPs treatment decreased the frequencies of DCs and Th17 in skin lesion(P<0.001), spleen and draining lymph nodes(P<0.05). In vitro study showed that BMDCs had a great capability to uptake DMNPs and decreased expressions of CD80 and CD86 were observed(P<0.001). DMNPs also showed a slow, long-time lasted cytotoxicity to BMDCs. Overall, we improved the therapeutic effect of MPA and provided a new choice in psoriasis systemic treatment.