Abstract
Psoriasis is a common chronic inflammatory skin disease mainly characterized by keratinocyte hyperproliferation and massive infiltration of inflammatory immune cells. Acitretin (ACT), an FDA-approved first-line systemic drug for psoriasis treatment, could suppress the proliferation of keratinocytes and downregulate the expression of inflammatory cytokines by modulating signal transducer and activator of transcription (STAT) signaling pathways. However, dose-dependent side effects of ACT limit its long-term administration in the clinic. Therefore, improving the therapeutic efficacy of ACT to reduce clinical dosage will benefit the patients. Here, we develop ACT-conjugated dextran nanoparticles (ACT-Dex NPs) and evaluated the potential for psoriasis treatment. Our results indicate that ACT-Dex NPs ameliorate psoriasis-like skin disease significantly at a low dosage which does not cause side effects, while neat ACT drugs at an equivalent dosage provide much less benefit. Moreover, we demonstrate that ACT-Dex NPs suppress keratinocyte proliferation more efficiently than neat ACT by enhancing the inhibitory effect on STAT3 phosphorylation. Thus, the proposed ACT-Dex NPs provide an effective and safe option for psoriasis treatment.
Highlights
Psoriasis has affected ∼ 2% of people worldwide
Acitretin-Conjugated Dextran Nanoparticles transducer and activator of transcription (STAT), suppressing the keratinocyte proliferation and downregulating the inflammatory cytokine expression). (Niu et al, 2012; An et al, 2017; Qin et al, 2017) Clinically, ACT could benefit patients with psoriasis at proper doses, which should not be lower than 25 mg/day. (Goldfarb et al, 1988; Gupta et al, 1989; Katz et al, 1999; Chularojanamontri et al, 2019) clinicians face a dilemma when setting the doses because both the therapeutic effects and side effects of ACT are dose-dependent; i.e., lower doses result in less efficacy, while higher doses result in significant side effects
The ACTconjugated dextran (ACT-Dex) conjugate was synthesized by an EDC/DMAPcatalyzed esterification between ACT and dextran (Figure 1A). 1H NMR was performed to confirm the structure of the resultant ACT-Dex (Supplementary Figure S1)
Summary
Psoriasis has affected ∼ 2% of people worldwide. The quality of life of psoriatic patients was negatively impacted due to the repetitive relapsing and remitting during their lifetime. (Parisi et al, 2013; Boehncke and Schön, 2015; Michalek et al, 2017) The characteristics of psoriasis are epidermis thickening and an inflammatory infiltrate of dermal and epidermal immune cells. (Goldfarb et al, 1988; Gupta et al, 1989; Katz et al, 1999; Chularojanamontri et al, 2019) clinicians face a dilemma when setting the doses because both the therapeutic effects and side effects of ACT are dose-dependent; i.e., lower doses result in less efficacy, while higher doses result in significant side effects. The combination of low-dose ACT and methotrexate remitted psoriasis-like skin lesions more effectively than monotherapy. We showed that ACT-Dex NPs could ameliorate psoriasis-like skin disease significantly at a low dosage which does not cause side effects, while neat ACT drugs at an equivalent dosage provided much less benefit. We demonstrated that ACT-Dex NPs suppressed keratinocyte proliferation more efficiently than neat ACT drugs by enhancing the inhibitory effect on STAT3 phosphorylation
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