International Journal of Nanomedicine (Jul 2018)
Chitosan-based nanoformulated (–)-epigallocatechin-3-gallate (EGCG) modulates human keratinocyte-induced responses and alleviates imiquimod-induced murine psoriasiform dermatitis
Abstract
Jean Christopher Chamcheu,1,2,* Imtiaz A Siddiqui,1,* Vaqar M Adhami,1,* Stephane Esnault,3 Dhruba J Bharali,4 Abiola S Babatunde,1,5 Stephanie Adame,1 Randall J Massey,6 Gary S Wood,1 B Jack Longley,1 Shaker A Mousa,4 Hasan Mukhtar11Department of Dermatology, School of Medicine and Public Health, University of Wisconsin, and the Middleton VA Medical Center, Madison, WI, USA; 2Department of Basic Pharmaceutical Sciences, School of Pharmacy, College of Health and Pharmaceutic Sciences, University of Louisiana at Monroe, Monroe, LA, USA; 3Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, The University of Wisconsin–Madison School of Medicine and Public Health, Madison, WI, USA; 4The Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Albany, NY, USA; 5Department of Hematology, University of Ilorin, Ilorin, Nigeria; 6Electron Microscope Facility, Medical School Research Support Progs, School of Medicine and Public Health, University of Wisconsin, and the Middleton VAMedical Center, Madison, WI, USA *These authors contributed equally to this work Background: Psoriasis is a chronic and currently incurable inflammatory skin disease characterized by hyperproliferation, aberrant differentiation, and inflammation, leading to disrupted skin barrier function. The use of natural agents that can abrogate these effects could be useful for the treatment of psoriasis. Earlier studies have shown that treatment of keratinocytes and mouse skin with the green tea polyphenol (-)-epigallocatechin-3-gallate (EGCG) mitigated inflammation and increased the expression of caspase-14 while promoting epidermal differentiation and cornification. However, bioavailability issues have restricted the development of EGCG for the treatment of psoriasis.Materials and methods: To overcome these limitations, we employed a chitosan-based polymeric nanoparticle formulation of EGCG (CHI-EGCG-NPs, hereafter termed nanoEGCG) suitable for topical delivery for treating psoriasis. We investigated and compared the efficacy of nanoEGCG versus native or free EGCG in vitro and in an in vivo imiquimod (IMQ)-induced murine psoriasis-like dermatitis model. The in vivo relevance and efficacy of nanoEGCG formulation (48 µg/mouse) were assessed in an IMQ-induced mouse psoriasis-like skin lesion model compared to free EGCG (1 mg/mouse).Results: Like free EGCG, nanoEGCG treatment induced differentiation, and decreased proliferation and inflammatory responses in cultured keratinocytes, but with a 4-fold dose advantage. Topically applied nanoEGCG elicited a significant (p<0.01) amelioration of psoriasiform pathological markers in IMQ-induced mouse skin lesions, including reductions in ear and skin thickness, erythema and scales, proliferation (Ki-67), infiltratory immune cells (mast cells, neutrophils, macrophages, and CD4+ T cells), and angiogenesis (CD31). We also observed increases in the protein expression of caspase-14, early (keratin-10) and late (filaggrin and loricrin) markers of differentiation, and the activator protein-1 factor (JunB). Importantly, a significant modulation of several psoriasis-related inflammatory cytokines and chemokines was observed compared to the high dose of free EGCG (p<0.05). Taken together, topically applied nanoEGCG displayed a >20-fold dose advantage over free EGCG.Conclusion: Based on these observations, our nanoEGCG formulation represents a promising drug-delivery strategy for treating psoriasis and possibly other inflammatory skin diseases. Keywords: chitosan nanoparticles, topical delivery of chitosan nanoformulated EGCG, psoriasis-like skin inflammation, phytochemical treatment of psoriasis, normal human epidermal keratinocytes, differentiation, anti-inflammatory action
