Chitosan-based nanoformulated (-)-epigallocatechin-3-gallate (EGCG) modulates human keratinocyte-induced responses and alleviates imiquimod-induced murine psoriasiform dermatitis.
Chitosan-based nanoformulated (-)-epigallocatechin-3-gallate (EGCG) modulates human keratinocyte-induced responses and alleviates imiquimod-induced murine psoriasiform dermatitis.
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DOI：
10.2147/ijn.s165966
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发表时间：
2018
影响因子：
8
通讯作者：
Mukhtar H
中科院分区：
文献类型：
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作者：
Chamcheu JC;Siddiqui IA;Adhami VM;Esnault S;Bharali DJ;Babatunde AS;Adame S;Massey RJ;Wood GS;Longley BJ;Mousa SA;Mukhtar H
银屑病是一种慢性且目前无法治愈的炎性皮肤病，其特征在于过度增殖、异常分化和炎症，导致皮肤屏障功能破坏。使用可以消除这些影响的天然药物可能有助于治疗银屑病。早期的研究表明，用绿色茶多酚（-）-表没食子儿茶素-3-没食子酸酯（EGCG）处理角质形成细胞和小鼠皮肤可减轻炎症，增加caspase-14的表达，同时促进表皮分化和角化。然而，生物利用度问题限制了EGCG治疗银屑病的发展。为了克服这些限制，我们采用了适合于局部递送以治疗银屑病的EGCG的基于壳聚糖的聚合物纳米颗粒制剂（CHI-EGCG-NPs，下文称为nanoEGCG）。我们研究并比较了nanoEGCG与天然或游离EGCG在体外和体内咪喹莫特（IMQ）诱导的鼠银屑病样皮炎模型中的疗效。与游离EGCG（1 mg/小鼠）相比，在MQ诱导的小鼠银屑病样皮肤病变模型中评估了nanoEGCG制剂（48 μg/小鼠）的体内相关性和功效。与游离EGCG一样，nanoEGCG处理诱导分化，并降低培养的角质形成细胞的增殖和炎症反应，但具有4倍的剂量优势。局部应用nanoEGCG可显著（p<0.01）改善MQ诱导的小鼠皮肤病变中的银屑病样病理标志物，包括耳部和皮肤厚度、红斑和鳞屑、增殖（Ki-67）、浸润性免疫细胞（肥大细胞、中性粒细胞、巨噬细胞和CD 4 + T细胞）和血管生成（CD 31）的减少。我们还观察到半胱天冬酶-14、早期（角蛋白-10）和晚期（聚丝蛋白和兜甲蛋白）分化标志物以及激活蛋白-1因子（JunB）的蛋白表达增加。重要的是，与高剂量的游离EGCG相比，观察到几种银屑病相关的炎性细胞因子和趋化因子的显著调节（p<0.05）。总的来说，局部施用的nanoEGCG显示出超过游离EGCG的>20倍的剂量优势。基于这些观察结果，我们的nanoEGCG制剂代表了治疗银屑病和其他可能的炎症性皮肤病的有前途的药物递送策略。
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. 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). 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. Based on these observations, our nanoEGCG formulation represents a promising drug-delivery strategy for treating psoriasis and possibly other inflammatory skin diseases.