基于调节KC和抗MV构建EPS/CPT纳米乳治疗寻常型银屑病及作用机制研究

Excessive proliferation and differentiation of keratinocytes (KC) are the key link in the pathogenesis of psoriasis. Microvascular (MV) hyperplasia at the skin lesions accompanies the whole pathogenesis progress of psoriasis. KC and MV are closely related to the development of psoriasis. In previous studies, it was found that the exopolysaccharides (EPS) produced by a marine bacteria not only had significant moisturizing and emulsifying properties, but also had the activity of inhibiting MV generation. In this study, EPS/calcipotriol (EPS/CPT) nanoemulsion was prepared by ultrasonic method with EPS as emulsifier and CPT as the loaded-drug. The physico-chemical properties of the nanoemulsion were studied. Finally, a series of in vitro cell, in vivo animal and cytokine experiments were conducted to study the effect and molecular mechanism of dual treatment of psoriasis vulgaris with this nanoemulsion. The nanoemulsion system integrated the functions of inhibiting MV activity, correcting KC proliferation and differentiation, and moisturizing, etc., which is expected to improve the therapeutic effect of psoriasis, and provide a new idea for the clinical treatment of psoriasis vulgaris and the application of EPS in the field of transdermal drug delivery.

角质形成细胞(KC)异常增生和分化是银屑病发病关键环节，皮损处微血管(MV)增生伴随银屑病整个发病过程，KC、MV与银屑病发展三者关系密切，据此提出同时调节KC和抑制MV生成的双重协同治疗寻常型银屑病策略。前期研究发现了一株海洋细菌产的胞外多糖（EPS）不仅具有显著的保湿和乳化性能，还具有抑制MV生成活性。基于此，本研究以EPS为乳化剂，以卡泊三醇(CPT)为所载药物，用超声波法制备EPS/CPT纳米乳，研究该纳米乳的物化性质，最后通过一系列体外细胞、体内动物及细胞因子实验研究该纳米乳双重治疗寻常型银屑病的作用及分子机制。该纳米乳系统综合了抑制MV活性、纠正KC增殖分化及保湿等功能，有望提高银屑病治疗效果，为临床治疗寻常型银屑病及EPS在皮肤递药方面的应用提供新思路。

银屑病作为全世界皮肤科领域重点研究和防治的疾病之一，治疗措施仍以调节角质形成细胞（KC）异常增殖和分化的局部药物对症治疗为主。银屑病微血管（MV）过度增生和异常是导致银屑病复发的重要结构基础。为解决局部药物治疗靶点较为单一的现状，以银屑病、KC和MV三者之间的密切关系为立论依据，提出了同时调节KC和抑制MV生成的双重协同治疗寻常型银屑病策略。前期研究中筛选了一株产EPS的海洋红树林细菌，发现了该EPS不但具有显著的乳化活性和保湿性，还具有良好的抗MV生成作用。基于此，本项目以EPS和卡泊三醇(CPT)分别为抗MV和调节KC有效成分，针对EPS和CPT如何有效渗透粗糙的银屑病皮肤的难题，构建了一种新型的EPS/CPT纳米乳(ECN)经皮给药系统。该纳米乳具有适中的黏度、优良的涂展性和较好的保湿性。体外药物释放结果显示出了一定的缓释作用。离体皮肤药物渗透实验显示该纳米乳增强了CPT的渗透能力和增加了药物在真皮中的积累量。经过一系列体外细胞、体内动物及细胞因子实验可以得出三点结论：一是制备的ECN粒径较小，透皮效果更佳；二是EPS的保湿性能，确实能改善药物不良反应和提高银屑病的治疗效果；三是ECN具有抑制KC和MV的双重作用，验证了双靶点作用确实能提高CPT治疗银屑病的效果。该研究综合了抑制MV活性、纠正KC增殖分化及保湿等功能，有望提高银屑病治疗效果，为临床治疗寻常型银屑病及EPS在皮肤递药方面的应用提供新思路。同时也为EPS在抗MV生成有效成分、乳化剂、活性生物大分子和医药材料等多个角色的应用、为拓宽银屑病治疗策略和提高治疗寻常型银屑病效果奠定了基础。