丝蛋白纳米纤维透皮载体设计及其治疗白癜风的机制研究

Vitiligo is a depigmented disease induced by dysfunctional melanocytes. The most effective treatment of vitiligo is to target to regulate the abnormal reaction of autoreactive T cells by immunotherapy, and inhibit the destruction target to melanocytes. Low transdermal efficiency of topical drugs is the main problem limiting the efficacy of vitiligo drugs. In this study, the JAK inhibitor, Ruxolitinib, was loaded into the silk fibroin nanofiber gel carriers (SNF-Gel), which were used to explore affection of the carrier’s physicochemical and mechanical properties on the behaviors and transdermal performance of the drug. The physicochemical and mechanical properties of SNF-Gel carriers are mediated by its size and conformational composition. Subsequently, the optimized silk fibroin nanofiber carriers were respectively combined with ablative laser technology and biological modification technology. Through control the grafting of transdermal molecules and regulate the treatment parameters of exfoliative lattice laser, we finished integration of different transdermal technologies, and improved the transdermal performance of SNF-Gel, forming a variety of safe and efficient long-acting transdermal drug delivery. The prepared Rux-SNF-Gel were used in the mouse vitiligo animal model. The pathological changes and its penetration effects of the drug-loaded nanofiber carriers in the skin of vitiligo lesions was tested at different stages. Simultaneously, the repigmentation of vitiligo skin and the dynamic changes of the secretion and expression levels of related inflammatory factors will be detected, providing a new vision for improving the treatment of vitiligo.

白癜风是一种黑素细胞功能障碍而产生的色素脱失性疾病，通过免疫治疗靶向调控自身反应性T细胞的异常反应，抑制对黑素细胞的破坏是治疗白癜风的有效策略。外用药透皮效率低下是限制白癜风药物疗效的主要瓶颈。本研究中，将JAK抑制剂卢索替尼载入丝蛋白纳米纤维凝胶载体中，探索丝蛋白载体尺寸和构象组成介导的载体理化和力学性能对药物控释行为和透皮性能的影响机制。随后，将优化的丝蛋白载体同激光点阵技术和分子修饰技术分别结合，通过透皮分子的接枝和点阵激光的参数调控，实现不同透皮技术的整合，提高丝蛋白载体的透皮性能，形成多种安全、高效的长效经皮给药方式。并将制备的载JAK抑制剂丝蛋白纳米纤维用于小鼠白癜风动物模型，系统观测载药纳米纤维载体在小鼠白癜风病变皮肤中的病理变化及其在皮肤组织内的渗透效果，并检测白癜风皮肤的白斑复色情况及相关炎性因子的分泌表达的动态变化，为改善白癜风的药物治疗提供新视野。

透皮给药是多种疾病治疗的一种有吸引力的选择，因为它减少了不良反应，提高了患者的依从性。外用药透皮效率低下是限制皮肤疾病药物疗效的主要瓶颈。本研究中，首先探讨了丝蛋白纳米纤维凝胶尺寸和构想组成的调控介导的载体理化和力学性能对药物控释行为和透皮性能的影响机制。成功制备出疏水的丝蛋白纳米纤维凝胶调控其尺寸赋予其理想的透皮递送能力。超声处理后丝蛋白纳米载体长度由2000 nm缩短至约40 nm。体外人体皮肤和体内动物研究表明，不同纳米尺寸的丝蛋白纳米载体的透皮行为不同。丝蛋白纳米纤维载体在不破坏角质层结构的情况下缓慢通过角质层。小尺寸载体的透皮容量有所提高。亲水性和疏水性药物都可以装载在丝蛋白纳米纤维载体上，这为不同的疾病治疗提供了广阔的前景。丝蛋白纳米纤维载体无细胞毒性和皮肤刺激，增强了其作为透皮载体的优势。随后，制备载JAK抑制剂鲁克替尼（RUX）丝蛋白纳米纤维载体复合物，通过体外表征、细胞和体内实验的检测。将优化的丝蛋白纳米载体同激光点阵技术结合，通过点阵激光的参数调控，提高丝蛋白纳米纤维载体的透皮性能，形成多种安全、高效的长效经皮给药方式。并将制备的载JAK抑制剂丝蛋白纳米纤维用于小鼠白癜风动物模型，系统观测载药纳米纤维载体在小鼠白癜风病变皮肤中的病理变化及其在皮肤组织内的渗透效果，并检测白癜风皮肤的白斑复色情况及相关炎性因子的分泌表达的动态变化，为改善白癜风的药物治疗提供新视野。