Methotrexate (MTX) is the first line agent for therapy against rheumatoid arthritis (RA); however, orally its efficacy is hampered by poor solubility, less permeability, short plasma half-life, and reduced bioavailability. Meanwhile, parenteral formulations are associated with severe adverse effects. In an attempt to improve the efficacy of MTX, we synthesized polycaprolactone-polyethylene glycol-polycaprolactone (PCL-PEG-PCL) triblock copolymer by a ring-opening copolymerization reaction and used it as a carrier for the fabrication of MTX-loaded nanomicelles. Surfactant-free, self-assembled nanomicelles were prepared by nanoprecipitation technique and optimized through central composite design. The optimized nanomicelles exhibited a size distribution of 31 nm and an encapsulation efficiency of 91%. In vitro, the nanomicelles exhibited hemocompatibility, sustained release, and significantly high uptake in lipopolysaccharide activated macrophages. To facilitate application on the skin, optimized nanomicelles were loaded into a Carbopol 934-based hydrogel with eucalyptus oil as a penetration enhancer. Eucalyptus oil significantly improved the permeation of nanomicelles through the skin (p < 0.001). When the hydrogel was applied on the RA mice model, nanomicelles exhibited preferentially highest accumulation in the inflamed joints than other organs. As compared with the free MTX, MTX nanomicelles significantly improved the pharmacokinetic (4.34-fold greater half-life, 3.68-fold higher AUC0-t, and 3.15-fold higher mean residence time) and pharmacodynamic profile ascertained through low inflammatory cytokines expression, improved oxidation protection, recovered behavioral responses, and radiological analysis. MTX nanomicelles-based hydrogel also significantly reduced the hepatotoxicity and did not activate the immune system. These results suggest that the MTX-loaded nanomicelles-based transdermal hydrogel can prove to be a promising agent against RA.

中文翻译：

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不含表面活性剂，自组装的基于萘甲酸的透皮水凝胶，可安全，有针对性地递送甲氨蝶呤抗类风湿关节炎。

甲氨蝶呤（MTX）是抗类风湿关节炎（RA）的一线治疗药物；但是，其口服性由于溶解度差，渗透性差，血浆半衰期短和生物利用度降低而受到阻碍。同时，肠胃外制剂与严重的不良反应有关。为了提高MTX的功效，我们通过开环共聚反应合成了聚己内酯-聚乙二醇-聚己内酯（PCL-PEG-PCL）三嵌段共聚物，并将其用作制造载有MTX的纳米胶束的载体。通过纳米沉淀技术制备了无表面活性剂的自组装纳米胶束，并通过中心复合设计对其进行了优化。优化的纳米胶束的尺寸分布为31 nm，包封效率为91％。体外，纳米胶束在脂多糖激活的巨噬细胞中表现出血液相容性，持续释放和显着高的摄取。为了促进在皮肤上的应用，将优化的纳米胶束装入以桉树油为渗透促进剂的Carbopol 934基水凝胶中。桉树油显着改善了纳米胶束通过皮肤的渗透性（p <0.001）。当将水凝胶应用于RA小鼠模型时，与其他器官相比，纳米胶束在发炎的关节中优先显示出最高的积累。与游离的MTX相比，MTX纳米胶束显着改善了药代动力学（半衰期延长了4.34倍，AUC0-t延长了3.68倍，平均停留时间延长了3.15倍），并且通过降低炎症细胞因子的表达确定了药效学特征抗氧化保护 恢复的行为反应和放射学分析。基于MTX纳米胶束的水凝胶也显着降低了肝毒性，并且没有激活免疫系统。这些结果表明，MTX负载的基于纳米胶束的透皮水凝胶可以证明是抗RA的有前途的药物。