载双氯芬酸和甲氨蝶呤纳米粒递药系统为类风湿关节炎的有效治疗方法。

BACKGROUND: Rheumatoid arthritis (RA) is a common acute inflammatory autoimmune connective tissue arthropathy. The genetic studies, tissue analyses, experimental animal models, and clinical investigations have confirmed that stromal tissue damage and pathology driven by RA mounts the chronic inflammation and dysregulated immune events. METHODS: We developed methotrexate (MTX)-loaded lipid-polymer hybrid nanoparticles (MTX-LPHNPs) and aceclofenac (ACE)-loaded nanostructured lipid carriers (ACE-NLCs) for the efficient co-delivery of MTX and ACE via intravenous and transdermal routes, respectively. Bio-assays were performed using ex-vivo skin permeation and transport, macrophage model of inflammation (MMI) (LPS-stimulated THP-1 macrophages), Wistar rats with experimental RA (induction of arthritis with Complete Freund's adjuvant; CFA and BCG), and programmed death of RA affected cells. In addition, gene transcription profiling and serum estimation of inflammatory, signaling, and cell death markers were performed on the blood samples collected from patients with RA. RESULTS: Higher permeation of ACE-NLCs/CE across skin layers confirming the greater "therapeutic index" of ACE. The systemic delivery of MTX-loaded LPHNPs via the parenteral (intravenous) route is shown to modulate the RA-induced inflammation and other immune events. The regulated immunological and signaling pathway(s) influence the immunological axis to program the death of inflamed cells in the MMI and the animals with the experimental RA. Our data suggested the CD40-mediated and Akt1 controlled cell death along with the inhibited autophagy in vitro. Moreover, the ex vivo gene transcription profiling in drug-treated PBMCs and serum analysis of immune/signalling markers confirmed the therapeutic role co-delivery of drug nanoparticles to treat RA. The animals with experimental RA receiving drug treatment were shown to regain the structure of paw bones and joints similar to the control and were comparable with the market formulations. CONCLUSION: Our findings confirmed the use of co-delivery of drug nanoformulations as the "combination drug regimen" to treat RA.

背景：类风湿关节炎（RA）是一种常见的急性炎症性自身免疫性结缔组织关节病。遗传研究、组织分析、实验动物模型和临床研究证实，基质组织损伤和 RA 驱动的病理学引发了慢性炎症和失调的免疫事件。

方法：我们开发了甲氨蝶呤（MTX）负载的脂质-聚合物杂化纳米粒子（MTX-LPHNPs）和依托考昔（ACE）负载的纳米结构脂质载体（ACE-NLCs），分别通过静脉内和透皮途径高效共递送 MTX 和 ACE。通过离体皮肤渗透和转运、炎症巨噬细胞模型（MMI）（LPS 刺激的 THP-1 巨噬细胞）、实验性 RA 的 Wistar 大鼠（用完全弗氏佐剂；CFA 和 BCG 诱导关节炎）和 RA 受影响细胞的程序性死亡进行生物测定。此外，还对 RA 患者的血液样本进行基因转录谱分析和炎症、信号和细胞死亡标志物的血清评估。

结果：ACE-NLCs/CE 跨皮肤层的更高渗透证实了 ACE 的更大“治疗指数”。通过静脉内途径系统递送 MTX 负载的 LPHNPs 可调节 RA 诱导的炎症和其他免疫事件。调节的免疫和信号通路（s）影响免疫轴，以编程 MMI 和实验性 RA 动物中炎症细胞的死亡。我们的数据表明，CD40 介导的和 Akt1 控制的细胞死亡以及体外自噬的抑制。此外，药物处理的 PBMCs 的离体基因转录谱分析和免疫/信号标志物的血清分析证实了共递送药物纳米颗粒治疗 RA 的治疗作用。接受药物治疗的实验性 RA 动物被证明恢复了类似对照的爪子骨骼和关节结构，并且与市场制剂相当。

结论：我们的研究结果证实了使用药物纳米制剂的共递送来治疗 RA，作为“联合药物方案”。