Singh Ekta, Osmani Riyaz Ali M, Banerjee Rinti, Abu Lila Amr Selim, Moin Afrasim, Almansour Khaled, Arab Hany H, Alotaibi Hadil Faris, Khafagy El-Sayed
Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Mumbai 400076, India.
Department of Pharmaceutics, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Mysuru 570015, India.
Pharmaceutics. 2022 Feb 26;14(3):519. doi: 10.3390/pharmaceutics14030519.
Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disorder with synovitis and articular pathology as its primary expositions. Leflunomide (Lfd) is an anti-rheumatic drug that is effective in the treatment of RA, but displays severe side effects upon prolonged systemic administration. Local therapy might represent a promising strategy to treat rheumatoid arthritis without eliciting systemic adverse effects. In this study, leflunomide-loaded poly(ε-caprolactone) nanoparticles (Lfd-NPs) were prepared and assessed as a local drug delivery system capable of alleviating RA-associated inflammation. Lfd-NPs were optimized using the Quality by Design (QbD) approach, applying a 3 full factorial design. In vitro drug release from NPs was examined in simulated synovial fluid. In addition, the in vivo efficacy of Lfd-NPs was evaluated in the Adjuvant Induced Arthritis (AIA) rodent model. Sustained drug release in simulated synovial fluid was observed for up to 168 h. A gradual reduction in paw volume and knee diameter was observed over the course of treatment, indicating the regression of the disease. In addition, significant reductions in serum proinflammatory markers and cytokines, including the C-reactive protein (CRP), rheumatoid factor (RF), TNF-α, IL1-β, and IL-6, were verified upon treatment with Lfd-NPs, suggesting the modulation of immune responses at the pathological site. Most importantly, no remarkable signs of toxicity were observed in Lfd-NP-treated animals. Collectively, intra-articularly administered Lfd-NPs might represent a potential therapeutic alternative to systemically administered drugs for the treatment of rheumatoid arthritis, without eliciting systemic adverse effects.
类风湿性关节炎（RA）是一种慢性炎症性自身免疫性疾病，滑膜炎和关节病变是其主要表现。来氟米特（Lfd）是一种抗风湿药物，对类风湿性关节炎的治疗有效，但长期全身给药会产生严重的副作用。局部治疗可能是一种有前景的治疗类风湿性关节炎的策略，且不会引发全身不良反应。在本研究中，制备了载有来氟米特的聚（ε-己内酯）纳米颗粒（Lfd-NPs），并将其评估为一种能够减轻类风湿性关节炎相关炎症的局部给药系统。采用质量源于设计（QbD）方法，应用3全因子设计对Lfd-NPs进行优化。在模拟滑液中检测纳米颗粒的体外药物释放。此外，在佐剂诱导的关节炎（AIA）啮齿动物模型中评估了Lfd-NPs的体内疗效。在模拟滑液中观察到药物持续释放长达168小时。在治疗过程中观察到爪体积和膝关节直径逐渐减小，表明疾病有所缓解。此外，在用Lfd-NPs治疗后，血清促炎标志物和细胞因子，包括C反应蛋白（CRP）、类风湿因子（RF）、肿瘤坏死因子-α（TNF-α）、白细胞介素-1β（IL1-β）和白细胞介素-6（IL-6）显著降低，表明在病理部位免疫反应得到调节。最重要的是，在接受Lfd-NP治疗的动物中未观察到明显的毒性迹象。总体而言，关节内注射Lfd-NPs可能是全身给药治疗类风湿性关节炎的一种潜在治疗替代方法，且不会引发全身不良反应。
