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Preparation of Tofacitinib-Loaded Poly(lactic-co-glycolic acid) Sustained Release Nanoparticles by High-Gravity Nanoprecipitation Technique and Its Performance in Rheumatoid Arthritis
Industrial & Engineering Chemistry Research ( IF 3.8 ) Pub Date : 2024-07-16 , DOI: 10.1021/acs.iecr.4c01304 Yali Zhang 1 , Xiaoxue Wang 1 , Jianjun Zhang 1
Industrial & Engineering Chemistry Research ( IF 3.8 ) Pub Date : 2024-07-16 , DOI: 10.1021/acs.iecr.4c01304 Yali Zhang 1 , Xiaoxue Wang 1 , Jianjun Zhang 1
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Rheumatoid arthritis (RA), an autoimmune disease, is related to environmental factors, sex hormones, genetics, and other factors, affecting 0.5–1% of the global population. The JAK-STAT pathway plays an important role in the signal transduction of inflammatory cytokines and chemokines in the pathogenesis of RA. Tofacitinib (TF), the first approved JAK inhibitor for treating RA, can reduce inflammatory reactions, improve RA conditions, prevent irreversible joint injury, and improve the quality of life of patients. However, the traditional oral administration of TF causes poor compliance and severe side effects owing to the long-term and high-frequency treatment. Therefore, highly efficient pharmaceutical formulations for TF are necessitated. Here, a novel TF-loaded poly(lactic-co-glycolic acid) (PLGA) sustained release nanoparticle (NanoTF-PLGA) was prepared using a high-gravity nanoprecipitation technique (HGNPT), and its therapeutic effect on RA was verified in vitro and in vivo. The influence of the different operation parameters of HGNPT on the particle size of PLGA, including the rotating speed of the rotating bed, the volume ratio of solvent to antisolvent, and the concentration of the surfactant, was investigated using an orthogonal design. The optimum reaction conditions for preparing PLGA nanoparticles were selected by optimizing the formula, and TF was then added to the reaction mixture to prepare NanoTF-PLGA. The results demonstrated that NanoTF-PLGA had a smaller size (603.8 nm), a more uniform shape, a higher drug loading efficiency, and long-term sustained release properties (over 14 days). Furthermore, in vitro experiments proved that NanoTF-PLGA could enter RAW264.7 cells by cell uptake, demonstrated good biocompatibility, inhibited the migration of RAW264.7 cells, and simultaneously inhibited the expression of IL-6, IL-1β, and TNF-α in a dose-dependent manner. In vivo experiments showed that subcutaneous administration of NanoTF-PLGA significantly alleviated articular cartilage injury and reduced the level of inflammatory cell infiltration into the joint cavity. This study presents a promising technique for preparing sustained drug formulations that can be extended to numerous therapeutic drugs.
中文翻译：
高重力纳米沉淀技术制备托法替尼聚乳酸-乙醇酸缓释纳米粒及其治疗类风湿关节炎的效果
类风湿性关节炎（RA）是一种自身免疫性疾病，与环境因素、性激素、遗传等因素有关，影响全球0.5%~1%的人口。 JAK-STAT通路在RA发病机制中炎症细胞因子和趋化因子的信号转导中发挥着重要作用。托法替尼（TF）是第一个被批准用于治疗RA的JAK抑制剂，可以减少炎症反应，改善RA病情，预防不可逆的关节损伤，提高患者的生活质量。然而，传统口服TF由于需要长期、高频次治疗，依从性差且副作用严重。因此，需要高效的 TF 药物制剂。在此，采用高重力纳米沉淀技术（HGNPT）制备了一种新型负载TF的聚乳酸-乙醇酸（PLGA）缓释纳米粒（NanoTF-PLGA），并在体外验证了其对RA的治疗效果和体内。采用正交设计研究了HGNPT的不同操作参数，包括旋转床转速、溶剂与反溶剂的体积比、表面活性剂的浓度对PLGA粒径的影响。通过优化配方，选择制备PLGA纳米粒子的最佳反应条件，然后将TF添加到反应混合物中，制备NanoTF-PLGA。结果表明，NanoTF-PLGA具有更小的尺寸（603.8 nm）、更均匀的形状、更高的载药效率和长期缓释特性（超过14天）。此外，体外实验证明NanoTF-PLGA可以进入RAW264。通过细胞摄取，显示出良好的生物相容性，抑制RAW264.7细胞的迁移，同时以剂量依赖性方式抑制IL-6、IL-1β和TNF-α的表达。体内实验表明，皮下注射NanoTF-PLGA可显着减轻关节软骨损伤，并降低炎症细胞浸润关节腔的水平。这项研究提出了一种有前途的技术，用于制备持续的药物制剂，该制剂可以扩展到多种治疗药物。
更新日期：2024-07-16
中文翻译：
高重力纳米沉淀技术制备托法替尼聚乳酸-乙醇酸缓释纳米粒及其治疗类风湿关节炎的效果
类风湿性关节炎（RA）是一种自身免疫性疾病，与环境因素、性激素、遗传等因素有关，影响全球0.5%~1%的人口。 JAK-STAT通路在RA发病机制中炎症细胞因子和趋化因子的信号转导中发挥着重要作用。托法替尼（TF）是第一个被批准用于治疗RA的JAK抑制剂，可以减少炎症反应，改善RA病情，预防不可逆的关节损伤，提高患者的生活质量。然而，传统口服TF由于需要长期、高频次治疗，依从性差且副作用严重。因此，需要高效的 TF 药物制剂。在此，采用高重力纳米沉淀技术（HGNPT）制备了一种新型负载TF的聚乳酸-乙醇酸（PLGA）缓释纳米粒（NanoTF-PLGA），并在体外验证了其对RA的治疗效果和体内。采用正交设计研究了HGNPT的不同操作参数，包括旋转床转速、溶剂与反溶剂的体积比、表面活性剂的浓度对PLGA粒径的影响。通过优化配方，选择制备PLGA纳米粒子的最佳反应条件，然后将TF添加到反应混合物中，制备NanoTF-PLGA。结果表明，NanoTF-PLGA具有更小的尺寸（603.8 nm）、更均匀的形状、更高的载药效率和长期缓释特性（超过14天）。此外，体外实验证明NanoTF-PLGA可以进入RAW264。通过细胞摄取，显示出良好的生物相容性，抑制RAW264.7细胞的迁移，同时以剂量依赖性方式抑制IL-6、IL-1β和TNF-α的表达。体内实验表明，皮下注射NanoTF-PLGA可显着减轻关节软骨损伤，并降低炎症细胞浸润关节腔的水平。这项研究提出了一种有前途的技术，用于制备持续的药物制剂，该制剂可以扩展到多种治疗药物。
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