Sun Weiwei, Ma Jinquan, Chen Minhao, Zhang Weidong, Xu Chunxiang, Nan Yunyi, Wu Weijie, Mao Xingxing, Cheng Xi, Cai Hao, Zhang Jianhua, Xu Hua, Wang Youhua
Department of Orthopaedics, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, China.
Department of Nursing, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, China.
Int Immunopharmacol. 2023 Feb;115:109714. doi: 10.1016/j.intimp.2023.109714. Epub 2023 Jan 17.
Rheumatoid arthritis (RA) is a systemic immune-mediated inflammatory disease that significantly impacts patients' quality of life. Fibroblast-like synovial cells (FLSs) within the synovial intima exhibit "tumor-like" properties such as increased proliferation, migration, and invasion. Activation of FLSs and secretion of pro-inflammation factors result in pannus formation and cartilage destruction. As an inhibitor of the cytokine, macrophage migration inhibitory factor (MIF), 4-Iodo-6-phenylpyrimidine (4-IPP) has been shown to reduce cell proliferation, migration, invasion, and the secretion of pro-inflammatory mediators in a variety of diseases. However, the usefulness of 4-IPP for RA treatment has not been assessed and was the purpose of this study. In vitro, 4-IPP was demonstrated to inhibit proliferation, migration, and invasion of RA FLSs, as well as the expression of pro-inflammatory cytokines. 4-IPP was also shown to inhibit MIF-induced phosphorylation of ERK, JNK, and p38, as well as reduce expression of COX2 and PGE2. In order to efficiently deliver 4-IPP to anatomical RA sites, we developed lactic-co-glycolic acid (PLGA) nanospheres, which not only protected 4-IPP from degradation but also controlled the release of 4-IPP. 4-IPP/PLGA nanospheres had potent anti-inflammatory activity and a high degree of biosafety. Results showed that local 4-IPP concentration was increased by nanosphere delivery, effectively reducing the inflammatory microenvironment as well as synovial inflammation, joint swelling, and cartilage destruction in a collagen-induced rheumatoid arthritis (CIA) rat model. Therefore, 4-IPP nanospheres are a sustained-release delivery system that may be an effective therapeutic strategy for RA treatment.
类风湿性关节炎（RA）是一种全身性免疫介导的炎症性疾病，严重影响患者的生活质量。滑膜内膜中的成纤维样滑膜细胞（FLS）表现出“肿瘤样”特性，如增殖、迁移和侵袭增加。FLS的激活和促炎因子的分泌导致血管翳形成和软骨破坏。作为细胞因子巨噬细胞迁移抑制因子（MIF）的抑制剂，4-碘-6-苯基嘧啶（4-IPP）已被证明可减少多种疾病中的细胞增殖、迁移、侵袭以及促炎介质的分泌。然而，4-IPP对RA治疗的有效性尚未得到评估，本研究旨在对此进行探讨。在体外，4-IPP被证明可抑制RA FLS的增殖、迁移和侵袭，以及促炎细胞因子的表达。4-IPP还被证明可抑制MIF诱导的ERK、JNK和p38的磷酸化，并降低COX2和PGE2的表达。为了将4-IPP有效地递送至RA的解剖部位，我们开发了聚乳酸-羟基乙酸共聚物（PLGA）纳米球，其不仅能保护4-IPP不被降解，还能控制4-IPP的释放。4-IPP/PLGA纳米球具有强大的抗炎活性和高度的生物安全性。结果表明，纳米球递送可提高局部4-IPP浓度，有效减轻胶原诱导的类风湿性关节炎（CIA）大鼠模型中的炎症微环境以及滑膜炎、关节肿胀和软骨破坏。因此，4-IPP纳米球是一种缓释递送系统，可能是RA治疗的有效策略。
