滑膜成纤维细胞和巨噬细胞双靶点可控递药系统对类风湿性关节炎的治疗作用及其机制研究

Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by synovial hyperplasia of the joints, and there is not effective treatment method. Recent studies have found that synovial fibroblasts and macrophages can be mutually activated, which promotes the proliferation of synovial fibroblasts and aggravates the inflammatory reaction. When methotrexate (MTX) and dexamethasone (DEX) were respectively administered to activated synovial fibroblasts and activated macrophages, it not only effectively inhibited the proliferation of synovial fibroblasts and reduced the secretion of inflammatory factor from macrophage, but also can block the mutual activation between two cells. However, after the systemic administration of MTX and DEX, its effect is not selective, and the systemically toxic side effect is serious. This project intends to utilize the characteristics of RA microenvironment to construct a dual-target controllable drug delivery system to deliver MTX and DEX to activated synovial fibroblasts and macrophages respectively. The proliferation of synovial fibroblasts will be inhibited and the mutual inducible activation between the two will be also blocked. The in vivo and in vitro targeted drug release characteristics of the drug delivery system will be deeply investigated, and the therapeutic effect and its mechanism of the drug delivery system on RA will be clarified at animal and cell level. This project can provide new perception for the design of RA-targeted drug delivery system, and supply theoretical and experimental evidence for the treatment of RA.

类风湿关节炎（RA）是一种以关节滑膜增生为特征的慢性炎症性疾病，目前尚缺乏有效的治疗手段。最新研究发现，滑膜成纤维细胞和巨噬细胞通过相互诱导激活，促进了滑膜成纤维细胞增殖并加重了炎症反应。我们将甲氨蝶呤（MTX）和地塞米松（DEX）分别作用于激活的滑膜成纤维细胞和激活的巨噬细胞，不仅能有效抑制滑膜成纤维细胞的增殖，减少巨噬细胞分泌炎性因子，还能双向阻断两种细胞间相互诱导激活。然而MTX和DEX系统给药后，作用无选择性，全身毒副作用显著。本项目拟利用RA微环境特点，构建针对滑膜成纤维细胞和巨噬细胞的双靶点可控递药系统，将MTX和DEX分别递送至RA中激活的滑膜成纤维细胞和巨噬细胞，抑制滑膜成纤维细胞增殖，并阻断两种细胞间相互诱导激活。深入研究递药系统的体内外靶向释药特性，从动物和细胞水平阐明递药系统对RA的治疗作用及机制，为研究RA靶向递药系统提供新思路，为治疗RA提供理论和实验依据。

RA是一种以关节滑膜炎为特征的慢性疾病。最新研究发现，滑膜成纤维细胞和巨噬细胞通过相互诱导激活，促进了RA的临床进程。课题组发现通过递药系统把MTX和DEX分别递送至激活的滑膜成纤维细胞和激活的巨噬细胞内，通过阻断两种细胞间的相互作用，可有效治疗RA。围绕“滑膜成纤维细胞和巨噬细胞双靶点可控递药系统对类风湿性关节炎的治疗作用及其机制研究”课题核心，我们成功构建滑膜成纤维细胞和巨噬细胞双靶点可控递药系统，并揭示其环境响应可“分类” 入胞释药的特征。并在细胞水平明确激活的滑膜成纤维细胞与激活的巨噬细胞在促炎与增殖之间的相关性，证实递药系统通过双向阻断滑膜成纤维细胞与巨噬细胞之间的恶性循环来实现对RA的治疗。本课题的顺利开展为RA治疗药物的研发提供新思路，为RA的治疗研究提供理论和实验数据。 项目始终按照计划展开工作，执行的结果主要反应在国际国内学术期刊发表学术论文6篇，申请发明专利2项，获批1项，指导本科生3名，培养硕士研究生1名，辅导博士研究生1名。