Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu 610041, China.
Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu 610041, China.
Biomaterials. 2017 Apr;122:10-22. doi: 10.1016/j.biomaterials.2017.01.008. Epub 2017 Jan 11.
The transcription factor NF-kB plays a pivotal role in the pathogenesis of rheumatoid arthritis. Here we attempt to slow arthritis progression by co-delivering the glucocorticoid dexamethasone (Dex) and small-interfering RNA targeting NF-kB p65 using our previously developed polymeric hybrid micelle system. These micelles contain two similar amphiphilic copolymers: polycaprolactone-polyethylenimine (PCL-PEI) and polycaprolactone-polyethyleneglycol (PCL-PEG). The hybrid micelles loaded with Dex and siRNA effectively inhibited NF-kB signaling in murine macrophages more efficiently than micelles containing either Dex or siRNA on their own. In addition, the co-delivery system was able to switch macrophages from the M1 to M2 state. Injecting hybrid micelles containing Dex and siRNA into mice with collagen-induced arthritis led the therapeutic agents to accumulate in inflamed joints and reduce inflammation, without damaging renal or liver function. Thus, blocking NF-kB activation in inflammatory tissue using micelle-based co-delivery may provide a new approach for treating inflammatory disease.
转录因子 NF-κB 在类风湿关节炎的发病机制中起着关键作用。在这里，我们试图通过使用我们之前开发的聚合物混合胶束系统共同递送糖皮质激素地塞米松 (Dex) 和针对 NF-κB p65 的小干扰 RNA (siRNA) 来减缓关节炎的进展。这些胶束包含两种类似的两亲性共聚物：聚己内酯-聚亚乙基亚胺 (PCL-PEI) 和聚己内酯-聚乙二醇 (PCL-PEG)。负载 Dex 和 siRNA 的混合胶束比单独含有 Dex 或 siRNA 的胶束更有效地抑制了鼠巨噬细胞中的 NF-κB 信号通路。此外，共递送系统能够将巨噬细胞从 M1 状态切换到 M2 状态。将含有 Dex 和 siRNA 的混合胶束注射到胶原诱导性关节炎的小鼠中，使治疗剂在炎症关节中积聚并减轻炎症，而不会损害肾功能或肝功能。因此，使用基于胶束的共递送来抑制炎症组织中的 NF-κB 激活可能为治疗炎症性疾病提供一种新方法。
