Liu Yanan, Ma Litao, Zhou Hui, Zhu Xufeng, Yu Qianqian, Chen Xu, Zhao Yingyu, Liu Jie
Department of Chemistry, Jinan University, Guangzhou 510632, China.
J Mater Chem B. 2018 Jun 7;6(21):3497-3514. doi: 10.1039/c8tb00080h. Epub 2018 May 17.
Rheumatoid arthritis (RA) is a chronic autoimmune disease and there is a lack of effective treatments. Nitric oxide (NO) plays an important role in inflammatory diseases, but the exact mechanism is not clear. We selected ruthenium complexes Ru(Phen)(4idip) (Ru) to induce the generation of NO in cells. SeNPs-PEG-RGD@Ru (Se@RuNPs) were prepared by modifying selenium nanoparticles with PEG, RGD and Ru. Se@RuNPs can promote uptake by Human Umbilical Vein Endothelial Cells (HUVECs) and trace the internalization and biodistribution. Experiments showed that Se@RuNPs target the abundant neovascular network of inflammatory sites to induce NO and promote the apoptosis of HUVECs and inhibit the growth of new vessels in local tissue. Moreover, NO activates autophagy by modulating signaling pathways related to AMPKα and mTOR, increasing the flux of autophagy, inhibiting the activity of NF-κB-p65, and modulating the levels of inflammatory cytokines. The exact mechanism of the inflammatory response regulated by NO is revealed. Histopathological analysis showed that the Se@RuNPs effectively reduced synovitis, cartilage corrosion and inflammatory cytokine expression levels, achieving satisfactory therapeutic effects. These unexpected results provide an effective strategy for target treatment of RA.
类风湿性关节炎（RA）是一种慢性自身免疫性疾病，目前缺乏有效的治疗方法。一氧化氮（NO）在炎症性疾病中起重要作用，但其确切机制尚不清楚。我们选择钌配合物Ru(Phen)(4idip)（Ru）来诱导细胞中NO的产生。通过用PEG、RGD和Ru修饰硒纳米颗粒制备了SeNPs-PEG-RGD@Ru（Se@RuNPs）。Se@RuNPs可以促进人脐静脉内皮细胞（HUVECs）的摄取，并追踪其内化和生物分布。实验表明，Se@RuNPs靶向炎症部位丰富的新生血管网络以诱导NO产生，促进HUVECs凋亡并抑制局部组织新血管生长。此外，NO通过调节与AMPKα和mTOR相关的信号通路激活自噬，增加自噬通量，抑制NF-κB-p65活性，并调节炎性细胞因子水平。揭示了NO调节炎症反应的确切机制。组织病理学分析表明，Se@RuNPs有效减轻了滑膜炎、软骨侵蚀和炎性细胞因子表达水平，取得了满意的治疗效果。这些意外的结果为RA的靶向治疗提供了一种有效的策略。
