State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Screening, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, Center of Advanced Pharmaceuticals and Biomaterials, China Pharmaceutical University, Nanjing 210009, China.
College of Pharmaceutical Science, Zhejiang Chinese Medical University, Hangzhou 311402, China.
Nano Lett. 2020 Mar 11;20(3):1542-1551. doi: 10.1021/acs.nanolett.9b04018. Epub 2020 Feb 10.
Neuroinflammation plays a pivotal part in the pathogenesis of stroke. Orphan nuclear receptor NR4A1 is involved in the inflammatory response of microglia and macrophages. In this study, we discovered an old drug, 9-aminoacridine (9-AA), as a novel NR4A1 activator from our in-house FDA-approved drug library, which exhibited anti-inflammatory activities through an NR4A1/IL-10/SOCS3 signaling pathway and modulated the microglia activation. To improve the druggability of 9-AA, different liposomal formulations were screened and investigated. 9-AA-loaded liposome (9-AA/L) was prepared to reduce the adverse effect of 9-AA. Furthermore, 9-AA-loaded PEG/cRGD dual-modified liposome (9-AA/L-PEG-cRGD) was obtained, which displayed prolonged circulation, improved biodistribution, and increased brain accumulation. In the transient middle cerebral artery occlusion (tMCAO) rat model, 9-AA/L-PEG-cRGD significantly reduced brain infarct area, ameliorated ischemic brain injury, and promoted long-term neurological function recovery. This "from drug discovery to drug delivery" methodology provides a potential therapeutic strategy using the liposomal 9-AA, the NR4A1 activator to suppress neuroinflammation for treatment of ischemic stroke.
神经炎症在中风的发病机制中起着关键作用。孤儿核受体 NR4A1 参与小胶质细胞和巨噬细胞的炎症反应。在这项研究中，我们从内部的 FDA 批准药物库中发现了一种老药，9-氨基吖啶（9-AA），作为一种新型的 NR4A1 激活剂，它通过 NR4A1/IL-10/SOCS3 信号通路发挥抗炎作用，并调节小胶质细胞的激活。为了提高 9-AA 的成药性，筛选并研究了不同的脂质体配方。制备了载有 9-AA 的脂质体（9-AA/L）以减轻 9-AA 的不良反应。此外，获得了载有 PEG/cRGD 双重修饰的 9-AA 的脂质体（9-AA/L-PEG-cRGD），其表现出延长的循环时间、改善的生物分布和增加的脑蓄积。在短暂性大脑中动脉闭塞（tMCAO）大鼠模型中，9-AA/L-PEG-cRGD 显著减小脑梗死面积，改善缺血性脑损伤，并促进长期神经功能恢复。这种“从药物发现到药物输送”的方法学提供了一种使用脂质体 9-AA 的潜在治疗策略，NR4A1 激活剂可抑制神经炎症，用于治疗缺血性中风。
