Liposomal 9-Aminoacridine for Treatment of Ischemic Stroke: From Drug Discovery to Drug Delivery

被引：49

作者：

Wang, Haojie ^{[1
]}

Xu, Xiao ^{[1
]}

Guan, Xin ^{[1
]}

Shen, Shiyang ^{[1
]}

Huang, Xuechao ^{[1
]}

Kai, Guoyin ^{[2
]}

Zhao, Shunyi ^{[1
]}

Ruan, Wenchen ^{[1
]}

Zhang, Luyong ^{[1
]}

Pang, Tao ^{[1
]}

Mo, Ran ^{[1
]}

机构：

[1] China Pharmaceut Univ, State Key Lab Nat Med, Jiangsu Key Lab Drug Screening,Ctr Adv Pharmaceut, Jiangsu Key Lab Drug Discovery Metab Dis,Jiangsu, Nanjing 210009, Peoples R China

[2] Zhejiang Chinese Med Univ, Coll Pharmaceut Sci, Hangzhou 311402, Peoples R China

来源：

NANO LETTERS | 2020年 / 20卷 / 03期

基金：

中国国家自然科学基金;

关键词：

drug delivery; liposome; 9-aminoacridine; NR4A1; ischemic stroke; STEALTH LIPOSOMES; EXPRESSION; BINDING; PROTEIN; NUR77; NANOPARTICLES; MACROPHAGES;

D O I：

10.1021/acs.nanolett.9b04018

中图分类号：

O6 [化学];

学科分类号：

0703 ;

摘要：

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.

引用

页码：1542 / 1551

页数：10

共 41 条

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