期刊
JOURNAL OF CONTROLLED RELEASE
卷 317, 期 -, 页码 259-272出版社
ELSEVIER
DOI: 10.1016/j.jconrel.2019.11.032
关键词
FoxO3a; Ginsenoside Rg3; Myocardial ischemia-reperfusion injury; ROS-responsive nanoparticles
资金
- National Key Subject of Drug Innovation [2018ZX09201009-007]
- National Key R&D Program of China [2018YFC1704500, 2017YFC1103500]
- National Natural Science Foundation of China [81774050, 81972063, 31700845, 81904054]
- Tianjin Science Foundation for Distinguished Young Scholars [17JCJQJC46200]
- Training Program Foundation for Innovative Research Team of Higher Education in Tianjin during the 13th FiveYear Plan Period [TD13-5050]
- National Science Foundation, United States (NSF-DMR) [1508511]
- NIAMS, United States [1R01AR067859]
- CSC Scholarships
Myocardial ischemia-reperfusion injury (MIRI) is a serious threat to the health and lives of patients without any effective therapy. Excessive production of reactive oxygen species (ROS) is considered a principal cause of MIRI. Some natural products, including ginsenoside Rg3 (Rg3), exhibit robust antioxidant activity. However, the lack of an effective delivery strategy for this hydrophobic compound hinders its clinical application. In addition, therapeutic targets and molecular mechanisms of Rg3 require further elucidation to establish its mode of action. This study aimed to generate ROS-responsive nanoparticles (PEG-b-PPS) via the self-assembly of diblock copolymers of poly (ethylene glycol) (PEG) and poly (propylene sulfide) (PPS) and use them for Rg3 encapsulation and delivery. We identified FoxO3a as the therapeutic target of Rg3 using molecular docking and gene silencing. In rat ischemia-reperfusion model, an intramyocardial injection of Rg3-loaded PEG-b-PPS nanoparticles improved the cardiac function and reduced the infarct size. The mechanism of action was established as Rg3 targeting of FoxO3a, which inhibited the promotion of oxidative stress, inflammation, and fibrosis via downstream signaling pathways. In conclusion, this approach, involving ROS-responsive drug release, together with the identification of the target and mechanism of action of Rg3, provided an effective strategy for treating ischemic diseases and oxidative stress and could accelerate the implementation of hydrophobic natural products in clinical applications.
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