TY - JOUR
T1 - Ginsenoside Rg3-loaded, reactive oxygen species-responsive polymeric nanoparticles for alleviating myocardial ischemia-reperfusion injury
AU - Li, Lan
AU - Wang, Yili
AU - Guo, Rui
AU - Li, Sheng
AU - Ni, Jingyu
AU - Gao, Shan
AU - Gao, Xiumei
AU - Mao, Jingyuan
AU - Zhu, Yan
AU - Wu, Pingli
AU - Wang, Hongjun
AU - Kong, Deling
AU - Zhang, Han
AU - Zhu, Meifeng
AU - Fan, Guanwei
N1 - Publisher Copyright:
© 2019
PY - 2020/1/10
Y1 - 2020/1/10
N2 - 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.
AB - 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.
KW - FoxO3a
KW - Ginsenoside Rg3
KW - Myocardial ischemia–reperfusion injury
KW - ROS-responsive nanoparticles
UR - http://www.scopus.com/inward/record.url?scp=85079089070&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85079089070&partnerID=8YFLogxK
U2 - 10.1016/j.jconrel.2019.11.032
DO - 10.1016/j.jconrel.2019.11.032
M3 - Article
C2 - 31783047
AN - SCOPUS:85079089070
SN - 0168-3659
VL - 317
SP - 259
EP - 272
JO - Journal of Controlled Release
JF - Journal of Controlled Release
ER -