Ginsenoside Rg3-loaded, reactive oxygen species-responsive polymeric nanoparticles for alleviating myocardial ischemia-reperfusion injury

Abstract

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 *

Roles of TRAFs in Ischemia-Reperfusion Injury

“…Explosive oxidative stress and inflammation response caused by various abnormal stimuli are common in the pathological process of IRI. Excessive accumulation of reactive oxygen species (ROS) and reactive nitrogen species are important pathological factors causing IRI in various organs, including retina, cerebral, myocardial, liver, kidney, lung and intestine ( Jia et al, 2019 , 2020 ; Li et al, 2020 ; Li et al, 2019d ; Lonati et al, 2019 ; Qin et al, 2019 ; Yi et al, 2020 ). Oxidative stress may promote the expression of pro-inflammatory regulatory factors, and inflammatory cells may similarly induce the overproduction of ROS, thus forming a vicious circle to promote the occurrence and development of various diseases, including IRI.…”

Bioresponsive drug delivery systems for the treatment of inflammatory diseases

“…In addition, microspheres were directly prepared by the well-established oil-in-water emulsion solvent evaporation method using PPS [ 245 ], while hydrogels can be fabricated using PPS-containing copolymers [ 246 ]. Nanoparticles, polymersomes, microparticles, and hydrogels based on PPS-derived biomaterials have been extensively investigated as ROS-responsive delivery vehicles for small molecule drugs, proteins, and therapeutic cells, in which therapeutics can be packaged by either physical entrapment or covalent conjugation [ [245] , [246] , [247] , [248] , [249] , [250] ].…”

“…For example, ROS-responsive nanoparticles self-assembled by a diblock copolymer PEG-b-PPS were used to encapsulate a natural product ginsenoside Rg3. In a rat model of myocardial ischemia-reperfusion injury, intramyocardial treatment with Rg3-loaded PEG-b-PPS nanoparticles significantly decreased the plasma levels of TNF-α, interleukin (IL)-1β, IL-6, and C-reactive protein (CRP), therefore resulting in notably improved cardiac function and reduced the infarct size [ 247 ]. In addition, fibrous patches based on polyurethane containing thioketal linkages were used as a ROS-responsive delivery platform of methylprednisolone, showing desirable effects with respect to free radical scavenging, rebuilding structures, and improving functions of infarcted myocardium after implantation in MI rats [ 233 ].…”

Biomedical Application of Reactive Oxygen Species–Responsive Nanocarriers in Cancer, Inflammation, and Neurodegenerative Diseases

“…In recent years, preclinical and clinical research has demonstrated that excessive ROS at the inflammatory site accelerates disease progress. Numerous studies utilize ROS as triggers in developing ROS-responsive NPs carrying anti-inflammatory drugs (Pu et al, 2014 ; Feng et al, 2016 ; Zhang et al, 2017 , 2020 ; Chen et al, 2019 ; Li et al, 2019 , 2020 ; Ni et al, 2020 ). The release of loaded drugs in the inflammatory joints improves patient symptoms.…”