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Published on: December 23, 2016
Shell-Sheddable Polymeric Micelles Alleviate Oxidative Stress and Inflammation for Enhanced Ischemic Stroke Therapy
Zhenhua Wang1,2, Jingmei Pan1,2, Ruiting Yuan1,2
1Institute of Biomedical Engineering, College of Medicine, Southwest Jiaotong University, Chengdu 610031, P. R. China.
Abstract:
As a ROS scavenger, resveratrol exerts a neuroprotective effect by polarizing the M1 microglia to the anti-inflammatory M2 phenotype for ischemic stroke treatment. However, the obstruction of the blood-brain barrier (BBB) seriously impairs the efficacy of resveratrol. Herein, we develop a stepwise targeting nanoplatform for enhanced ischemic stroke therapy, which is fabricated by pH-responsive poly(ethylene glycol)-acetal-polycaprolactone-poly(ethylene glycol) (PEG-Acetal-PCL-PEG) and modified with cRGD and triphenylphosphine (TPP) on a long PEG chain and a short PEG chain, respectively. The as-designed micelle system features effective BBB penetration through cRGD-mediated transcytosis. Once entering the ischemic brain tissues and endocytosed by microglia, the long PEG shell can be detached from the micelles in the acidic lysosomes, subsequently exposing TPP to target mitochondria. Thus, the micelles can effectively alleviate oxidative stress and inflammation by enhanced delivery of resveratrol to microglia mitochondria, reversing the microglia phenotype through the scavenging of ROS. This work offers a promising strategy to treat ischemia-reperfusion injury.
Insights
This study presents a novel nanoplatform for enhanced ischemic stroke therapy. The system effectively delivers resveratrol to brain microglia, reducing oxidative stress and inflammation for improved neuroprotection.
Area of Science:
- Neuroscience
- Biomaterials Science
- Pharmacology
Background:
- Resveratrol shows neuroprotective effects against ischemic stroke by modulating microglial polarization.
- The blood-brain barrier (BBB) limits resveratrol's efficacy in treating ischemic stroke.
- Microglia play a critical role in neuroinflammation and stroke pathology.
Purpose of the Study:
- To develop a stepwise targeting nanoplatform for enhanced resveratrol delivery to microglia mitochondria for ischemic stroke treatment.
- To overcome the BBB penetration challenge and improve therapeutic efficacy.
- To investigate the potential of this nanoplatform in reversing microglial phenotype and alleviating oxidative stress.
Main Methods:
- Fabrication of pH-responsive poly(ethylene glycol)-acetal-polycaprolactone-poly(ethylene glycol) (PEG-Acetal-PCL-PEG) micelles.
- Modification of micelles with cRGD for BBB penetration and triphenylphosphine (TPP) for mitochondrial targeting.
- In vitro and in vivo evaluation of BBB crossing, cellular uptake, and therapeutic effects in an ischemic stroke model.
Main Results:
- The cRGD modification facilitated effective BBB penetration via transcytosis.
- Detachment of the long PEG shell in acidic lysosomes exposed TPP for mitochondrial targeting within microglia.
- Enhanced resveratrol delivery to microglia mitochondria effectively scavenged reactive oxygen species (ROS), reduced inflammation, and reversed M1 to M2 microglial polarization.
Conclusions:
- The developed stepwise targeting nanoplatform significantly enhances resveratrol delivery and efficacy for ischemic stroke therapy.
- This strategy offers a promising approach to overcome BBB limitations and target intracellular organelles in microglia.
- The nanoplatform demonstrates potential for treating ischemia-reperfusion injury by modulating neuroinflammation and oxidative stress.
