Journal
THERANOSTICS
Volume 7, Issue 4, Pages 884-898Publisher
IVYSPRING INT PUBL
DOI: 10.7150/thno.18219
Keywords
ischemic stroke; blood-brain-barrier; neuroprotective therapy; agonistic micelle; edaravone
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Funding
- National Basic Research Program of China (973 Program) [2013CB733801, 2013CB733802]
- National Natural Science Foundation of China [81571741, 81371624, 81525014, 81371538]
- Shanghai Foundation for Development of Science and Technology [15140901300]
- Shuguang Program - Shanghai Education Development Foundation
- Shanghai Municipal Education Commission
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Thrombolysis has been a standard treatment for ischemic stroke. However, only 2-7% patients benefit from it because the thrombolytic agent has to be injected within 4.5 h after the onset of symptoms to avoid the increasing risk of intracerebral hemorrhage. As the only clinically approved neuroprotective drug, edaravone (EDV) rescues ischemic brain tissues by eradicating over-produced reactive oxygen species (ROS) without the limitation of therapeutic time-window. However, EDV's short circulation half-life and inadequate cerebral uptake attenuate its therapeutic efficacy. Here we developed an EDV-encapsulated agonistic micelle (EDV-AM) to specifically deliver EDV into brain ischemia by actively tuning blood-brain barrier (BBB) permeability. The EDV-AM actively up-regulated endothelial monolayer permeability in vitro. HPLC studies showed that EDV-AM delivered more EDV into brain ischemia than free EDV after intravenous injection. Magnetic resonance imaging also demonstrated that EDV-AM more rapidly salvaged ischemic tissue than free EDV. Diffusion tensor imaging indicated the highest efficiency of EDV-AM in accelerating axonal remodeling in the ipsilesional white matter and improving functional behaviors of ischemic stroke models. The agonistic micelle holds promise to improve the therapeutic efficiency of ischemic stroke patients who miss the thrombolytic treatment.
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