title: Edaravone-Encapsulated Agonistic Micelles Rescue Ischemic Brain Tissue by Tuning Blood-Brain Barrier Permeability.
abstract: 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 permeabilityin 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.
authors.affiliation: Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, P. R. China.
authors.forename: Qu
authors.initials: Q
authors.lastname: Jin
authors.affiliation: Jiangsu Key Laboratory of Molecular and Functional Imaging Department of Radiology, Zhongda Hospital, Medical School of Southeast University, 87 Dingjiaqiao Road, Nanjing 210009, P. R. China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Cai
authors.affiliation: Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, P. R. China.
authors.forename: Sihan
authors.initials: S
authors.lastname: Li
authors.affiliation: Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, P. R. China.
authors.forename: Haoran
authors.initials: H
authors.lastname: Liu
authors.affiliation: Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, P. R. China.
authors.forename: Xingyu
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Jiangsu Key Laboratory of Molecular and Functional Imaging Department of Radiology, Zhongda Hospital, Medical School of Southeast University, 87 Dingjiaqiao Road, Nanjing 210009, P. R. China.
authors.forename: Chunqiang
authors.initials: C
authors.lastname: Lu
authors.affiliation: Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, P. R. China.
authors.forename: Xihui
authors.initials: X
authors.lastname: Gao
authors.affiliation: Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, P. R. China.
authors.forename: Jun
authors.initials: J
authors.lastname: Qian
authors.affiliation: Department of Radiology, Huashan Hospital, Fudan University, 12 Wulumuqi Middle Road, Shanghai 200041, P. R. China.
authors.forename: Jun
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Jiangsu Key Laboratory of Molecular and Functional Imaging Department of Radiology, Zhongda Hospital, Medical School of Southeast University, 87 Dingjiaqiao Road, Nanjing 210009, P. R. China.
authors.forename: Shenghong
authors.initials: S
authors.lastname: Ju
authors.affiliation: Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, P. R. China.
authors.forename: Cong
authors.initials: C
authors.lastname: Li
mesh_terms: D000818:Animals; D000983:Antipyrine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D001812:Blood-Brain Barrier / Q000187:drug effects*; D002545:Brain Ischemia / Q000000981:diagnostic imaging / Q000188:drug therapy*; D002478:Cells, Cultured; D000077553:Edaravone; D042783:Endothelial Cells / Q000187:drug effects; D016166:Free Radical Scavengers / Q000008:administration & dosage* / Q000493:pharmacokinetics; D008279:Magnetic Resonance Imaging; D008813:Mice, Inbred ICR; D008823:Micelles; D018696:Neuroprotective Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D010539:Permeability / Q000528:radiation effects*; D016896:Treatment Outcome
chemical_list: D016166:Free Radical Scavengers; D008823:Micelles; D018696:Neuroprotective Agents; D000077553:Edaravone; D000983:Antipyrine
keywords: agonistic micelle; blood-brain-barrier; edaravone.; ischemic stroke; neuroprotective therapy