title: Salvaging brain ischemia by increasing neuroprotectant uptake via nanoagonist mediated blood brain barrier permeability enhancement.
abstract: Ischemic stroke is a leading cause of adult disability and cognitive impairment worldwide. Neuroprotective therapy aims to save neurons by impeding the deleterious ischemic insults. However, the low efficiency of the neuroprotectants crossing blood brain barrier (BBB) prevents their clinical translation. In this work, a nanoagonist (NA) was developed to enhance neuroprotectant uptake by specifically increasing BBB permeability in brain ischemia. This NA first targeted ischemic brain vasculatures, temporarily opened local BBB by activating adenosine 2A receptors, and up-regulated the neuroprotectant uptake in brain ischemia. This NA significantly increased the delivery of superoxide dismutase (SOD), a free radical scavenger, into mouse brain ischemia. The combined treatment of NA/SOD achieved a five-fold ischemic volume reduction rate compared to the animal models treated with SOD alone. Non-invasive magnetic resonance imaging (MRI) confirmed the ischemia targeted BBB opening, increased brain drug delivery efficiency and up-regulated therapeutic response during the combined NA/SOD treatment. Since the inefficient brain drug delivery is a general problem for the treatment of central nervous system (CNS) diseases, this work provides a novel strategy to deliver therapeutics by crossing BBB with high efficiency and targeting specificity.
authors.affiliation: Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, 826 Zhangheng Rd., Shanghai 201203, China.
authors.forename: Shuyan
authors.initials: S
authors.lastname: Zheng
authors.affiliation: Jiangsu Key Laboratory of Molecular and Functional Imaging Department of Radiology, Zhongda Hospital, Medical School of Southeast University, 87 Dingjiaqiao Rd., Nanjing 210009, China.
authors.forename: Ying-Ying
authors.initials: YY
authors.lastname: Bai
authors.affiliation: Department of Biomedical Engineering, The Pennsylvania State University, University Park, PA 16802, USA.
authors.forename: Yikang
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, 826 Zhangheng Rd., Shanghai 201203, China.
authors.forename: Xihui
authors.initials: X
authors.lastname: Gao
authors.affiliation: School of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Rd., Shenyang 110016, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, 826 Zhangheng Rd., Shanghai 201203, China.
authors.forename: Yinzhi
authors.initials: Y
authors.lastname: Changyi
authors.affiliation: Jiangsu Key Laboratory of Molecular and Functional Imaging Department of Radiology, Zhongda Hospital, Medical School of Southeast University, 87 Dingjiaqiao Rd., Nanjing 210009, China.
authors.forename: Yuancheng
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Jiangsu Key Laboratory of Molecular and Functional Imaging Department of Radiology, Zhongda Hospital, Medical School of Southeast University, 87 Dingjiaqiao Rd., Nanjing 210009, China.
authors.forename: Di
authors.initials: D
authors.lastname: Chang
authors.affiliation: Jiangsu Key Laboratory of Molecular and Functional Imaging Department of Radiology, Zhongda Hospital, Medical School of Southeast University, 87 Dingjiaqiao Rd., Nanjing 210009, China. Electronic address: jsh0836@hotmail.com.
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 Rd., Shanghai 201203, China. Electronic address: congli@fudan.edu.cn.
authors.forename: Cong
authors.initials: C
authors.lastname: Li
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism*; D002545:Brain Ischemia / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D002199:Capillary Permeability / Q000187:drug effects; D004357:Drug Synergism; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000493:pharmacokinetics; D011605:Psychoses, Substance-Induced; D013482:Superoxide Dismutase / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D016896:Treatment Outcome
chemical_list: D018696:Neuroprotective Agents; D013482:Superoxide Dismutase
keywords: Adenosine receptor; Blood brain barrier; Ischemic stroke; Nanoagonist; Neuroprotective therapy