title: Targeted drug delivery to ischemic stroke via chlorotoxin-anchored, lexiscan-loaded nanoparticles.
abstract: Ischemic stroke is a leading cause of disability and death worldwide. Current drug treatment for stroke remains inadequate due to the existence of the blood-brain barrier. We proposed an innovative nanotechnology-based autocatalytic targeting approach, in which the blood-brain barrier modulator lexiscan is encapsulated in nanoparticles to enhance blood-brain barrier permeability and autocatalytically augment the brain stroke-targeting delivery efficiency of chlorotoxin-anchored nanoparticles. The nanoparticles efficiently and specifically accumulated in the brain ischemic microenvironment and the targeting efficiency autocatalytically increased with subsequent administrations. When Nogo-66 receptor antagonist peptide NEP1-40, a potential therapeutic agent for ischemic stroke, was loaded, nanoparticles significantly reduced infarct volumes and enhanced survival. Our findings suggest that the autocatalytic targeting approach is a promising strategy for drug delivery to the ischemic microenvironment inside the brain. Nanoparticles developed in this study may serve as a new approach for the clinical management of stroke.
authors.affiliation: Department of Neurosurgery, Yale University, New Haven, CT, USA; School of Life Science and Technology, Harbin Institute of Technology, Harbin, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Han
authors.affiliation: Department of Neurosurgery, Yale University, New Haven, CT, USA; Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Cai
authors.affiliation: Department of Neurosurgery, Yale University, New Haven, CT, USA; Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, China.
authors.forename: Daofeng
authors.initials: D
authors.lastname: Tian
authors.affiliation: Department of Neurosurgery, Yale University, New Haven, CT, USA.
authors.forename: Derek K
authors.initials: DK
authors.lastname: Kong
authors.affiliation: Department of Neurosurgery, Yale University, New Haven, CT, USA; The laboratory of Cell Biology and Translational Medicine, Xi'an Medical University, Xi'an, China.
authors.forename: Xingchun
authors.initials: X
authors.lastname: Gou
authors.affiliation: Department of Neurosurgery, Yale University, New Haven, CT, USA.
authors.forename: Zeming
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Department of Neurology, Yale University, New Haven, CT, USA.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Strittmatter
authors.affiliation: Division of Biostatistics, School of Public Health, Yale University, New Haven, CT, USA.
authors.forename: Zuoheng
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Neurosurgery, Yale University, New Haven, CT, USA; Department of Neurology, Yale University, New Haven, CT, USA.
authors.forename: Kevin N
authors.initials: KN
authors.lastname: Sheth
authors.affiliation: Department of Neurosurgery, Yale University, New Haven, CT, USA; Department of Biomedical Engineering, Yale University, New Haven, CT, USA. Electronic address: jiangbing.zhou@yale.edu.
authors.forename: Jiangbing
authors.initials: J
authors.lastname: Zhou
mesh_terms: D058908:Adenosine A2 Receptor Agonists / Q000008:administration & dosage*; D000818:Animals; D001812:Blood-Brain Barrier; D002545:Brain Ischemia / Q000188:drug therapy*; D016503:Drug Delivery Systems; D006801:Humans; D008297:Male; D008810:Mice, Inbred C57BL; D053758:Nanoparticles; D011687:Purines / Q000008:administration & dosage*; D011720:Pyrazoles / Q000008:administration & dosage*; D020521:Stroke / Q000188:drug therapy*
chemical_list: D058908:Adenosine A2 Receptor Agonists; D011687:Purines; D011720:Pyrazoles; C430916:regadenoson
keywords: Autocatalytic targeting; Blood–brain barrier; Chlorotoxin; Lexiscan; Nanoparticles; Stroke