Journal
BIOMATERIALS
Volume 66, Issue -, Pages 9-20Publisher
ELSEVIER SCI LTD
DOI: 10.1016/j.biomaterials.2015.07.006
Keywords
Ischemic stroke; Nanoagonist; Blood brain barrier; Adenosine receptor; Neuroprotective therapy
Funding
- National Basic Research Program of China (973 Program) [2013CB733801, 2011CB910404]
- National Natural Science Foundation of China [81371624, 81171384]
- New Century Excellent Talents in University Award
- Shanghai Foundation for Development of Science and Technology [13NM1400400, 15140901300]
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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. Noninvasive magnetic resonance imaging (MM) 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. (C) 2015 Elsevier Ltd. All rights reserved.
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