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Adv Mater. 2019 Jan 11:e1807591. doi: 10.1002/adma.201807591. [Epub ahead of print]

Neural Stem Cells Transfected with Reactive Oxygen Species-Responsive Polyplexes for Effective Treatment of Ischemic Stroke.

Author information

1
Institute of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, 310058, P. R. China.
2
Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cell and Regenerative Medicine, Zhejiang University, Hangzhou, Zhejiang, 310058, P. R. China.
3
Center for Bionanoengineering and Key Laboratory of Biomass Chemical Engineering of Ministry of Education, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou, Zhejiang, 310027, P. R. China.
4
Department of Radiology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310016, P. R. China.
5
Institute of Materials Science and Engineering, A*STAR, Singapore, 138634, Singapore.
6
Department of Regeneration Science and Engineering, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, 606-8501, Japan.

Abstract

Neural stem cells (NSCs), capable of ischemia-homing, regeneration, and differentiation, exert strong therapeutic potentials in treating ischemic stroke, but the curative effect is limited in the harsh microenvironment of ischemic regions rich in reactive oxygen species (ROS). Gene transfection to make NSCs overexpress brain-derived neurotrophic factor (BDNF) can enhance their therapeutic efficacy; however, viral vectors must be used because current nonviral vectors are unable to efficiently transfect NSCs. The first polymeric vector, ROS-responsive charge-reversal poly[(2-acryloyl)ethyl(p-boronic acid benzyl)diethylammonium bromide] (B-PDEA), is shown here, that mediates efficient gene transfection of NSCs and greatly enhances their therapeutics in ischemic stroke treatment. The cationic B-PDEA/DNA polyplexes can effectively transfect NSCs; in the cytosol, the B-PDEA is oxidized by intracellular ROS into negatively charged polyacrylic acid, quickly releasing the BDNF plasmids for efficient transcription and secreting a high level of BDNF. After i.v. injection in ischemic stroke mice, the transfected NSCs (BDNF-NSCs) can home to ischemic regions as efficiently as the pristine NSCs but more efficiently produce BDNF, leading to significantly augmented BDNF levels, which in turn enhances the mouse survival rate to 60%, from 0% (nontreated mice) or ≈20% (NSC-treated mice), and enables more rapid and superior functional reconstruction.

KEYWORDS:

brain-derived neurotrophic factor; cerebral ischemia; neural stem cell therapy; nonviral gene delivery; reactive oxygen species-responsive polymers

PMID:
30633395
DOI:
10.1002/adma.201807591

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