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      Exosome-mediated targeted delivery of miR-210 for angiogenic therapy after cerebral ischemia in mice

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          Abstract

          Background

          Accumulating evidence shows that microRNA-210 (miR-210) holds great promise to improve angiogenesis for brain tissue repair after cerebral ischemia. However, safe and efficient delivery of miR-210 via intravenous administration is still a challenge. In the past decade, exosomes have emerged as a novel endogenous delivery system. Here, c(RGDyK) peptide is conjugated to exosomes, and they are loaded with cholesterol-modified miR-210 (RGD-exo:miR-210).

          Results

          In a transient middle cerebral artery occlusion (MCAO) mouse model, the RGD-exo:miR-210 targets the lesion region of the ischemic brain after intravenous administration, resulting in an increase in miR-210 at the site. Furthermore, RGD-exo:miR-210 are administered once every other day for 14 days, and the expressions of integrin β 3, vascular endothelial growth factor (VEGF) and CD34 are significantly upregulated. The animal survival rate is also enhanced.

          Conclusions

          These results suggest a strategy for the targeted delivery of miR-210 to ischemic brain and provide an angiogenic agent for the treatment of ischemic stroke.

          Electronic supplementary material

          The online version of this article (10.1186/s12951-019-0461-7) contains supplementary material, which is available to authorized users.

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          Electroporation-induced siRNA precipitation obscures the efficiency of siRNA loading into extracellular vesicles.

          R M Schiffelers, Koen Raemdonck, Kevin Braeckmans … (2014)
          Extracellular vesicles (EVs) are specialised endogenous carriers of proteins and nucleic acids and are involved in intercellular communication. EVs are therefore proposed as candidate drug delivery systems for the delivery of nucleic acids and other macromolecules. However, the preparation of EV-based drug delivery systems is hampered by the lack of techniques to load the vesicles with nucleic acids. In this work we have now characterised in detail the use of an electroporation method for this purpose. When EVs were electroporated with fluorescently labelled siRNA, siRNA retention was comparable with previously published results (20-25% based on fluorescence spectroscopy and fluorescence fluctuation spectroscopy), and electroporation with unlabelled siRNA resulted in significant siRNA retention in the EV pellet as measured by RT-PCR. Remarkably, when siRNA was electroporated in the absence of EVs, a similar or even greater siRNA retention was measured. Nanoparticle tracking analysis and confocal microscopy showed extensive formation of insoluble siRNA aggregates after electroporation, which could be dramatically reduced by addition of EDTA. Other strategies to reduce aggregate formation, including the use of cuvettes with conductive polymer electrodes and the use of an acidic citrate electroporation buffer, resulted in a more efficient reduction of siRNA precipitation than EDTA. However, under these conditions, siRNA retention was below 0.05% and no significant differences in siRNA retention could be measured between samples electroporated in the presence or absence of EVs. Our results show that electroporation of EVs with siRNA is accompanied by extensive siRNA aggregate formation, which may cause overestimation of the amount of siRNA actually loaded into EVs. Moreover, our data clearly illustrate that electroporation is far less efficient than previously described, and highlight the necessity for alternative methods to prepare siRNA-loaded EVs. © 2013.
          Article 0 comments Cited 201 times – based on 0 reviews     Review now
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            Integrin-based therapeutics: biological basis, clinical use and new drugs

            Klaus Ley, Jesús Rivera-Nieves, William J Sandborn … (2016)
            Integrins are activatable molecules that are involved in adhesion and signalling. Of the 24 known human integrins, 3 are currently targeted therapeutically by monoclonal antibodies, peptides or small molecules: drugs targeting the platelet αIIbβ3 integrin are used to prevent thrombotic complications after percutaneous coronary interventions, and compounds targeting the lymphocyte α4β1 and α4β7 integrins have indications in multiple sclerosis and inflammatory bowel disease. New antibodies and small molecules targeting β7 integrins (α4β7 and αEβ7 integrins) and their ligands are in clinical development for the treatment of inflammatory bowel diseases. Integrin-based therapeutics have shown clinically significant benefits in many patients, leading to continued medical interest in the further development of novel integrin inhibitors. Of note, almost all integrin antagonists in use or in late-stage clinical trials target either the ligand-binding site or the ligand itself.
            Article 0 comments Cited 151 times – based on 0 reviews     Review now
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              Treatment of stroke with a PSD-95 inhibitor in the gyrencephalic primate brain.

              Douglas J. Cook, Lucy Teves, Michael Tymianski (2012)
              All attempts at treating strokes by pharmacologically reducing the human brain's vulnerability to ischaemia have failed, leaving stroke as a leading cause of death, disability and massive socioeconomic loss worldwide. Over decades, research has failed to translate over 1,000 experimental treatments from discovery in cells and rodents to use in humans, a scientific crisis that gave rise to the prevailing belief that pharmacological neuroprotection is not feasible or practicable in higher-order brains. To provide a strategy for advancing stroke therapy, we used higher-order gyrencephalic non-human primates, which bear genetic, anatomical and behavioural similarities to humans and tested neuroprotection by PSD-95 inhibitors--promising compounds that uncouple postsynaptic density protein PSD-95 from neurotoxic signalling pathways. Here we show that stroke damage can be prevented in non-human primates in which a PSD-95 inhibitor is administered after stroke onset in clinically relevant situations. This treatment reduced infarct volumes as gauged by magnetic resonance imaging and histology, preserved the capacity of ischaemic cells to maintain gene transcription in genome-wide screens of ischaemic brain tissue, and significantly preserved neurological function in neurobehavioural assays. The degree of tissue neuroprotection by magnetic resonance imaging corresponded strongly to the preservation of neurological function, supporting the intuitive but unproven dictum that integrity of brain tissue can reflect functional outcome. Our findings establish that tissue neuroprotection and improved functional outcome after stroke is unequivocally achievable in gyrencephalic non-human primates treated with PSD-95 inhibitors. Efforts must ensue to translate these findings to humans.
              Article 0 comments Cited 119 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Huixin Zhang: zhanghuixin@njmu.edu.cn
                Jin Wu: wujin@njmu.edu.cn
                Jiahuan Wu: 2907778485@qq.com
                Qi Fan: Fanqi1997@126.com
                Jingchao Zhou: 15651972775@163.com
                Junwen Wu: 17766091037@163.com
                Sichen Liu: 1057158731@qq.com
                Jie Zang: 1021420353@qq.com
                Jinhai Ye: yejinhai@njmu.edu.cn
                Ming Xiao: mingx@njmu.edu.cn
                Tian Tian: ttian@njmu.edu.cn
                Jun Gao:
                ORCID: http://orcid.org/0000-0002-5925-537X
                gaojun@njmu.edu.cn
                Journal
                Journal ID (nlm-ta): J Nanobiotechnology
                Journal ID (iso-abbrev): J Nanobiotechnology
                Title: Journal of Nanobiotechnology
                Publisher: BioMed Central (London )
                ISSN (Electronic): 1477-3155
                Publication date (Electronic): 19 February 2019
                Publication date PMC-release: 19 February 2019
                Publication date Collection: 2019
                Volume: 17
                Electronic Location Identifier: 29
                Affiliations
                [1 ]ISNI 0000 0000 9255 8984, GRID grid.89957.3a, The Department of Neurobiology, Key Laboratory of Human Functional Genomics of Jiangsu, , Nanjing Medical University, ; Nanjing, 211166 Jiangsu China
                [2 ]GRID grid.452511.6, The Department of Neurology, , The Second Affiliated Hospital of Nanjing Medical University, ; Nanjing, 210011 Jiangsu China
                [3 ]ISNI 0000 0000 9255 8984, GRID grid.89957.3a, The School of Basic Medical Science, , Nanjing Medical University, ; Nanjing, 211166 Jiangsu China
                [4 ]ISNI 0000 0000 9255 8984, GRID grid.89957.3a, The Department of Oral and Maxillofacial Surgery, The Affiliated Stomatology Hospital of Nanjing Medical University, , Nanjing Medical University, ; Nanjing, 210029 China
                [5 ]ISNI 0000 0000 9255 8984, GRID grid.89957.3a, Jiangsu Key Laboratory of Neurodegeneration, , Nanjing Medical University, ; Nanjing, 211166 Jiangsu China
                Author information
                http://orcid.org/0000-0002-5925-537X
                Article
                Publisher ID: 461
                DOI: 10.1186/s12951-019-0461-7
                PMC ID: 6379944
                PubMed ID: 30782171
                SO-VID: 73563734-24bb-4efb-93dc-003b48eb4f6e
                Copyright © © The Author(s) 2019
                License:

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                Date received : 23 October 2018
                Date accepted : 23 January 2019
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;
                Award ID: 81222013
                Award ID: 81673416
                Award ID: 81671070
                Award ID: 81371123
                Award Recipient :
                Funded by: Key R&D Program of Jiangsu Province
                Award ID: BE2016761
                Award ID: 2017CX010
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100004608, Natural Science Foundation of Jiangsu Province;
                Award ID: BK20170107
                Award Recipient :
                Funded by: Nordisk komité for jordbruks- og matforskning (NO)
                Award ID: 2242018K3DN24
                Award Recipient :
                Funded by: the Scientific Research Innovation Projects for Graduates of Jiangsu Province Grant
                Award ID: JX22013425
                Award Recipient :
                Funded by: Qing-Lan Project, the Jiangsu Provincial Medical Key Talent Project
                Award ID: ZDRCA2016087
                Award Recipient :
                Categories
                Subject: Research
                Custom metadata
                issue-copyright-statement © The Author(s) 2019

                ScienceOpen disciplines: Biotechnology
                Keywords: ischemia,mir-210,exosomes,angiogenesis
                Data availability:
                ScienceOpen disciplines: Biotechnology
                Keywords: ischemia, mir-210, exosomes, angiogenesis

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