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Mitochondria-targeted cyclosporin A delivery system to treat myocardial ischemia reperfusion injury of rats
BACKGROUND: Cyclosporin A (CsA) is a promising therapeutic drug for myocardial ischemia reperfusion injury (MI/RI) because of its definite inhibition to the opening of mitochondrial permeability transition pore (mPTP). However, the application of cyclosporin A to treat MI/RI is limited due to its im...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6346555/ https://www.ncbi.nlm.nih.gov/pubmed/30683110 http://dx.doi.org/10.1186/s12951-019-0451-9 |
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author | Zhang, Chang-xiong Cheng, Ying Liu, Dao-zhou Liu, Miao Cui, Han Zhang, Bang-le Mei, Qi-bing Zhou, Si-yuan |
author_facet | Zhang, Chang-xiong Cheng, Ying Liu, Dao-zhou Liu, Miao Cui, Han Zhang, Bang-le Mei, Qi-bing Zhou, Si-yuan |
author_sort | Zhang, Chang-xiong |
collection | PubMed |
description | BACKGROUND: Cyclosporin A (CsA) is a promising therapeutic drug for myocardial ischemia reperfusion injury (MI/RI) because of its definite inhibition to the opening of mitochondrial permeability transition pore (mPTP). However, the application of cyclosporin A to treat MI/RI is limited due to its immunosuppressive effect to other normal organ and tissues. SS31 represents a novel mitochondria-targeted peptide which can guide drug to accumulate into mitochondria. In this paper, mitochondria-targeted nanoparticles (CsA@PLGA-PEG-SS31) were prepared to precisely deliver cyclosporin A into mitochondria of ischemic cardiomyocytes to treat MI/RI. RESULTS: CsA@PLGA-PEG-SS31 was prepared by nanoprecipitation. CsA@PLGA-PEG-SS31 showed small particle size (~ 50 nm) and positive charge due to the modification of SS31 on the surface of nanoparticles. CsA@PLGA-PEG-SS31 was stable for more than 30 days and displayed a biphasic drug release pattern. The in vitro results showed that the intracellular uptake of CsA@PLGA-PEG-SS31 was significantly enhanced in hypoxia reoxygenation (H/R) injured H9c2 cells. CsA@PLGA-PEG-SS31 delivered CsA into mitochondria of H/R injured H9c2 cells and subsequently increased the viability of H/R injured H9c2 cell through inhibiting the opening of mPTP and production of reactive oxygen species. In vivo results showed that CsA@PLGA-PEG-SS31 accumulated in ischemic myocardium of MI/RI rat heart. Apoptosis of cardiomyocyte was alleviated in MI/RI rats treated with CsA@PLGA-PEG-SS31, which resulted in the myocardial salvage and improvement of cardiac function. Besides, CsA@PLGA-PEG-SS31 protected myocardium from damage by reducing the recruitment of inflammatory cells and maintaining the integrity of mitochondrial function in MI/RI rats. CONCLUSION: CsA@PLGA-PEG-SS31 exhibited significant cardioprotective effects against MI/RI in rats hearts through protecting mitochondrial integrity, decreasing apoptosis of cardiomyocytes and myocardial infract area. Thus, CsA@PLGA-PEG-SS31 offered a promising therapeutic method for patients with acute myocardial infarction. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12951-019-0451-9) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-6346555 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-63465552019-01-29 Mitochondria-targeted cyclosporin A delivery system to treat myocardial ischemia reperfusion injury of rats Zhang, Chang-xiong Cheng, Ying Liu, Dao-zhou Liu, Miao Cui, Han Zhang, Bang-le Mei, Qi-bing Zhou, Si-yuan J Nanobiotechnology Research BACKGROUND: Cyclosporin A (CsA) is a promising therapeutic drug for myocardial ischemia reperfusion injury (MI/RI) because of its definite inhibition to the opening of mitochondrial permeability transition pore (mPTP). However, the application of cyclosporin A to treat MI/RI is limited due to its immunosuppressive effect to other normal organ and tissues. SS31 represents a novel mitochondria-targeted peptide which can guide drug to accumulate into mitochondria. In this paper, mitochondria-targeted nanoparticles (CsA@PLGA-PEG-SS31) were prepared to precisely deliver cyclosporin A into mitochondria of ischemic cardiomyocytes to treat MI/RI. RESULTS: CsA@PLGA-PEG-SS31 was prepared by nanoprecipitation. CsA@PLGA-PEG-SS31 showed small particle size (~ 50 nm) and positive charge due to the modification of SS31 on the surface of nanoparticles. CsA@PLGA-PEG-SS31 was stable for more than 30 days and displayed a biphasic drug release pattern. The in vitro results showed that the intracellular uptake of CsA@PLGA-PEG-SS31 was significantly enhanced in hypoxia reoxygenation (H/R) injured H9c2 cells. CsA@PLGA-PEG-SS31 delivered CsA into mitochondria of H/R injured H9c2 cells and subsequently increased the viability of H/R injured H9c2 cell through inhibiting the opening of mPTP and production of reactive oxygen species. In vivo results showed that CsA@PLGA-PEG-SS31 accumulated in ischemic myocardium of MI/RI rat heart. Apoptosis of cardiomyocyte was alleviated in MI/RI rats treated with CsA@PLGA-PEG-SS31, which resulted in the myocardial salvage and improvement of cardiac function. Besides, CsA@PLGA-PEG-SS31 protected myocardium from damage by reducing the recruitment of inflammatory cells and maintaining the integrity of mitochondrial function in MI/RI rats. CONCLUSION: CsA@PLGA-PEG-SS31 exhibited significant cardioprotective effects against MI/RI in rats hearts through protecting mitochondrial integrity, decreasing apoptosis of cardiomyocytes and myocardial infract area. Thus, CsA@PLGA-PEG-SS31 offered a promising therapeutic method for patients with acute myocardial infarction. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12951-019-0451-9) contains supplementary material, which is available to authorized users. BioMed Central 2019-01-25 /pmc/articles/PMC6346555/ /pubmed/30683110 http://dx.doi.org/10.1186/s12951-019-0451-9 Text en © The Author(s) 2019 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. |
spellingShingle | Research Zhang, Chang-xiong Cheng, Ying Liu, Dao-zhou Liu, Miao Cui, Han Zhang, Bang-le Mei, Qi-bing Zhou, Si-yuan Mitochondria-targeted cyclosporin A delivery system to treat myocardial ischemia reperfusion injury of rats |
title | Mitochondria-targeted cyclosporin A delivery system to treat myocardial ischemia reperfusion injury of rats |
title_full | Mitochondria-targeted cyclosporin A delivery system to treat myocardial ischemia reperfusion injury of rats |
title_fullStr | Mitochondria-targeted cyclosporin A delivery system to treat myocardial ischemia reperfusion injury of rats |
title_full_unstemmed | Mitochondria-targeted cyclosporin A delivery system to treat myocardial ischemia reperfusion injury of rats |
title_short | Mitochondria-targeted cyclosporin A delivery system to treat myocardial ischemia reperfusion injury of rats |
title_sort | mitochondria-targeted cyclosporin a delivery system to treat myocardial ischemia reperfusion injury of rats |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6346555/ https://www.ncbi.nlm.nih.gov/pubmed/30683110 http://dx.doi.org/10.1186/s12951-019-0451-9 |
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