Micelles Loaded With Puerarin And Modified With Triphenylphosphonium Cation Possess Mitochondrial Targeting And Demonstrate Enhanced Protective Effect Against Isoprenaline-Induced H9c2 Cells Apoptosis

Wen-qun Li,1–3,* Jun-yong Wu,1–3,* Da-xiong Xiang,1–3 Shi-lin Luo,1–3 Xiong-bin Hu,1–3 Tian-tian Tang,1–3 Tao-li Sun,4 Xin-yi Liu1–3 1Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha 410011,...

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Autores principales:	Li W, Wu J, Xiang D, Luo S, Hu X, Tang T, Sun T, Liu X
Formato:	article
Lenguaje:	EN
Publicado:	Dove Medical Press 2019
Materias:	mitochondrial targeting anti-apoptosis ischemic myocardium TPP Medicine (General) R5-920
Acceso en línea:	https://doaj.org/article/69e9853f55b64426b6aa0ee04ffb50d3
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spelling	oai:doaj.org-article:69e9853f55b64426b6aa0ee04ffb50d32021-12-02T04:46:09ZMicelles Loaded With Puerarin And Modified With Triphenylphosphonium Cation Possess Mitochondrial Targeting And Demonstrate Enhanced Protective Effect Against Isoprenaline-Induced H9c2 Cells Apoptosis1178-2013https://doaj.org/article/69e9853f55b64426b6aa0ee04ffb50d32019-10-01T00:00:00Zhttps://www.dovepress.com/micelles-loaded-with-puerarin-and-modified-with-triphenylphosphonium-c-peer-reviewed-article-IJNhttps://doaj.org/toc/1178-2013Wen-qun Li,1–3,* Jun-yong Wu,1–3,* Da-xiong Xiang,1–3 Shi-lin Luo,1–3 Xiong-bin Hu,1–3 Tian-tian Tang,1–3 Tao-li Sun,4 Xin-yi Liu1–3 1Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha 410011, People’s Republic of China; 2Institution of Clinical Pharmacy, Central South University, Changsha 410011, People’s Republic of China; 3Hunan Provincial Engineering Research Center of Translational Medicine and Innovative Drugs, Changsha 410011, People’s Republic of China; 4Key Laboratory Breeding Base of Hu’nan Oriented Fundamental and Applied Research of Innovative Pharmaceutics, College of Pharmacy, Changsha Medical University, Changsha 410219, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xin-yi LiuDepartment of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, People’s Republic of ChinaTel +86-731-8529-2093Email liuxinyi128@csu.edu.cnBackground: The protective role of puerarin (PUE) against myocardial infarction is closely related to its regulation on mitochondria. However, free PUE can hardly reach the mitochondria of ischemic cardiomyocytes due to the lack of mitochondrial targeting of PUE. Here PUE was loaded into mitochondria-targeted micelles (PUE@TPP/PEG-PE) for precisely delivering PUE into mitochondria with the aim of enhancing the anti-apoptosis effect.Methods: The mitochondriotropic polymer TPP-PEG-PE was synthesized for the preparation of PUE@TPP/PEG-PE micelles modified with triphenylphosphonium (TPP) cation. The physicochemical properties and anti-apoptosis effect of PUE@TPP/PEG-PE micelles were investigated. The coumarin 6 (C6)-labeled TPP/PEG-PE (C6@TPP/PEG-PE) micelles were used to observe the enhanced cellular uptake, mitochondrial targeting and lysosomes escape. Moreover, in vivo and ex vivo biodistribution of lipophilic near-infrared dye 1,1ʹ-dioctadecyl-3,3,3′,3ʹ-tetramethylindotricarbocyanine iodide (DiR)-labeled PUE@TPP/PEG-PE (DiR@TPP/PEG-PE) micelles were detected through fluorescence imaging.Results: The successful synthesis of TPP-PEG-PE conjugate was confirmed. PUE@TPP/PEG-PE micelles had a particle size of 17.1 nm, a zeta potential of −6.2 mV, and a sustained-release behavior. The in vitro results showed that the intracellular uptake of C6@TPP/PEG-PE micelles was significantly enhanced in H9c2 cells. C6@TPP/PEG-PE micelles could deliver C6 to mitochondria and reduce the capture of lysosomes. In addition, compared with the PUE@PEG-PE micelles and free PUE, the PUE@TPP/PEG-PE micelles exerted an enhanced protective effect against isoprenaline-induced H9c2 cell apoptosis, as evident by the decreased percentage of apoptotic cells, Caspase-3 activity, ROS level, Bax expression, and increased Bcl-2 expression. The in vivo detecting results of the targeting effect using DiR probe also indicated that TPP/PEG-PE micelles could accumulate and retain in the ischemic myocardium.Conclusion: The results of this study demonstrate the promising potential of applying PUE@TPP/PEG-PE micelles in mitochondria-targeted drug delivery to achieve maximum therapeutic effects of PUE.Keywords: mitochondrial targeting, anti-apoptosis, ischemic myocardium, TPPLi WWu JXiang DLuo SHu XTang TSun TLiu XDove Medical Pressarticlemitochondrial targetinganti-apoptosisischemic myocardiumTPPMedicine (General)R5-920ENInternational Journal of Nanomedicine, Vol Volume 14, Pp 8345-8360 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	mitochondrial targeting anti-apoptosis ischemic myocardium TPP Medicine (General) R5-920
spellingShingle	mitochondrial targeting anti-apoptosis ischemic myocardium TPP Medicine (General) R5-920 Li W Wu J Xiang D Luo S Hu X Tang T Sun T Liu X Micelles Loaded With Puerarin And Modified With Triphenylphosphonium Cation Possess Mitochondrial Targeting And Demonstrate Enhanced Protective Effect Against Isoprenaline-Induced H9c2 Cells Apoptosis
description	Wen-qun Li,1–3,* Jun-yong Wu,1–3,* Da-xiong Xiang,1–3 Shi-lin Luo,1–3 Xiong-bin Hu,1–3 Tian-tian Tang,1–3 Tao-li Sun,4 Xin-yi Liu1–3 1Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha 410011, People’s Republic of China; 2Institution of Clinical Pharmacy, Central South University, Changsha 410011, People’s Republic of China; 3Hunan Provincial Engineering Research Center of Translational Medicine and Innovative Drugs, Changsha 410011, People’s Republic of China; 4Key Laboratory Breeding Base of Hu’nan Oriented Fundamental and Applied Research of Innovative Pharmaceutics, College of Pharmacy, Changsha Medical University, Changsha 410219, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xin-yi LiuDepartment of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, People’s Republic of ChinaTel +86-731-8529-2093Email liuxinyi128@csu.edu.cnBackground: The protective role of puerarin (PUE) against myocardial infarction is closely related to its regulation on mitochondria. However, free PUE can hardly reach the mitochondria of ischemic cardiomyocytes due to the lack of mitochondrial targeting of PUE. Here PUE was loaded into mitochondria-targeted micelles (PUE@TPP/PEG-PE) for precisely delivering PUE into mitochondria with the aim of enhancing the anti-apoptosis effect.Methods: The mitochondriotropic polymer TPP-PEG-PE was synthesized for the preparation of PUE@TPP/PEG-PE micelles modified with triphenylphosphonium (TPP) cation. The physicochemical properties and anti-apoptosis effect of PUE@TPP/PEG-PE micelles were investigated. The coumarin 6 (C6)-labeled TPP/PEG-PE (C6@TPP/PEG-PE) micelles were used to observe the enhanced cellular uptake, mitochondrial targeting and lysosomes escape. Moreover, in vivo and ex vivo biodistribution of lipophilic near-infrared dye 1,1ʹ-dioctadecyl-3,3,3′,3ʹ-tetramethylindotricarbocyanine iodide (DiR)-labeled PUE@TPP/PEG-PE (DiR@TPP/PEG-PE) micelles were detected through fluorescence imaging.Results: The successful synthesis of TPP-PEG-PE conjugate was confirmed. PUE@TPP/PEG-PE micelles had a particle size of 17.1 nm, a zeta potential of −6.2 mV, and a sustained-release behavior. The in vitro results showed that the intracellular uptake of C6@TPP/PEG-PE micelles was significantly enhanced in H9c2 cells. C6@TPP/PEG-PE micelles could deliver C6 to mitochondria and reduce the capture of lysosomes. In addition, compared with the PUE@PEG-PE micelles and free PUE, the PUE@TPP/PEG-PE micelles exerted an enhanced protective effect against isoprenaline-induced H9c2 cell apoptosis, as evident by the decreased percentage of apoptotic cells, Caspase-3 activity, ROS level, Bax expression, and increased Bcl-2 expression. The in vivo detecting results of the targeting effect using DiR probe also indicated that TPP/PEG-PE micelles could accumulate and retain in the ischemic myocardium.Conclusion: The results of this study demonstrate the promising potential of applying PUE@TPP/PEG-PE micelles in mitochondria-targeted drug delivery to achieve maximum therapeutic effects of PUE.Keywords: mitochondrial targeting, anti-apoptosis, ischemic myocardium, TPP
format	article
author	Li W Wu J Xiang D Luo S Hu X Tang T Sun T Liu X
author_facet	Li W Wu J Xiang D Luo S Hu X Tang T Sun T Liu X
author_sort	Li W
title	Micelles Loaded With Puerarin And Modified With Triphenylphosphonium Cation Possess Mitochondrial Targeting And Demonstrate Enhanced Protective Effect Against Isoprenaline-Induced H9c2 Cells Apoptosis
title_short	Micelles Loaded With Puerarin And Modified With Triphenylphosphonium Cation Possess Mitochondrial Targeting And Demonstrate Enhanced Protective Effect Against Isoprenaline-Induced H9c2 Cells Apoptosis
title_full	Micelles Loaded With Puerarin And Modified With Triphenylphosphonium Cation Possess Mitochondrial Targeting And Demonstrate Enhanced Protective Effect Against Isoprenaline-Induced H9c2 Cells Apoptosis
title_fullStr	Micelles Loaded With Puerarin And Modified With Triphenylphosphonium Cation Possess Mitochondrial Targeting And Demonstrate Enhanced Protective Effect Against Isoprenaline-Induced H9c2 Cells Apoptosis
title_full_unstemmed	Micelles Loaded With Puerarin And Modified With Triphenylphosphonium Cation Possess Mitochondrial Targeting And Demonstrate Enhanced Protective Effect Against Isoprenaline-Induced H9c2 Cells Apoptosis
title_sort	micelles loaded with puerarin and modified with triphenylphosphonium cation possess mitochondrial targeting and demonstrate enhanced protective effect against isoprenaline-induced h9c2 cells apoptosis
publisher	Dove Medical Press
publishDate	2019
url	https://doaj.org/article/69e9853f55b64426b6aa0ee04ffb50d3
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Micelles Loaded With Puerarin And Modified With Triphenylphosphonium Cation Possess Mitochondrial Targeting And Demonstrate Enhanced Protective Effect Against Isoprenaline-Induced H9c2 Cells Apoptosis

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