Regulating intracellular ROS signal by a dual pH/reducing-responsive nanogels system promotes tumor cell apoptosis

Kai Dong,* Qiuya Lei,* Runhao Guo, Xianglong Wu, Yanni Zhang, Ning Cui, Jian-Yu Shi, Tingli LuKey Laboratory for Space Bioscience and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi’an, Shaanxi, People’s Republic of China*These authors contribute...

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Autores principales:	Dong K, Lei Q, Guo R, Wu X, Zhang Y, Cui N, Shi JY, Lu T
Formato:	article
Lenguaje:	EN
Publicado:	Dove Medical Press 2019
Materias:	Reactive oxygen species Oxidative stress Cinnamaldehyde TPGS Nanogels Medicine (General) R5-920
Acceso en línea:	https://doaj.org/article/6ad772ebaa7a4795a4f43733363be208
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spelling	oai:doaj.org-article:6ad772ebaa7a4795a4f43733363be2082021-12-02T06:18:04ZRegulating intracellular ROS signal by a dual pH/reducing-responsive nanogels system promotes tumor cell apoptosis1178-2013https://doaj.org/article/6ad772ebaa7a4795a4f43733363be2082019-07-01T00:00:00Zhttps://www.dovepress.com/regulating-intracellular-ros-signal-by-a-dual-phreducing-responsive-na-peer-reviewed-article-IJNhttps://doaj.org/toc/1178-2013Kai Dong,* Qiuya Lei,* Runhao Guo, Xianglong Wu, Yanni Zhang, Ning Cui, Jian-Yu Shi, Tingli LuKey Laboratory for Space Bioscience and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi’an, Shaanxi, People’s Republic of China*These authors contributed equally to this workPurpose: The levels of reactive oxygen species (ROS) in tumor cells are much higher than that in normal cells, and rise rapidly under the influence of exogenous or endogenous inducing factors, eventually leading to the apoptosis of tumor cells. Therefore, this study prepared a dual pH/reducing-responsive poly (N-isopropylacrylamide-co-Cinnamaldehyde-co-D-α-tocopheryl polyethylene glycol 1000 succinate, PssNCT) nanogels, which employed two exogenous ROS inducers, cinnamaldehyde (CA) and D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS), to selectively induce apoptosis by regulating ROS levels in tumor cells.Methods: The PssNCT nanogels were prepared by the free radical precipitation polymerization under the crosslink between pH-sensitive hydrazone and reducing-sensitive disulfide bonds, followed by the physicochemical and morphological characteristics investigations. Plasma stability, dual pH/reducing responsive degradation and in vitro release were also assessed. In cell experiments, cytotoxicity in different cells were first detected. The intracellular ROS levels and mitochondrial functions of tumor cells were then evaluated. Moreover, the apoptosis and western-blot assays were employed to verify the association between ROS levels elevation and apoptosis in tumor cells.Results: The nanogels exhibited a round-like hollow structure with the diameter smaller than 200nm. The nanogels were stable in plasma, while showed rapid degradation in acidic and reducing environments, thus achieving significant release of CA and TPGS in these media. Furthermore, the sufficient amplification of ROS signals was induced by the synergistically function of CA and TPGS on mitochondria, which resulted in the opening of the mitochondrial apoptotic pathway and enhanced cytotoxicity on MCF-7 cells. However, nanogels barely affected L929 cells owing to their lower intracellular ROS basal levels.Conclusion: The specific ROS regulation method achieved by these nanogels could be explored to selectively kill tumor cells according to the difference of ROS signals in different kinds of cells.Keywords: reactive oxygen species, oxidative stress, cinnamaldehyde, TPGS, nanogelsDong KLei QGuo RWu XZhang YCui NShi JYLu TDove Medical PressarticleReactive oxygen speciesOxidative stressCinnamaldehydeTPGSNanogelsMedicine (General)R5-920ENInternational Journal of Nanomedicine, Vol Volume 14, Pp 5713-5728 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	Reactive oxygen species Oxidative stress Cinnamaldehyde TPGS Nanogels Medicine (General) R5-920
spellingShingle	Reactive oxygen species Oxidative stress Cinnamaldehyde TPGS Nanogels Medicine (General) R5-920 Dong K Lei Q Guo R Wu X Zhang Y Cui N Shi JY Lu T Regulating intracellular ROS signal by a dual pH/reducing-responsive nanogels system promotes tumor cell apoptosis
description	Kai Dong,* Qiuya Lei,* Runhao Guo, Xianglong Wu, Yanni Zhang, Ning Cui, Jian-Yu Shi, Tingli LuKey Laboratory for Space Bioscience and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi’an, Shaanxi, People’s Republic of China*These authors contributed equally to this workPurpose: The levels of reactive oxygen species (ROS) in tumor cells are much higher than that in normal cells, and rise rapidly under the influence of exogenous or endogenous inducing factors, eventually leading to the apoptosis of tumor cells. Therefore, this study prepared a dual pH/reducing-responsive poly (N-isopropylacrylamide-co-Cinnamaldehyde-co-D-α-tocopheryl polyethylene glycol 1000 succinate, PssNCT) nanogels, which employed two exogenous ROS inducers, cinnamaldehyde (CA) and D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS), to selectively induce apoptosis by regulating ROS levels in tumor cells.Methods: The PssNCT nanogels were prepared by the free radical precipitation polymerization under the crosslink between pH-sensitive hydrazone and reducing-sensitive disulfide bonds, followed by the physicochemical and morphological characteristics investigations. Plasma stability, dual pH/reducing responsive degradation and in vitro release were also assessed. In cell experiments, cytotoxicity in different cells were first detected. The intracellular ROS levels and mitochondrial functions of tumor cells were then evaluated. Moreover, the apoptosis and western-blot assays were employed to verify the association between ROS levels elevation and apoptosis in tumor cells.Results: The nanogels exhibited a round-like hollow structure with the diameter smaller than 200nm. The nanogels were stable in plasma, while showed rapid degradation in acidic and reducing environments, thus achieving significant release of CA and TPGS in these media. Furthermore, the sufficient amplification of ROS signals was induced by the synergistically function of CA and TPGS on mitochondria, which resulted in the opening of the mitochondrial apoptotic pathway and enhanced cytotoxicity on MCF-7 cells. However, nanogels barely affected L929 cells owing to their lower intracellular ROS basal levels.Conclusion: The specific ROS regulation method achieved by these nanogels could be explored to selectively kill tumor cells according to the difference of ROS signals in different kinds of cells.Keywords: reactive oxygen species, oxidative stress, cinnamaldehyde, TPGS, nanogels
format	article
author	Dong K Lei Q Guo R Wu X Zhang Y Cui N Shi JY Lu T
author_facet	Dong K Lei Q Guo R Wu X Zhang Y Cui N Shi JY Lu T
author_sort	Dong K
title	Regulating intracellular ROS signal by a dual pH/reducing-responsive nanogels system promotes tumor cell apoptosis
title_short	Regulating intracellular ROS signal by a dual pH/reducing-responsive nanogels system promotes tumor cell apoptosis
title_full	Regulating intracellular ROS signal by a dual pH/reducing-responsive nanogels system promotes tumor cell apoptosis
title_fullStr	Regulating intracellular ROS signal by a dual pH/reducing-responsive nanogels system promotes tumor cell apoptosis
title_full_unstemmed	Regulating intracellular ROS signal by a dual pH/reducing-responsive nanogels system promotes tumor cell apoptosis
title_sort	regulating intracellular ros signal by a dual ph/reducing-responsive nanogels system promotes tumor cell apoptosis
publisher	Dove Medical Press
publishDate	2019
url	https://doaj.org/article/6ad772ebaa7a4795a4f43733363be208
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Regulating intracellular ROS signal by a dual pH/reducing-responsive nanogels system promotes tumor cell apoptosis

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