Stepwise pH-responsive nanoparticles for enhanced cellular uptake and on-demand intracellular release of doxorubicin

Wei-liang Chen,1 Fang Li,1 Yan Tang,1 Shu-di Yang,1 Ji-zhao Li,1 Zhi-qiang Yuan,1 Yang Liu,1 Xiao-feng Zhou,2 Chun Liu,3 Xue-nong Zhang1 1Department of Pharmaceutics, College of Pharmaceutical Sciences, Soochow University, Suzhou, 2Department of Ultrasound, Changshu Hospital of Traditional Chinese...

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Autores principales:	Chen WL, Li F, Tang Y, Yang SD, Li JZ, Yuan ZQ, Liu Y, Zhou XF, Liu C, Zhang XN
Formato:	article
Lenguaje:	EN
Publicado:	Dove Medical Press 2017
Materias:	stepwise pH-responsive charge reversal on-demand drug release Efficient delivery. Medicine (General) R5-920
Acceso en línea:	https://doaj.org/article/3d70b8a200a94ac587487802f787b7df
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spelling	oai:doaj.org-article:3d70b8a200a94ac587487802f787b7df2021-12-02T02:41:35ZStepwise pH-responsive nanoparticles for enhanced cellular uptake and on-demand intracellular release of doxorubicin1178-2013https://doaj.org/article/3d70b8a200a94ac587487802f787b7df2017-06-01T00:00:00Zhttps://www.dovepress.com/stepwise-ph-responsive-nanoparticles-for-enhanced-cellular-uptake-and--peer-reviewed-article-IJNhttps://doaj.org/toc/1178-2013Wei-liang Chen,1 Fang Li,1 Yan Tang,1 Shu-di Yang,1 Ji-zhao Li,1 Zhi-qiang Yuan,1 Yang Liu,1 Xiao-feng Zhou,2 Chun Liu,3 Xue-nong Zhang1 1Department of Pharmaceutics, College of Pharmaceutical Sciences, Soochow University, Suzhou, 2Department of Ultrasound, Changshu Hospital of Traditional Chinese Medicine, Changshu, 3Department of Pharmacy, The Hospital of Suzhou People’s Hospital Affiliated to Nanjing Medical University, Suzhou, People’s Republic of China Abstract: Physicochemical properties, including particle size, zeta potential, and drug release behavior, affect targeting efficiency, cellular uptake, and antitumor effect of nanocarriers in a formulated drug-delivery system. In this study, a novel stepwise pH-responsive nanodrug delivery system was developed to efficiently deliver and significantly promote the therapeutic effect of doxorubicin (DOX). The system comprised dimethylmaleic acid-chitosan-urocanic acid and elicited stepwise responses to extracellular and intracellular pH. The nanoparticles (NPs), which possessed negative surface charge under physiological conditions and an appropriate nanosize, exhibited advantageous stability during blood circulation and enhanced accumulation in tumor sites via enhanced permeability and retention effect. The tumor cellular uptake of DOX-loaded NPs was significantly promoted by the first-step pH response, wherein surface charge reversion of NPs from negative to positive was triggered by the slightly acidic tumor extracellular environment. After internalization into tumor cells, the second-step pH response in endo/lysosome acidic environment elicited the on-demand intracellular release of DOX from NPs, thereby increasing cytotoxicity against tumor cells. Furthermore, stepwise pH-responsive NPs showed enhanced antiproliferation effect and reduced systemic side effect in vivo. Hence, the stepwise pH-responsive NPs provide a promising strategy for efficient delivery of antitumor agents. Keywords: stepwise pH-responsive, charge reversal, on-demand drug release, efficient deliveryChen WLLi FTang YYang SDLi JZYuan ZQLiu YZhou XFLiu CZhang XNDove Medical Pressarticlestepwise pH-responsivecharge reversalon-demand drug releaseEfficient delivery.Medicine (General)R5-920ENInternational Journal of Nanomedicine, Vol Volume 12, Pp 4241-4256 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	stepwise pH-responsive charge reversal on-demand drug release Efficient delivery. Medicine (General) R5-920
spellingShingle	stepwise pH-responsive charge reversal on-demand drug release Efficient delivery. Medicine (General) R5-920 Chen WL Li F Tang Y Yang SD Li JZ Yuan ZQ Liu Y Zhou XF Liu C Zhang XN Stepwise pH-responsive nanoparticles for enhanced cellular uptake and on-demand intracellular release of doxorubicin
description	Wei-liang Chen,1 Fang Li,1 Yan Tang,1 Shu-di Yang,1 Ji-zhao Li,1 Zhi-qiang Yuan,1 Yang Liu,1 Xiao-feng Zhou,2 Chun Liu,3 Xue-nong Zhang1 1Department of Pharmaceutics, College of Pharmaceutical Sciences, Soochow University, Suzhou, 2Department of Ultrasound, Changshu Hospital of Traditional Chinese Medicine, Changshu, 3Department of Pharmacy, The Hospital of Suzhou People’s Hospital Affiliated to Nanjing Medical University, Suzhou, People’s Republic of China Abstract: Physicochemical properties, including particle size, zeta potential, and drug release behavior, affect targeting efficiency, cellular uptake, and antitumor effect of nanocarriers in a formulated drug-delivery system. In this study, a novel stepwise pH-responsive nanodrug delivery system was developed to efficiently deliver and significantly promote the therapeutic effect of doxorubicin (DOX). The system comprised dimethylmaleic acid-chitosan-urocanic acid and elicited stepwise responses to extracellular and intracellular pH. The nanoparticles (NPs), which possessed negative surface charge under physiological conditions and an appropriate nanosize, exhibited advantageous stability during blood circulation and enhanced accumulation in tumor sites via enhanced permeability and retention effect. The tumor cellular uptake of DOX-loaded NPs was significantly promoted by the first-step pH response, wherein surface charge reversion of NPs from negative to positive was triggered by the slightly acidic tumor extracellular environment. After internalization into tumor cells, the second-step pH response in endo/lysosome acidic environment elicited the on-demand intracellular release of DOX from NPs, thereby increasing cytotoxicity against tumor cells. Furthermore, stepwise pH-responsive NPs showed enhanced antiproliferation effect and reduced systemic side effect in vivo. Hence, the stepwise pH-responsive NPs provide a promising strategy for efficient delivery of antitumor agents. Keywords: stepwise pH-responsive, charge reversal, on-demand drug release, efficient delivery
format	article
author	Chen WL Li F Tang Y Yang SD Li JZ Yuan ZQ Liu Y Zhou XF Liu C Zhang XN
author_facet	Chen WL Li F Tang Y Yang SD Li JZ Yuan ZQ Liu Y Zhou XF Liu C Zhang XN
author_sort	Chen WL
title	Stepwise pH-responsive nanoparticles for enhanced cellular uptake and on-demand intracellular release of doxorubicin
title_short	Stepwise pH-responsive nanoparticles for enhanced cellular uptake and on-demand intracellular release of doxorubicin
title_full	Stepwise pH-responsive nanoparticles for enhanced cellular uptake and on-demand intracellular release of doxorubicin
title_fullStr	Stepwise pH-responsive nanoparticles for enhanced cellular uptake and on-demand intracellular release of doxorubicin
title_full_unstemmed	Stepwise pH-responsive nanoparticles for enhanced cellular uptake and on-demand intracellular release of doxorubicin
title_sort	stepwise ph-responsive nanoparticles for enhanced cellular uptake and on-demand intracellular release of doxorubicin
publisher	Dove Medical Press
publishDate	2017
url	https://doaj.org/article/3d70b8a200a94ac587487802f787b7df
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Stepwise pH-responsive nanoparticles for enhanced cellular uptake and on-demand intracellular release of doxorubicin

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