Low-density lipoprotein-coupled micelles with reduction and pH dual sensitivity for intelligent co-delivery of paclitaxel and siRNA to breast tumor

Wen-jing Zhu,1,* Shu-di Yang,1,* Chen-xi Qu,1 Qiao-ling Zhu,1,2 Wei-liang Chen,1 Fang Li,1 Zhi-qiang Yuan,1 Yang Liu,1 Ben-gang You,1 Xue-nong Zhang1 1Department of Pharmaceutics, College of Pharmaceutical Sciences, Soochow University, Suzhou, 2Department of Clinical Medicine, Nanjing Gulou Hospita...

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Autores principales:	Zhu WJ, Yang SD, Qu CX, Zhu QL, Chen WL, Li F, Yuan ZQ, Liu Y, You BG, Zhang XN
Formato:	article
Lenguaje:	EN
Publicado:	Dove Medical Press 2017
Materias:	multidrug resistance micelles co-delivery environmentally sensitive tumor targeting Medicine (General) R5-920
Acceso en línea:	https://doaj.org/article/487ade9366ab4c4fb74dc54368b0206f
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spelling	oai:doaj.org-article:487ade9366ab4c4fb74dc54368b0206f2021-12-02T02:34:23ZLow-density lipoprotein-coupled micelles with reduction and pH dual sensitivity for intelligent co-delivery of paclitaxel and siRNA to breast tumor1178-2013https://doaj.org/article/487ade9366ab4c4fb74dc54368b0206f2017-04-01T00:00:00Zhttps://www.dovepress.com/low-density-lipoprotein-coupled-micelles-with-reduction-and-ph-dual-se-peer-reviewed-article-IJNhttps://doaj.org/toc/1178-2013Wen-jing Zhu,1,* Shu-di Yang,1,* Chen-xi Qu,1 Qiao-ling Zhu,1,2 Wei-liang Chen,1 Fang Li,1 Zhi-qiang Yuan,1 Yang Liu,1 Ben-gang You,1 Xue-nong Zhang1 1Department of Pharmaceutics, College of Pharmaceutical Sciences, Soochow University, Suzhou, 2Department of Clinical Medicine, Nanjing Gulou Hospital, Nanjing, People’s Republic of China *These authors contributed equally to this work Abstract: Multidrug resistance (MDR) is a major obstacle for the clinical therapy of malignant human cancers. The discovery of RNA interference provides efficient gene silencing within tumor cells for reversing MDR. In this study, a new “binary polymer” low-density lipoprotein–N-succinyl chitosan–cystamine–urocanic acid (LDL–NSC–SS–UA) with dual pH/redox sensitivity and targeting effect was synthesized for the co-delivery of breast cancer resistance protein small interfering RNA (siRNA) and paclitaxel (PTX). In vivo, the co-delivering micelles can accumulate in tumor tissue via the enhanced permeability and retention effect and the specific recognition and combination of LDL and LDL receptor, which is overexpressed on the surface of tumor cell membranes. The siRNA–PTX-loaded micelles inhibited gene and drug release under physiological conditions while promoting fast release in an acid microenvironment or in the presence of glutathione. The micelles escaped from the lysosome through the proton sponge effect. Additionally, the micelles exhibited superior antitumor activity and downregulated the protein and mRNA expression levels of breast cancer resistance protein in MCF-7/Taxol cells. The biodistribution and antitumor studies proved that the siRNA–PTX-loaded micelles possessed prolonged circulation time with a remarkable tumor-targeting effect and effectively inhibited tumor growth. Therefore, the novel dual pH/redox-sensitive polymers co-delivering siRNA and PTX with excellent biocompatibility and effective reversal of MDR demonstrate a considerable potential in cancer therapy. Keywords: multidrug resistance, micelle, co-delivery, environmentally sensitive, tumor targeting Zhu WJYang SDQu CXZhu QLChen WLLi FYuan ZQLiu YYou BGZhang XNDove Medical Pressarticlemultidrug resistancemicellesco-deliveryenvironmentally sensitivetumor targetingMedicine (General)R5-920ENInternational Journal of Nanomedicine, Vol Volume 12, Pp 3375-3393 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	multidrug resistance micelles co-delivery environmentally sensitive tumor targeting Medicine (General) R5-920
spellingShingle	multidrug resistance micelles co-delivery environmentally sensitive tumor targeting Medicine (General) R5-920 Zhu WJ Yang SD Qu CX Zhu QL Chen WL Li F Yuan ZQ Liu Y You BG Zhang XN Low-density lipoprotein-coupled micelles with reduction and pH dual sensitivity for intelligent co-delivery of paclitaxel and siRNA to breast tumor
description	Wen-jing Zhu,1,* Shu-di Yang,1,* Chen-xi Qu,1 Qiao-ling Zhu,1,2 Wei-liang Chen,1 Fang Li,1 Zhi-qiang Yuan,1 Yang Liu,1 Ben-gang You,1 Xue-nong Zhang1 1Department of Pharmaceutics, College of Pharmaceutical Sciences, Soochow University, Suzhou, 2Department of Clinical Medicine, Nanjing Gulou Hospital, Nanjing, People’s Republic of China *These authors contributed equally to this work Abstract: Multidrug resistance (MDR) is a major obstacle for the clinical therapy of malignant human cancers. The discovery of RNA interference provides efficient gene silencing within tumor cells for reversing MDR. In this study, a new “binary polymer” low-density lipoprotein–N-succinyl chitosan–cystamine–urocanic acid (LDL–NSC–SS–UA) with dual pH/redox sensitivity and targeting effect was synthesized for the co-delivery of breast cancer resistance protein small interfering RNA (siRNA) and paclitaxel (PTX). In vivo, the co-delivering micelles can accumulate in tumor tissue via the enhanced permeability and retention effect and the specific recognition and combination of LDL and LDL receptor, which is overexpressed on the surface of tumor cell membranes. The siRNA–PTX-loaded micelles inhibited gene and drug release under physiological conditions while promoting fast release in an acid microenvironment or in the presence of glutathione. The micelles escaped from the lysosome through the proton sponge effect. Additionally, the micelles exhibited superior antitumor activity and downregulated the protein and mRNA expression levels of breast cancer resistance protein in MCF-7/Taxol cells. The biodistribution and antitumor studies proved that the siRNA–PTX-loaded micelles possessed prolonged circulation time with a remarkable tumor-targeting effect and effectively inhibited tumor growth. Therefore, the novel dual pH/redox-sensitive polymers co-delivering siRNA and PTX with excellent biocompatibility and effective reversal of MDR demonstrate a considerable potential in cancer therapy. Keywords: multidrug resistance, micelle, co-delivery, environmentally sensitive, tumor targeting
format	article
author	Zhu WJ Yang SD Qu CX Zhu QL Chen WL Li F Yuan ZQ Liu Y You BG Zhang XN
author_facet	Zhu WJ Yang SD Qu CX Zhu QL Chen WL Li F Yuan ZQ Liu Y You BG Zhang XN
author_sort	Zhu WJ
title	Low-density lipoprotein-coupled micelles with reduction and pH dual sensitivity for intelligent co-delivery of paclitaxel and siRNA to breast tumor
title_short	Low-density lipoprotein-coupled micelles with reduction and pH dual sensitivity for intelligent co-delivery of paclitaxel and siRNA to breast tumor
title_full	Low-density lipoprotein-coupled micelles with reduction and pH dual sensitivity for intelligent co-delivery of paclitaxel and siRNA to breast tumor
title_fullStr	Low-density lipoprotein-coupled micelles with reduction and pH dual sensitivity for intelligent co-delivery of paclitaxel and siRNA to breast tumor
title_full_unstemmed	Low-density lipoprotein-coupled micelles with reduction and pH dual sensitivity for intelligent co-delivery of paclitaxel and siRNA to breast tumor
title_sort	low-density lipoprotein-coupled micelles with reduction and ph dual sensitivity for intelligent co-delivery of paclitaxel and sirna to breast tumor
publisher	Dove Medical Press
publishDate	2017
url	https://doaj.org/article/487ade9366ab4c4fb74dc54368b0206f
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Low-density lipoprotein-coupled micelles with reduction and pH dual sensitivity for intelligent co-delivery of paclitaxel and siRNA to breast tumor

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