Synergistic effects of A-B-C-type amphiphilic copolymer on reversal of drug resistance in MCF-7/ADR breast carcinoma

Lu Zhang,1–3 Jiafei Lu,3 Liyan Qiu1 1Ministry of Education (MOE) Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou, 2Drug Clinical Trial Office, The First Affiliated Hospital of Wenzhou Medical Un...

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Autores principales:	Zhang L, Lu J, Qiu L
Formato:	article
Lenguaje:	EN
Publicado:	Dove Medical Press 2016
Materias:	multidrug resistance P-glycoprotein micelle doxorubicin zebraﬁsh Medicine (General) R5-920
Acceso en línea:	https://doaj.org/article/c250cd0ffe624a3bb7b3aa279ef017d5
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spelling	oai:doaj.org-article:c250cd0ffe624a3bb7b3aa279ef017d52021-12-02T08:07:35ZSynergistic effects of A-B-C-type amphiphilic copolymer on reversal of drug resistance in MCF-7/ADR breast carcinoma1178-2013https://doaj.org/article/c250cd0ffe624a3bb7b3aa279ef017d52016-10-01T00:00:00Zhttps://www.dovepress.com/synergistic-effects-of-a-b-c-type-amphiphilic-copolymer-on-reversal-of-peer-reviewed-article-IJNhttps://doaj.org/toc/1178-2013Lu Zhang,1–3 Jiafei Lu,3 Liyan Qiu1 1Ministry of Education (MOE) Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou, 2Drug Clinical Trial Office, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 3College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, People’s Republic of China Abstract: P-glycoprotein (P-gp) overexpression has become the most common cause of occurrence of multidrug resistance in clinical settings. We aimed to construct a micellar polymer carrier to sensitize drug-resistant tumors to doxorubicin (DOX). This A-B-C-type amphiphilic copolymer was prepared by the sequential linkage of β-cyclodextrin, hydrophobic poly(D,L-lactide), and hydrophilic poly(ethylene glycol). Upon incubation of the DOX-loaded micelles with DOX-resistant human breast carcinoma MCF-7/ADR cells, significantly enhanced cytotoxicity and apoptosis were achieved. A series of studies on the action mechanism showed that the polymer components such as β-cyclodextrin, hydrophobic poly(D,L-lactide) segment, and poly(ethylene glycol) coordinatively contributed to the improved intracellular ATP depletion and ATPase activity, increased intracellular uptake of P-gp substrates via competitive binding to P-gp, and decreased P-gp expression in MCF-7/ADR cells. More interestingly, a similar phenomenon was observed in the zebrafish xenograft model, resulting in ~64% inhibition of MCF-7/ADR tumor growth. These results implied that the polymeric micelles displayed great potentials as P-gp modulators to reverse DOX resistance in MCF-7/ADR breast carcinoma. Keywords: multidrug resistance, P-glycoprotein, micelle, doxorubicin, zebrafishZhang LLu JQiu LDove Medical Pressarticlemultidrug resistanceP-glycoproteinmicelledoxorubicinzebraﬁshMedicine (General)R5-920ENInternational Journal of Nanomedicine, Vol Volume 11, Pp 5205-5220 (2016)
institution	DOAJ
collection	DOAJ
language	EN
topic	multidrug resistance P-glycoprotein micelle doxorubicin zebraﬁsh Medicine (General) R5-920
spellingShingle	multidrug resistance P-glycoprotein micelle doxorubicin zebraﬁsh Medicine (General) R5-920 Zhang L Lu J Qiu L Synergistic effects of A-B-C-type amphiphilic copolymer on reversal of drug resistance in MCF-7/ADR breast carcinoma
description	Lu Zhang,1–3 Jiafei Lu,3 Liyan Qiu1 1Ministry of Education (MOE) Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou, 2Drug Clinical Trial Office, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 3College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, People’s Republic of China Abstract: P-glycoprotein (P-gp) overexpression has become the most common cause of occurrence of multidrug resistance in clinical settings. We aimed to construct a micellar polymer carrier to sensitize drug-resistant tumors to doxorubicin (DOX). This A-B-C-type amphiphilic copolymer was prepared by the sequential linkage of β-cyclodextrin, hydrophobic poly(D,L-lactide), and hydrophilic poly(ethylene glycol). Upon incubation of the DOX-loaded micelles with DOX-resistant human breast carcinoma MCF-7/ADR cells, significantly enhanced cytotoxicity and apoptosis were achieved. A series of studies on the action mechanism showed that the polymer components such as β-cyclodextrin, hydrophobic poly(D,L-lactide) segment, and poly(ethylene glycol) coordinatively contributed to the improved intracellular ATP depletion and ATPase activity, increased intracellular uptake of P-gp substrates via competitive binding to P-gp, and decreased P-gp expression in MCF-7/ADR cells. More interestingly, a similar phenomenon was observed in the zebrafish xenograft model, resulting in ~64% inhibition of MCF-7/ADR tumor growth. These results implied that the polymeric micelles displayed great potentials as P-gp modulators to reverse DOX resistance in MCF-7/ADR breast carcinoma. Keywords: multidrug resistance, P-glycoprotein, micelle, doxorubicin, zebrafish
format	article
author	Zhang L Lu J Qiu L
author_facet	Zhang L Lu J Qiu L
author_sort	Zhang L
title	Synergistic effects of A-B-C-type amphiphilic copolymer on reversal of drug resistance in MCF-7/ADR breast carcinoma
title_short	Synergistic effects of A-B-C-type amphiphilic copolymer on reversal of drug resistance in MCF-7/ADR breast carcinoma
title_full	Synergistic effects of A-B-C-type amphiphilic copolymer on reversal of drug resistance in MCF-7/ADR breast carcinoma
title_fullStr	Synergistic effects of A-B-C-type amphiphilic copolymer on reversal of drug resistance in MCF-7/ADR breast carcinoma
title_full_unstemmed	Synergistic effects of A-B-C-type amphiphilic copolymer on reversal of drug resistance in MCF-7/ADR breast carcinoma
title_sort	synergistic effects of a-b-c-type amphiphilic copolymer on reversal of drug resistance in mcf-7/adr breast carcinoma
publisher	Dove Medical Press
publishDate	2016
url	https://doaj.org/article/c250cd0ffe624a3bb7b3aa279ef017d5
work_keys_str_mv	AT zhangl synergisticeffectsofabctypeamphiphiliccopolymeronreversalofdrugresistanceinmcf7adrbreastcarcinoma AT luj synergisticeffectsofabctypeamphiphiliccopolymeronreversalofdrugresistanceinmcf7adrbreastcarcinoma AT qiul synergisticeffectsofabctypeamphiphiliccopolymeronreversalofdrugresistanceinmcf7adrbreastcarcinoma
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Synergistic effects of A-B-C-type amphiphilic copolymer on reversal of drug resistance in MCF-7/ADR breast carcinoma

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