Simultaneous delivery of anti-miR21 with doxorubicin prodrug by mimetic lipoprotein nanoparticles for synergistic effect against drug resistance in cancer cells

Mengjie Rui, Yang Qu, Tong Gao, Yanru Ge, Chunlai Feng, Ximing Xu Department of Pharmaceutics, School of Pharmacy, Jiangsu University, Zhenjiang, People’s Republic of China Abstract: The development of drug resistance in cancer cells is one of the major obstacles to achieving effective c...

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Autores principales:	Rui M, Qu Y, Gao T, Ge Y, Feng C, Xu X
Formato:	article
Lenguaje:	EN
Publicado:	Dove Medical Press 2016
Materias:	Drug resistance MicroRNA-21 inhibitor Doxorubicin prodrug Nuclear localization signal peptide Lipoprotein-mimicking nanoparticles Breast cancer therapy Medicine (General) R5-920
Acceso en línea:	https://doaj.org/article/4f5ead172efe415899e769adc8982537
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spelling	oai:doaj.org-article:4f5ead172efe415899e769adc89825372021-12-02T00:38:51ZSimultaneous delivery of anti-miR21 with doxorubicin prodrug by mimetic lipoprotein nanoparticles for synergistic effect against drug resistance in cancer cells1178-2013https://doaj.org/article/4f5ead172efe415899e769adc89825372016-12-01T00:00:00Zhttps://www.dovepress.com/simultaneous-delivery-of-anti-mir21-with-doxorubicin-prodrug-by-mimeti-peer-reviewed-article-IJNhttps://doaj.org/toc/1178-2013Mengjie Rui, Yang Qu, Tong Gao, Yanru Ge, Chunlai Feng, Ximing Xu Department of Pharmaceutics, School of Pharmacy, Jiangsu University, Zhenjiang, People’s Republic of China Abstract: The development of drug resistance in cancer cells is one of the major obstacles to achieving effective chemotherapy. We hypothesized that the combination of a doxorubicin (Dox) prodrug and microRNA (miR)21 inhibitor might show synergistic antitumor effects on drug-resistant breast cancer cells. In this study, we aimed to develop new high-density lipoprotein-mimicking nanoparticles (HMNs) for coencapsulation and codelivery of this potential combination. Dox was coupled with a nuclear localization signal (NLS) peptide to construct a prodrug (NLS-Dox), thereby electrostatically condensing miR21 inhibitor (anti-miR21) to form cationic complexes. The HMNs were formulated by shielding these complexes with anionic lipids and Apo AI proteins. We have characterized that the coloaded HMNs had uniformly dispersed distribution, favorable negatively charged surface, and high coencapsulation efficiency. The HMN formulation effectively codelivered NLS-Dox and anti-miR21 into Dox-resistant breast cancer MCF7/ADR cells and wild-type MCF7 cells via a high-density-lipoprotein receptor-mediated pathway, which facilitated the escape of Pgp drug efflux. The coloaded HMNs consisting of NLS-Dox/anti-miR21 demonstrated greater cytotoxicity with enhanced intracellular accumulation in resistant MCF7/ADR cells compared with free Dox solution. The reversal of drug resistance by coloaded HMNs might be attributed to the suppression of miR21 expression and the related antiapoptosis network. Furthermore, the codelivery of anti-miR21 and NLS-Dox by HMNs showed synergistic antiproliferative effects in MCF7/ADR-bearing nude mice, and was more effective in tumor inhibition than other drug formulations. These data suggested that codelivery of anti-miR21 and chemotherapeutic agents by HMNs might be a promising strategy for antitumor therapy, and could restore the drug sensitivity of cancer cells, alter intracellular drug distribution, and ultimately enhance chemotherapeutic effects. Keywords: drug resistance, microRNA21 inhibitor, doxorubicin prodrug, nuclear localization signal peptide, lipoprotein-mimicking nanoparticles, breast cancer therapyRui MQu YGao TGe YFeng CXu XDove Medical PressarticleDrug resistanceMicroRNA-21 inhibitorDoxorubicin prodrugNuclear localization signal peptideLipoprotein-mimicking nanoparticlesBreast cancer therapyMedicine (General)R5-920ENInternational Journal of Nanomedicine, Vol Volume 12, Pp 217-237 (2016)
institution	DOAJ
collection	DOAJ
language	EN
topic	Drug resistance MicroRNA-21 inhibitor Doxorubicin prodrug Nuclear localization signal peptide Lipoprotein-mimicking nanoparticles Breast cancer therapy Medicine (General) R5-920
spellingShingle	Drug resistance MicroRNA-21 inhibitor Doxorubicin prodrug Nuclear localization signal peptide Lipoprotein-mimicking nanoparticles Breast cancer therapy Medicine (General) R5-920 Rui M Qu Y Gao T Ge Y Feng C Xu X Simultaneous delivery of anti-miR21 with doxorubicin prodrug by mimetic lipoprotein nanoparticles for synergistic effect against drug resistance in cancer cells
description	Mengjie Rui, Yang Qu, Tong Gao, Yanru Ge, Chunlai Feng, Ximing Xu Department of Pharmaceutics, School of Pharmacy, Jiangsu University, Zhenjiang, People’s Republic of China Abstract: The development of drug resistance in cancer cells is one of the major obstacles to achieving effective chemotherapy. We hypothesized that the combination of a doxorubicin (Dox) prodrug and microRNA (miR)21 inhibitor might show synergistic antitumor effects on drug-resistant breast cancer cells. In this study, we aimed to develop new high-density lipoprotein-mimicking nanoparticles (HMNs) for coencapsulation and codelivery of this potential combination. Dox was coupled with a nuclear localization signal (NLS) peptide to construct a prodrug (NLS-Dox), thereby electrostatically condensing miR21 inhibitor (anti-miR21) to form cationic complexes. The HMNs were formulated by shielding these complexes with anionic lipids and Apo AI proteins. We have characterized that the coloaded HMNs had uniformly dispersed distribution, favorable negatively charged surface, and high coencapsulation efficiency. The HMN formulation effectively codelivered NLS-Dox and anti-miR21 into Dox-resistant breast cancer MCF7/ADR cells and wild-type MCF7 cells via a high-density-lipoprotein receptor-mediated pathway, which facilitated the escape of Pgp drug efflux. The coloaded HMNs consisting of NLS-Dox/anti-miR21 demonstrated greater cytotoxicity with enhanced intracellular accumulation in resistant MCF7/ADR cells compared with free Dox solution. The reversal of drug resistance by coloaded HMNs might be attributed to the suppression of miR21 expression and the related antiapoptosis network. Furthermore, the codelivery of anti-miR21 and NLS-Dox by HMNs showed synergistic antiproliferative effects in MCF7/ADR-bearing nude mice, and was more effective in tumor inhibition than other drug formulations. These data suggested that codelivery of anti-miR21 and chemotherapeutic agents by HMNs might be a promising strategy for antitumor therapy, and could restore the drug sensitivity of cancer cells, alter intracellular drug distribution, and ultimately enhance chemotherapeutic effects. Keywords: drug resistance, microRNA21 inhibitor, doxorubicin prodrug, nuclear localization signal peptide, lipoprotein-mimicking nanoparticles, breast cancer therapy
format	article
author	Rui M Qu Y Gao T Ge Y Feng C Xu X
author_facet	Rui M Qu Y Gao T Ge Y Feng C Xu X
author_sort	Rui M
title	Simultaneous delivery of anti-miR21 with doxorubicin prodrug by mimetic lipoprotein nanoparticles for synergistic effect against drug resistance in cancer cells
title_short	Simultaneous delivery of anti-miR21 with doxorubicin prodrug by mimetic lipoprotein nanoparticles for synergistic effect against drug resistance in cancer cells
title_full	Simultaneous delivery of anti-miR21 with doxorubicin prodrug by mimetic lipoprotein nanoparticles for synergistic effect against drug resistance in cancer cells
title_fullStr	Simultaneous delivery of anti-miR21 with doxorubicin prodrug by mimetic lipoprotein nanoparticles for synergistic effect against drug resistance in cancer cells
title_full_unstemmed	Simultaneous delivery of anti-miR21 with doxorubicin prodrug by mimetic lipoprotein nanoparticles for synergistic effect against drug resistance in cancer cells
title_sort	simultaneous delivery of anti-mir21 with doxorubicin prodrug by mimetic lipoprotein nanoparticles for synergistic effect against drug resistance in cancer cells
publisher	Dove Medical Press
publishDate	2016
url	https://doaj.org/article/4f5ead172efe415899e769adc8982537
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Simultaneous delivery of anti-miR21 with doxorubicin prodrug by mimetic lipoprotein nanoparticles for synergistic effect against drug resistance in cancer cells

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