Encapsulating Halofuginone Hydrobromide in TPGS Polymeric Micelles Enhances Efficacy Against Triple-Negative Breast Cancer Cells

Runan Zuo,1 Jingjing Zhang,1 Xinhao Song,1 Shiheng Hu,1 Xiuge Gao,1 Junqi Wang,1 Hui Ji,1 Chunlei Ji,1 Lin Peng,1 Hongbin Si,2 Gonghe Li,2 Kun Fang,3 Junren Zhang,1 Shanxiang Jiang,1 Dawei Guo1 1Center for Veterinary Drug Research and Evaluation, MOE Joint International Research Laboratory of Animal...

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Autores principales:	Zuo R, Zhang J, Song X, Hu S, Gao X, Wang J, Ji H, Ji C, Peng L, Si H, Li G, Fang K, Jiang S, Guo D
Formato:	article
Lenguaje:	EN
Publicado:	Dove Medical Press 2021
Materias:	halofuginone hydrobromide triple negative breast cancer tpgs polymer micelles Medicine (General) R5-920
Acceso en línea:	https://doaj.org/article/4d5b1a48f7b44e73801efdb85ba096d8
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id	oai:doaj.org-article:4d5b1a48f7b44e73801efdb85ba096d8
record_format	dspace
institution	DOAJ
collection	DOAJ
language	EN
topic	halofuginone hydrobromide triple negative breast cancer tpgs polymer micelles Medicine (General) R5-920
spellingShingle	halofuginone hydrobromide triple negative breast cancer tpgs polymer micelles Medicine (General) R5-920 Zuo R Zhang J Song X Hu S Gao X Wang J Ji H Ji C Peng L Si H Li G Fang K Zhang J Jiang S Guo D Encapsulating Halofuginone Hydrobromide in TPGS Polymeric Micelles Enhances Efficacy Against Triple-Negative Breast Cancer Cells
description	Runan Zuo,1 Jingjing Zhang,1 Xinhao Song,1 Shiheng Hu,1 Xiuge Gao,1 Junqi Wang,1 Hui Ji,1 Chunlei Ji,1 Lin Peng,1 Hongbin Si,2 Gonghe Li,2 Kun Fang,3 Junren Zhang,1 Shanxiang Jiang,1 Dawei Guo1 1Center for Veterinary Drug Research and Evaluation, MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, 210095, People’s Republic of China; 2College of Animal Science and Technology, Guangxi University, Nanning, 530004, People’s Republic of China; 3Division of Life Sciences and Medicine, The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei, 230001, People’s Republic of ChinaCorrespondence: Dawei Guo; Shanxiang JiangCenter for Veterinary Drug Research and Evaluation, MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, 1 Weigang, Nanjing, 210095, People’s Republic of ChinaTel + 86-25-84396215Fax + 86-25-84398669Email gdawei0123@njau.edu.cn; nauvy@sina.comBackground: Halofuginone hydrobromide (HF) is a synthetic analogue of the naturally occurring quinazolinone alkaloid febrifugine, which has potential therapeutic effects against breast cancer, however, its poor water solubility greatly limits its pharmaceutical application. D-α-tocopherol polyethylene glycol 1000 succinate (TPGS) is a water-soluble derivative of vitamin E, which can self-assemble to form polymeric micelles (PMs) for encapsulating insoluble anti-tumor drugs, thereby effectively enhancing their anti-cancer effects.Methods: HF-loaded TPGS PMs (HTPMs) were manufactured using a thin-film hydration technique, followed by a series of characterizations, including the hydrodynamic diameter (HD), zeta potential (ZP), stability, drug loading (DL), encapsulation efficiency (EE), and in vitro drug release. The anti-cancer effects and potential mechanism of HTPMs were investigated in the breast cell lines MDA-MB-231 and MCF-7, and normal breast epithelial cell line Eph-ev. The breast cancer-bearing BALB/c nude mouse model was successfully established by subcutaneous injection of MDA-MB-231 cells and used to evaluate the in vivo therapeutic effect and safety of the HTPMs.Results: The optimized HTPMs had an HD of 17.8± 0.5 nm and ZP of 14.40± 0.1 mV. These PMs exhibited DL of 12.94 ± 0.46% and EE of 90.6 ± 0.85%, along with excellent storage stability, dilution tolerance and sustained drug release in pH-dependent manner within 24 h compared to free HF. Additionally, the HTPMs had stronger inhibitory effects than free HF and paclitaxel against MDA-MB-231 triple-negative breast cancer cells, and little toxicity in normal breast epithelial Eph-ev cells. The HTPMs induced cell cycle arrest and apoptosis of MDA-MB-231 by disrupting the mitochondrial membrane potential and enhancing reactive oxygen species formation. Evaluation of in vivo anti-tumor efficacy demonstrated that HTPMs exerted a stronger tumor inhibition rate (68.17%) than free HF, and exhibited excellent biocompatibility.Conclusion: The findings from this study indicate that HTPMs holds great clinical potential for treating triple-negative breast cancer.Keywords: halofuginone hydrobromide, triple-negative breast cancer, TPGS, polymer micelles
format	article
author	Zuo R Zhang J Song X Hu S Gao X Wang J Ji H Ji C Peng L Si H Li G Fang K Zhang J Jiang S Guo D
author_facet	Zuo R Zhang J Song X Hu S Gao X Wang J Ji H Ji C Peng L Si H Li G Fang K Zhang J Jiang S Guo D
author_sort	Zuo R
title	Encapsulating Halofuginone Hydrobromide in TPGS Polymeric Micelles Enhances Efficacy Against Triple-Negative Breast Cancer Cells
title_short	Encapsulating Halofuginone Hydrobromide in TPGS Polymeric Micelles Enhances Efficacy Against Triple-Negative Breast Cancer Cells
title_full	Encapsulating Halofuginone Hydrobromide in TPGS Polymeric Micelles Enhances Efficacy Against Triple-Negative Breast Cancer Cells
title_fullStr	Encapsulating Halofuginone Hydrobromide in TPGS Polymeric Micelles Enhances Efficacy Against Triple-Negative Breast Cancer Cells
title_full_unstemmed	Encapsulating Halofuginone Hydrobromide in TPGS Polymeric Micelles Enhances Efficacy Against Triple-Negative Breast Cancer Cells
title_sort	encapsulating halofuginone hydrobromide in tpgs polymeric micelles enhances efficacy against triple-negative breast cancer cells
publisher	Dove Medical Press
publishDate	2021
url	https://doaj.org/article/4d5b1a48f7b44e73801efdb85ba096d8
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spelling	oai:doaj.org-article:4d5b1a48f7b44e73801efdb85ba096d82021-12-02T14:18:14ZEncapsulating Halofuginone Hydrobromide in TPGS Polymeric Micelles Enhances Efficacy Against Triple-Negative Breast Cancer Cells1178-2013https://doaj.org/article/4d5b1a48f7b44e73801efdb85ba096d82021-02-01T00:00:00Zhttps://www.dovepress.com/encapsulating-halofuginone-hydrobromide-in-tpgs-polymeric-micelles-enh-peer-reviewed-article-IJNhttps://doaj.org/toc/1178-2013Runan Zuo,1 Jingjing Zhang,1 Xinhao Song,1 Shiheng Hu,1 Xiuge Gao,1 Junqi Wang,1 Hui Ji,1 Chunlei Ji,1 Lin Peng,1 Hongbin Si,2 Gonghe Li,2 Kun Fang,3 Junren Zhang,1 Shanxiang Jiang,1 Dawei Guo1 1Center for Veterinary Drug Research and Evaluation, MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, 210095, People’s Republic of China; 2College of Animal Science and Technology, Guangxi University, Nanning, 530004, People’s Republic of China; 3Division of Life Sciences and Medicine, The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei, 230001, People’s Republic of ChinaCorrespondence: Dawei Guo; Shanxiang JiangCenter for Veterinary Drug Research and Evaluation, MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, 1 Weigang, Nanjing, 210095, People’s Republic of ChinaTel + 86-25-84396215Fax + 86-25-84398669Email gdawei0123@njau.edu.cn; nauvy@sina.comBackground: Halofuginone hydrobromide (HF) is a synthetic analogue of the naturally occurring quinazolinone alkaloid febrifugine, which has potential therapeutic effects against breast cancer, however, its poor water solubility greatly limits its pharmaceutical application. D-α-tocopherol polyethylene glycol 1000 succinate (TPGS) is a water-soluble derivative of vitamin E, which can self-assemble to form polymeric micelles (PMs) for encapsulating insoluble anti-tumor drugs, thereby effectively enhancing their anti-cancer effects.Methods: HF-loaded TPGS PMs (HTPMs) were manufactured using a thin-film hydration technique, followed by a series of characterizations, including the hydrodynamic diameter (HD), zeta potential (ZP), stability, drug loading (DL), encapsulation efficiency (EE), and in vitro drug release. The anti-cancer effects and potential mechanism of HTPMs were investigated in the breast cell lines MDA-MB-231 and MCF-7, and normal breast epithelial cell line Eph-ev. The breast cancer-bearing BALB/c nude mouse model was successfully established by subcutaneous injection of MDA-MB-231 cells and used to evaluate the in vivo therapeutic effect and safety of the HTPMs.Results: The optimized HTPMs had an HD of 17.8± 0.5 nm and ZP of 14.40± 0.1 mV. These PMs exhibited DL of 12.94 ± 0.46% and EE of 90.6 ± 0.85%, along with excellent storage stability, dilution tolerance and sustained drug release in pH-dependent manner within 24 h compared to free HF. Additionally, the HTPMs had stronger inhibitory effects than free HF and paclitaxel against MDA-MB-231 triple-negative breast cancer cells, and little toxicity in normal breast epithelial Eph-ev cells. The HTPMs induced cell cycle arrest and apoptosis of MDA-MB-231 by disrupting the mitochondrial membrane potential and enhancing reactive oxygen species formation. Evaluation of in vivo anti-tumor efficacy demonstrated that HTPMs exerted a stronger tumor inhibition rate (68.17%) than free HF, and exhibited excellent biocompatibility.Conclusion: The findings from this study indicate that HTPMs holds great clinical potential for treating triple-negative breast cancer.Keywords: halofuginone hydrobromide, triple-negative breast cancer, TPGS, polymer micellesZuo RZhang JSong XHu SGao XWang JJi HJi CPeng LSi HLi GFang KZhang JJiang SGuo DDove Medical Pressarticlehalofuginone hydrobromidetriple negative breast cancertpgspolymer micellesMedicine (General)R5-920ENInternational Journal of Nanomedicine, Vol Volume 16, Pp 1587-1600 (2021)

Encapsulating Halofuginone Hydrobromide in TPGS Polymeric Micelles Enhances Efficacy Against Triple-Negative Breast Cancer Cells

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