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

Authors 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

Received 9 November 2020

Accepted for publication 4 February 2021

Published 26 February 2021 Volume 2021:16 Pages 1587—1600


Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 2

Editor who approved publication: Prof. Dr. Thomas J. Webster

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 China

Correspondence: Dawei Guo; Shanxiang Jiang
Center 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 China
Tel + 86-25-84396215
Fax + 86-25-84398669
Email [email protected]; [email protected]

Background: 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

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