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, Nanjing, 210095, People's Republic of China.
College of Animal Science and Technology, Guangxi University, Nanning, 530004, People's Republic of China.
Int J Nanomedicine. 2021 Feb 26;16:1587-1600. doi: 10.2147/IJN.S289096. eCollection 2021.
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.
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.
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.
The findings from this study indicate that HTPMs holds great clinical potential for treating triple-negative breast cancer.
卤夫酮氢溴酸盐（HF）是天然喹唑啉酮生物碱菲布芬的合成类似物，具有治疗乳腺癌的潜在疗效，但由于其水溶性差，极大地限制了其在药物方面的应用。D-α-生育酚聚乙二醇 1000 琥珀酸酯（TPGS）是维生素 E 的水溶性衍生物，可自组装形成聚合物胶束（PMs）以包裹难溶性抗肿瘤药物，从而有效增强其抗癌作用。
采用薄膜水化法制备载卤夫酮 TPGS 聚合物胶束（HTPMs），并对其进行一系列特性研究，包括水动力学直径（HD）、Zeta 电位（ZP）、稳定性、载药量（DL）、包封率（EE）和体外药物释放。在乳腺癌细胞系 MDA-MB-231 和 MCF-7 及正常乳腺上皮细胞系 Eph-ev 中研究了 HTPMs 的抗癌作用及其潜在机制。通过皮下注射 MDA-MB-231 细胞成功建立了乳腺癌荷瘤 BALB/c 裸鼠模型，并用于评价 HTPMs 的体内治疗效果和安全性。
优化的 HTPMs 的 HD 为 17.8±0.5nm，ZP 为 14.40±0.1mV。这些 PMs 的 DL 为 12.94±0.46%，EE 为 90.6±0.85%，具有良好的储存稳定性、稀释耐受性和在 pH 依赖性下 24 小时内持续药物释放。与游离 HF 相比，HTPMs 对 MDA-MB-231 三阴性乳腺癌细胞具有更强的抑制作用，对正常乳腺上皮 Eph-ev 细胞毒性较小。HTPMs 通过破坏线粒体膜电位和增强活性氧的形成诱导 MDA-MB-231 细胞周期停滞和凋亡。体内抗肿瘤疗效评价表明，HTPMs 的肿瘤抑制率（68.17%）强于游离 HF，且具有良好的生物相容性。
本研究结果表明，HTPMs 具有治疗三阴性乳腺癌的临床潜力。
