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

Abstract

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.

Orally Administered Halofuginone-Loaded TPGS Polymeric Micelles Against Triple-Negative Breast Cancer: Enhanced Absorption and Efficacy with Reduced Toxicity and Metastasis

“…The optimal formulation of HTPM had an HD of 17.8 ± 0.5 nm ( Figure 2A ), which contributes to the penetration of and/or interaction with dense microvilli (microvillus diameter ∼100 nm). 17 In addition, the PDI of HTPM was 0.212 ± 0.1, suggesting its high homogeneity. A recent investigation has shown that the ZP of drug-free TPGS polymer micelles was negative.…”

“… 27 Herein, HTPM have been successfully prepared by the thin-film hydration method ( Figure 1 ), as reported previously. 17 For oral delivery, the particle size and surface charge of the self-assembled micelles appear to be the most important parameters, which greatly influence the transport route of micelles through the intestinal epithelium membrane and determine their stability. 40 Thus, the HD, PDI, and ZP were determined by DLS.…”

“… 27 Herein, HTPM were prepared using the thin-film hydration method as reported previously. 17 Briefly, HF and TPGS were first dissolved in methanol to obtain the transparent organic phase. Then, the organic phase was gradually evaporated to form a thin film on the surface of the distillation flask.…”

“…13–16 Recently, we have demonstrated that encapsulating HF in TPGS polymeric micelles (HTPM) enhance the efficacy against subcutaneous TNBC xenografts of nude mice after intravenous administration. 17 However, oral administration is a considerably more convenient route and is often more acceptable to patients, especially for those who need to receive medications repeatedly, but is not always as efficient as other, more invasive routes. Generally, the kinetics of drug absorption and distribution may vary significantly between the different routes of administration, and bioavailability following oral administration may be relatively lower.…”

Emergence of Nanotechnology as a Powerful Cavalry against Triple-Negative Breast Cancer (TNBC)

“…They also exhibited enhanced tumor growth inhibition (68.17%) in comparison to free drugs. Hence it was concluded that polymeric micelles hold significant clinical potential for the treatment of TNBC [ 258 ].…”