Title:MPEG-PCL Nanomicelles Platform for Synergistic Metformin and Chrysin Delivery
to Breast Cancer in Mice
Volume: 22
Issue: 2
Author(s): Daiqin Luo*, Xinjun Wang*, Xiaomei Zhong, Jianying Chang, Mingyuan He, Heran Wang, Yongxia Li, Chaofen Zhao, Yan Luo and Li Ran*
Affiliation:
- Department of Oncology, Affiliated Hospital of Guizhou Medical University /Department of Oncology, Guizhou Cancer Hospital,
Gui Yang, GuiZhou, 550004, China
- Clinical Research Center, The Affiliated Hospital of Guizhou Medical University, Guiyang,
Guizhou, 550004, China
- Department of Oncology, Affiliated Hospital of Guizhou Medical University /Department of Oncology, Guizhou Cancer Hospital,
Gui Yang, GuiZhou, 550004, China
Keywords:
Breast cancer, chrysin, metformin, micelle, synergistic effect, hTERT.
Abstract: Background: Metformin (MET) is a well-known anti-diabetic drug that also has anti-cancer effects. However,
high therapeutic doses of MET on cancer cells and the low efficacy of combinatory therapeutic approaches limit
its clinical application. Recent studies have shown that chrysin (CHR) can improve the pharmaceutical efficacy of
MET by suppressing human telomerase reverse transcriptase (hTERT) and cyclin D1 gene expression.
Objective: This study aimed to develop different ratios of methoxy poly(ethylene glycol)-b-poly(e-caprolactone)
(MPEG-PCL) micelles for breast cancer to co-deliver a synergistic CHR/MET combination.
Methods: CHR/MET drug-loaded micelles were prepared by modified thin-film hydration.Fourier infrared spectrum,
gel permeation chromatography, transmission electron microscopy, and high-performance liquid chromatography were
used to evaluate the physicochemical properties of nanostructures. Cell proliferation and cell apoptosis were assessed
by MTT and Annexin V-FITC/PI double staining method. The gene expression of hTERT and cyclin D1 was measured
by real-time PCR assay. A subcutaneous mouse T47D xenograft model was established to evaluate the in vivo efficiency.
Results: When the ratio of MPEG-PCL was 1:1.7, the highest drug loading rate and encapsulation efficiency of CHR
(11.31±0.37) and MET (12.22±0.44) were observed. Uniform MPEG-PCL micelles of 51.70±1.91 nm allowed MET to
incorporate with CHR, which were co-delivered to breast cancer cells. We demonstrated that CHR/MET co-delivery
micelles showed a good synergistic effect on inhibiting proliferation in T47D cells (combination index=0.87) by suppressing
hTERT and cyclin D1 gene expression. Compared to the free CHR/MET group, the apoptosis rate on T47D
cells by CHR/MET nano-micelles significantly improved from 71.33% to 79.25%. The tumour volume and tumour
weight of the CHR/MET group increased more slowly than that of the single-drug treatment group (P<0.05). Compared
to the CHR/MET group, the tumour volume and tumour weight of the CHR/MET nano-micelle group decreased
by 42% and 59%, respectively.
Conclusion: We demonstrated that ratiometric CHR/MET micelles could provide an effective technique for the treatment
of breast cancer.
