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Abstract
Purpose
Hormone-dependent breast cancer is the most common form of breast cancer, and inhibiting 17β-HSD1 can play an attractive role in decreasing estrogen and cancer cell proliferation. However, the majority of existing inhibitors have been developed from estrogens and inevitably possess residual estrogenicity. siRNA knockdown provides a highly specific way to block a targeted enzyme, being especially useful to avoid estrogenicity. Application of 17β-HSD1-siRNA in vivo is limited by the establishment of an animal model, as well as the potential nuclease activity in vivo. We tried to reveal the in vivo potential of 17β-HSD1-siRNA-based breast cancer therapy.
Materials and methods
To establish a competent animal model, daily subcutaneous injection of an estrone micellar aqueous solution was adopted to provide the substrate for estradiol biosynthesis. The effects of three different doses of estrone (0.1, 0.5, and 2.5 µg/kg/day) on tumor growth in T47D-17β-HSD1-inoculated group were investigated and compared with the animals inoculated with wild type T47D cells. To solve in vivo delivery problem of siRNA, “17β-HSD1-siRNA/LPD”, a PEGylated and modified liposome–polycation–DNA nanoparticle containing 17β-HSD1-siRNA was prepared by the thin film hydration method and postinsertion technology. Finally, “17β-HSD1-siRNA/LPD” was tested in the optimized model. Tumor growth and 17β-HSD1 expression were assessed.
Results
Comparison with the untreated group revealed significant suppression of tumor growth in “17β-HSD1-siRNA/LPD”-treated group when HSD17B1 gene expression was knocked down.
Conclusion
These findings showed promising in vivo assessments of 17β-HSD1-siRNA candidates. This is the first report of an in vivo application of siRNA for steroid-converting enzymes in a nude mouse model.
Acknowledgments
This work was supported by the National Key Technologies R & D Program of China during the 13th Five-Year Plan Period (grant No. 2016YFC1000902), the Major Key Basic Research Fundamental Program of Shanghai Science and Technology Committee (grant No. 14JC1492300), the Scientific Research Project of Shanghai Municipal Health and Family Planning Commission (grant number: 20144Y0049) and Shanghai Biomedical Science and Technology Support Projects (grant number: 14431902000). The authors thank Dr Qianxi Zhu from Shanghai Institute of Planned Parenthood Research for the great help in the statistical analysis and Dr Muriel Kelly for the help in English language improvement of the manuscript.
Disclosure
The authors report no conflicts of interest in this work.