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HOXB7 siRNA delivered by hybrid nanoparticles and the co-therapy with tamoxifen: promising strategy against hormone receptor positive breast cancer
1 , 1 , 2 , 3 , 1 , 4 , * 4
1  Graduate Program in Biological Sciences, Institute of Biological Sciences, Federal University of Juiz de Fora, Brazil
2  Graduate Program in Pharmaceutical Sciences, Federal University of Juiz de Fora, Brazil
3  Graduate Program in Pharmacy, Federal University of Santa Catarina, Brazil
4  Department of Pharmaceutical Sciences, Federal University of Juiz de Fora, Brazil


Breast cancer is the most common type of cancer that affects and kills women annually in the world. It affects more than two million women and is responsible for the death of approximately 25% of them. Almost 70% of breast cancer diagnosis are positive for hormone receptor and have a good prognosis. However, resistance to drugs used in hormone therapy, such as tamoxifen, is usual and about 40% of recurrences do not respond to it. In some cases, the overexpression of HOXB7 gene is related to this mechanism and its silencing can reverse the response to tamoxifen. Here we used copolymer-coated calcium phosphate nanoparticles to deliver HOXB7 siRNA and restore the sensitization of MCF7 cells to tamoxifen. Nanoparticle synthesis and characterization were performed and cell viability and gene expression were evaluated. Hybrid nanoparticle presented Z-average diameter of 88nm and PdI of 0.1, while showing good entrapment of siRNA molecules. We also observed a decrease in HOXB7 gene expression (~65%) promoted by the siRNA molecule delivered by the nanoparticles. The gene silencing has good correlation to the cell viability assay: a reduction in breast cancer viability was observed in 48 (31%) and 72 (38%) hours. As for the co-treatment with tamoxifen, cell viability started dropping after 15 hours, which did not occur in the treatment only with tamoxifen at the same concentration. This result indicates that the biological effect was possibly related to RNAi effect and suggests that HOXB7 may be promoting cell sensitization to tamoxifen without reducing cell viability. Also, we found that the IC50 of tamoxifen was reduced by about 25% of initial dose when sensitizing MCF7 cells (co-treatment). Overall, these results suggest that the nanoparticles were effective in promoting gene silencing and that the co-therapy can be a promising tool for the treatment of hormone receptor positive breast cancers.

Keywords: RNAi therapy; calcium phosphate; nanoparticles; siRNA; co-therapy