Phloretin–Chitosan Nanoparticles and Tamoxifen: Synergistic Modulation of BRCA Genes and Enhanced Sensitization in Breast Cancer

This study aims to evaluate the therapeutic potential of phloretin–chitosan nanoparticles (Ph-ChNPs), alone and in combination with the anticancer drug tamoxifen, in modulating breast cancer markers and improving in vivo treatment outcomes. Ph-ChNPs were prepared by ionic gelation in the presence of Tripolyphosphate (TPP) solution as a crosslinker agent. The nanoparticles were characterized using DLS, TEM, UV-VIS and FT-IR spectroscopy. In vitro cytotoxic assay of Ph-ChNPs on MCF-7 breast cancer cell lines revealed anticancer activity with an IC50 value of 32.12 ± 1.63 µg/mL. In vivo studies were carried out on mice, treated with DMBA to induce breast cancer and followed the effect of the prepared nanoparticle, either alone or with combination with tamoxifen, on mice health. The biochemical parameters measured after treatment with Ph-ChNPs alone showed an improvement in lipid profile with decreased total cholesterol (TC) and Triglyceride (TG) levels and increased HDL-c levels. Ph-ChNPs significantly reduced IL-6 and cyclin D1 levels, with a slight increase in cyclin E2 levels. Antioxidant enzyme levels were improved, and oxidative stress markers were reduced. The combination treatment showed a synergistic effect in reducing inflammation and cell proliferation. DMBA-injected mice had substantially increased BRCA1 and BRCA2 gene expression. Ph-ChNP-treated mice showed well-organized mammary gland structures, while DMBA-injected mice displayed dense tumor cell aggregations. Ph-ChNPs and tamoxifen treatments improved histopathological variations, with the combination treatment showing significant apoptosis of tumor cells. This study demonstrates the significant potential of Ph-ChNPs combined with tamoxifen in breast cancer treatment. The combination therapy effectively reduces tumor growth, induces apoptosis and modulates critical breast cancer markers, offering a promising therapeutic strategy.