Engineered pluronic nanomicelles containing ATRA and sodium butyrate for selective TNBC differentiation therapy

We formulated a micellar nanosystem for selective differentiation therapy of breast cancer stem cells (BCSCs). Hyaluronic acid (HA) coating was used to target CD44⁺ BCSCs, while codelivery of all-trans retinoic acid (ATRA) and histone deacetylase inhibitor (HDACi) was used to revert epigenetic silencing of the RARβ gene, sensitizing resistant tumor cells to treatment. Nanomicelles were formulated using the thin‑film hydration (TFH) method. The anti-cancer effects of nanoparticles (NPs) were evaluated on MDA-MB-231, MDA-MB-468, MCF-7 and MCF10-A cell lines with different stemness properties. The size of the NPs HA-PF127@ATRA, HA-PF127@SB and HA-PF127@ATRA@SB were determined to be 32.02 nm, 47.46 nm and 52.10 nm, respectively. HA-PF127@ATRA@SB NPs mitigated ATRA resistance in MDA-MB-231 cells, significantly inhibited migration, promoted maximum spheroid size reduction, and achieved lower IC₅₀ values compared to the blank drugs. Importantly, it reduced stemness markers ALDH1A1, CD24 and restored retinoic acid receptor beta (RARβ) gene expression in MDA-MB-231 cells, whereas opposite trends were observed in MDA‑MB‑468 and MCF‑7 cells. Finally, nanomicell therapy favored the induction of late apoptosis in MDA-MB-231 cells, while most of the MDA-MB-468 and MCF-7 cells were in the early apoptosis phase. The nanomicelles demonstrate favorable physicochemical characteristics, and elicit maximum and tumor-specific anti-cancer effects based on differentiation therapy upon BCSC-enriched tumors.