Development of Stearic Acid Nanoemulsion for Therapeutic Delivery of Talazoparib Against Breast Cancer.

Objectives: Talazoparib (TZL) is a potent PARP inhibitor but suffers from poor aqueous solubility, dissolution-limited absorption, and dose-limiting systemic toxicities, which together restrict its antitumor efficacy in some breast cancer settings. This study aimed to develop a stearic acid-based nanoemulsion (SANE) to improve the delivery of TZL and enhance its antitumor activity and preliminarily explore its impact on DNA damage response-related pathways. Methods: SANE-TZL was prepared using a high-pressure homogenization method, and its physicochemical properties were characterized. MCF-7 and MDA-MB-231 breast cancer cells were used to evaluate cellular uptake, cytotoxicity, and changes in key DNA damage response markers. In vivo therapeutic efficacy and safety were assessed in an MDA-MB-231 xenograft mouse model. Results: SANE-TZL exhibited a uniform particle size of approximately 118 nm with excellent stability. In MCF-7 cells, SANE-TZL significantly enhanced drug internalization, resulting in an 8.4-fold reduction in IC50 compared to free TZL. Consistently, in MDA-MB-231 cells, SANE-TZL also showed markedly increased antiproliferative activity. At the molecular level, SANE-TZL modulated the expression of several DNA damage response-related genes, including BRCA1, RAD51, and SLFN11, in a manner consistent with impaired DNA repair capacity. In vivo, high-dose SANE-TZL achieved a tumor growth inhibition (TGI) rate of 58.55%, which was higher than that of the free TZL group (41.86%) and the blank eSANE group (17.59%). No evident hematological or organ toxicities were observed in the SANE-TZL-treated groups. Conclusions: SANE-TZL markedly improves the delivery efficiency and antitumor activity of TZL in breast cancer models while maintaining a favorable safety profile. By combining a functional stearic acid carrier with TZL, this nanoemulsion formulation represents a safe and potent strategy to enhance PARP inhibitor-based chemotherapy in breast cancer, and it may provide a basis for further mechanistic studies on DNA damage response modulation.