Abstract
AIMS: This study aimed to develop optimized doxorubicin (DOX) and pterostilbene (PTS) co-loaded solid lipid nanoparticles (SLNs) for synergistic triple-negative breast cancer (TNBC) therapy, enhancing drug stability, tumor targeting, and therapeutic efficacy. MATERIALS & METHODS: Calibration curves for DOX and PTS were validated. Synergy was assessed in MDA-MB-231 cells via Combination Index (CI) and Loewe-HSA models. SLNs were optimized using Box-Behnken Design (BBD), evaluating lipid content, surfactant concentration, and sonication time. Formulations were characterized by Zetasizer, high-resolution transmission electron microscopy (HR-TEM), Fourier-transform infrared (FTIR), X-ray powder diffraction (XRD), and differential scanning calorimetry (DSC). In in-vitro cytotoxicity, Reactive Oxygen Species (ROS) generation, apoptosis, and mitochondrial depolarization were assessed. Pharmacokinetics and tumor regression were studied in rats. RESULTS: The optimal 1:4 (DOX:PTS) ratio showed strong synergy (CI = 0.83). BBD-optimized SLNs had 97.92 nm size, high entrapment (DOX: 54.%; PTS: 77.5%), and pH-responsive release (78.78% DOX at pH 5.5). SLNs exhibited enhanced cytotoxicity (IC₅₀ = 0.833 µg/mL), elevated ROS (59.5%), and apoptosis induction. In in-vivo, SLNs prolonged circulation, increased tumor accumulation, and reduced tumor volume (701.50 ± 11.83 mm(3) vs. 3506.58 ± 17.06 mm(3) control). CONCLUSIONS: DOX-PTS SLNs demonstrated synergistic anticancer effects, improved stability, and targeted delivery, offering a promising strategy for TNBC treatment.