Folic Acid-Conjugated Solid Lipid Nanoparticles for Ratiometric Combination Delivery of Docetaxel and Erlotinib in Triple-Negative Breast Cancer Therapy.

Triple-negative breast cancer (TNBC) is an aggressive subtype with limited therapeutic options and poor clinical outcomes. This study evaluated folic acid-functionalized solid lipid nanoparticles co-loaded with docetaxel and erlotinib (FA-DOC/ERL-SLNs) as an oral targeted therapy for TNBC. FA-DOC/ERL-SLNs exhibited the lowest IC₅₀ values of 0.82 ± 0.05 μM and 0.92 ± 0.03 μM in MDA-MB-231 and 4T1 cells, respectively, with enhanced cellular uptake compared with free drugs and non-targeted SLNs. The formulation also induced higher apoptosis (apoptosis indices of 1.42 and 1.45), greater G2/M cell-cycle arrest, autophagy inhibition, and reduced clonogenicity and migration. Pharmacokinetic studies demonstrated markedly improved oral bioavailability, with AUC₀-t increasing from 1.03 to 45.69 μg·h/mL for docetaxel and from 18.30 to 87.76 μg·h/mL for erlotinib. In 4T1 tumor-bearing mice, FA-DOC/ERL-SLNs reduced tumor volume by approximately 1.5-fold compared with non-targeted SLNs and 2.5-3.0-fold compared with free drugs, without significant body weight loss or systemic toxicity. These findings demonstrate that FA-DOC/ERL-SLNs enhance the efficacy and safety of oral docetaxel-erlotinib combination therapy and represent a promising targeted nanocarrier platform for TNBC treatment.