Integrin αvβ3-Targeted SLNs for Co-Delivery of Paclitaxel and Quercetin in Triple-Negative Breast Cancer.

The pronounced therapeutic recalcitrance of triple-negative breast cancer (TNBC) fundamentally stems from its molecular target paucity and aggressive pathophysiology. Although paclitaxel and quercetin (PTX/Q) have been explored as complementary agents, their concurrent use is limited by poor solubility, rapid systemic clearance, and dose-related toxicities. To address these constraints, we developed a C-peptide-functionalized solid lipid nanoparticle (SLN) system designed to enhance the codelivery of PTX and Q to αvβ3-expressing TNBC cells. The optimized SLN-PTX-Q-pep formulation exhibited a spherical morphology, a mean hydrodynamic diameter of approximately 415 nm, and high encapsulation efficiencies for both PTX (96.9 ± 0.6%) and Q (91.8 ± 1.5%). Thermal analysis and fluorescence spectroscopy confirmed that the drugs were molecularly dispersed within the lipid matrix. The formulation demonstrated excellent blood compatibility, with less than 1.5% hemolysis, and exhibited pH-responsive drug release, with accelerated liberation under mildly acidic, tumor-relevant conditions (pH 5.8). In vitro studies on 4T1 TNBC cells revealed that the targeted nanoformulation achieved a lower PTX IC50 value compared to nontargeted controls. Functional assays confirmed enhanced apoptosis (Annexin V staining), reduced cell migration, and suppression of intracellular reactive oxygen species (ROS). Competitive binding assays verified that the peptide-functionalized SLNs specifically interact with the αvβ3 integrin receptor. In vivo, SPECT imaging demonstrated superior tumor accumulation of the targeted nanoparticles. Correspondingly, mice treated with SLN-PTX-Q-pep showed a significant reduction in tumor growth and lower final tumor burdens, with no signs of systemic toxicity as confirmed by stable body weight, serum biochemistry, and histological analysis of major organs. Collectively, these findings establish that C-peptide-functionalized SLNs are a robust platform for the coordinated delivery of PTX and Q, enhancing tumor-targeted accumulation and therapeutic efficacy in a preclinical TNBC model. This work provides a strong basis for the continued development of dual-drug nanocarriers for difficult-to-treat breast cancers.