Lipid-chondroitin sulfate conjugate modified PLGA nanocarriers of salinomycin for enhanced TRAIL-mediated apoptosis in triple negative breast cancer.

Triple-negative breast cancer (TNBC), characterized by the absence of estrogen receptors, progesterone receptors, and HER2 expression, is an aggressive subtype with limited treatment options, underscoring the need for novel therapeutic strategies. This study presents the development of chondroitin sulfate-conjugated, octadecylamine-modified PLGA lipid-polymer hybrid nanoparticles (CS-SAL-LPNPs) for targeted delivery of salinomycin (SAL), a Wnt/β-catenin pathway inhibitor, to sensitize TNBC cells to apoptosis induced by TRAIL through targeted CD44 receptor-mediated uptake. Successful nanoparticle conjugation was confirmed using FTIR and NMR spectroscopy, yielding nanoparticles of 172.36 ± 5.24 nm with a zeta potential of - 26.84 ± 0.25 mV, optimal for cellular uptake and stability. The cellular uptake of CS-SAL-LPNPs was significantly enhanced, as confirmed by confocal microscopy and flow cytometry, showing a statistically significant (p < 0.05; n ≥ 3) 1.45-fold higher fluorescence intensity compared to non-targeted systems. CS-SAL-LPNPs exhibited potent cytotoxicity, with a IC of 3.5 µM, and effectively modulated apoptosis-related protein expression by downregulating anti-apoptotic proteins such as Bcl-2 and survivin while upregulating the pro-apoptotic protein caspase-3. These changes indicate disruption of the Wnt/β-catenin signaling pathway, enhancing TRAIL-mediated apoptosis in TNBC cells. These findings demonstrate promising in vitro therapeutic efficacy of CS-SAL-LPNPs, warranting further preclinical in vivo studies for comprehensive validation.