Tumor-Responsive PLGA-SS-HA Nanoparticles for Zinc Complex Delivery Suppress Prostate Cancer via TR3/FTH1 Pathway

Abstract

Therapeutic resistance and redox imbalance remain major challenges in advanced prostate cancer, necessitating targeted delivery with pathway-specific strategies. In the present work, we designed a tumor-specific PLGA-SS-HA nanoparticle proposed for the controlled delivery of zinc complexes to modulate the TR3/FTH1 pathway. The amphiphilic conjugate forms nanoparticles of approximately 80 nm in diameter. The disulfide bond allows for the triggered delivery of Zn²⁺ (80%–90% within 24 h) in the presence of glutathione under reductive conditions, while preventing premature release under physiological conditions. PLGA-SS-HA@Zn demonstrated enhanced anticancer efficacy compared with free ZnPPIX, reducing IC₅₀ values to 30–38 µg/mL in PC-3 cells and 35–42 µg/mL in DU-145 cells, whereas normal RWPE-1 cells exhibited IC₅₀ values >70 µg/mL, indicating selective cytotoxicity. At a mechanistic level, there is clear evidence of a significant accumulation of ROS, loss of mitochondrial membrane potential, and apoptosis in more than 60% of the cells. At a molecular level, treatment induced ∼3-fold upregulation of TR3 and Bax, suppression of FTH1 and Bcl-2, and robust activation of cleaved caspase-3 and PARP, confirming engagement of the intrinsic apoptotic pathway. Together, this redox-sensitive nanoplatform enhances zinc-mediated oxidative stress and selectively suppresses prostate cancer, providing a mechanistically defined therapeutic strategy.