This study investigates the efficacy of phytochemical nanoformulations-specifically curcumin and thymoquinone delivered via gold nanoparticles (AuNPs)-against melanoma A375 cells in both 2D and 3D bioprinted gelatin-alginate scaffolds. Phytochemicals such as curcumin, thymoquinone, EGCG, and betulin exhibit multi-target anticancer effects, but their clinical translation is limited by poor solubility, rapid metabolism, and low tumor penetration. We compared free phytochemicals, AuNP co-administration, and AuNP-phytochemical conjugates, assessing their effects on viability, ROS generation, and mitochondrial membrane potential over time. In 2D cultures, all agents exhibited dose-dependent cytotoxicity, with curcumin and thymoquinone proving to be the most potent. However, in 3D scaffolds mimicking tumor microenvironments, only AuNP-phytochemical conjugates sustained mitochondrial and redox stress, overcoming adaptation barriers and providing durable suppression of melanoma viability.Free and co-administered agents displayed metabolic rebound and limited efficacy due to diffusion constraints and ECM-driven resistance. Our findings demonstrate that nanoformulation, especially via conjugation, is crucial for maintaining prolonged pharmacological pressure in 3D tumor-like contexts, highlighting the importance of delivery strategy and microenvironment in preclinical development of phytochemical-based melanoma therapies.
Kirac et al. (Mon,) studied this question.