Ferroptotic cancer therapy has been extensively investigated since the coining of the ferroptosis concept. However, the therapeutic efficacy of ferroptosis induction in heterogeneous and plastic melanoma has been compromised because the melanocytic and transitory cell subpopulation is resistant to iron-dependent oxidative stress. The Research Group at SPST recently reported a phenotype-altering liposomal nanomedicine to enable the ferroptosis-resistant subtypes of melanoma cells to be vulnerable to lipid peroxidation via senescence induction. The strategy involves the ratiometric co-encapsulation of a cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor (palbociclib) and a ferroptosis inducer (auranofin) within cRGD peptide-modified targeted liposomes. Both drugs showed a synergistic anti-cancer effect in the model B16F10 melanoma cells, as evidenced by the combination index analysis (< 1). The liposomes could efficiently deliver both drugs into B16F10 cells in a targeted manner. Afterward, the liposomes potently induced the intracellular redox imbalance and lipid peroxidation. Palbociclib significantly provoked cell cycle arrest at the G0/G1 phase, which sensitized auranofin-caused ferroptosis through senescence induction. Meanwhile, palbociclib depleted intracellular glutathione (GSH) and reduced nicotinamide adenine dinucleotide phosphate (NADPH), further boosting ferroptosis (Fig. 1). The proof-of-concept was also demonstrated in the B16F10 tumor-bearing mice model. The current work offers a promising ferroptosis-targeting strategy for effectively treating heterogeneous melanoma by manipulating cellular plasticity.

This work has been published in ACS Nano.

https://pubs.acs.org/doi/full/10.1021/acsnano.3c10142

Fig 1. Schematic illustration of reversing ferroptosis resistance in melanoma cells by targeted liposomes.