Metallofullerenol Inhibits Cellular Iron Uptake by Inducing Transferrin Tetramerization

Herein, A549 tumor cell proliferation was confirmed to be positively dependent on the concentration of Fe³⁺ or transferrin (Tf). Gd@C₈₂(OH)₂₂ or C₆₀(OH)₂₂ effectively inhibited the iron uptake and the subsequent proliferation of A549 cells. The conformational changes of Tf mixed with FeCl₃, GdCl₃, C₆₀(OH)₂₂ or Gd@C₈₂(OH)₂₂ were obtained by SAXS. The results demonstrate that Tf homodimers can be decomposed into monomers in the presence of FeCl₃, GdCl₃ or C₆₀(OH)₂₂, but associated into tetramers in the presence of Gd@C₈₂(OH)₂₂. The larger change of SAXS shapes between Tf+C₆₀(OH)₂₂ and Tf+FeCl₃ implies that C₆₀(OH)₂₂ is bound to Tf, blocking the iron‐binding site. The larger deviation of the SAXS shape from a possible crystal structure of Tf tetramer implies that Gd@C₈₂(OH)₂₂ is bound to the Tf tetramer, thus disturbing iron transport. This study well explains the inhibition mechanism of Gd@C₈₂(OH)₂₂ and C₆₀(OH)₂₂ on the iron uptake and the proliferation of A549 tumor cells and highlights the specific interactions of a nanomedicine with the target biomolecules in cancer therapy.