Metallofullerenol Inhibits Cellular Iron Uptake by Inducing Transferrin Tetramerization

Abstract

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.

Keywords: cancer therapy; iron uptake; nanomedicine; small-angle X-ray scattering; transferrin.