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Open Access Publications from the University of California

Engineered recognition of tetravalent zirconium and thorium by chelator-protein systems: Toward flexible radiotherapy and imaging platforms

  • Author(s): Captain, I
  • Deblonde, GJP
  • Rupert, PB
  • An, DD
  • Illy, MC
  • Rostan, E
  • Ralston, CY
  • Strong, RK
  • Abergel, RJ
  • et al.

© 2016 American Chemical Society. Targeted α therapy holds tremendous potential as a cancer treatment: it offers the possibility of delivering a highly cytotoxic dose to targeted cells while minimizing damage to surrounding healthy tissue. The metallic α-generating radioisotopes225Ac and227Th are promising radionuclides for therapeutic use, provided adequate chelation and targeting. Here we demonstrate a new chelating platform composed of a multidentate high-affinity oxygen-donating ligand 3,4,3-LI(CAM) bound to the mammalian protein siderocalin. Respective stability constants log β110= 29.65 ± 0.65, 57.26 ± 0.20, and 47.71 ± 0.08, determined for the EuIII(a lanthanide surrogate for AcIII), ZrIV, and ThIVcomplexes of 3,4,3-LI(CAM) through spectrophotometric titrations, reveal this ligand to be one of the most powerful chelators for both trivalent and tetravalent metal ions at physiological pH. The resulting metal-ligand complexes are also recognized with extremely high affinity by the siderophore-binding protein siderocalin, with dissociation constants below 40 nM and tight electrostatic interactions, as evidenced by X-ray structures of the protein:ligand:metal adducts with ZrIVand ThIV. Finally, differences in biodistribution profiles between free and siderocalin-bound238PuIV-3,4,3-LI(CAM) complexes confirm in vivo stability of the protein construct. The siderocalin:3,4,3-LI(CAM) assembly can therefore serve as a "lock" to consolidate binding to the therapeutic225Ac and227Th isotopes or to the positron emission tomography emitter89Zr, independent of metal valence state.

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