title: Engineered Recognition of Tetravalent Zirconium and Thorium by Chelator-Protein Systems: Toward Flexible Radiotherapy and Imaging Platforms.
abstract: 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.
authors: Chemical Sciences Division, Lawrence Berkeley National Laboratory , Berkeley, California 94720, United States.
authors: Ilya
authors: I
authors: Captain
authors: Chemical Sciences Division, Lawrence Berkeley National Laboratory , Berkeley, California 94720, United States.
authors: Gauthier J-P
authors: GJ
authors: Deblonde
authors: Division of Basic Sciences, Fred Hutchinson Cancer Research Center , Seattle, Washington 98109, United States.
authors: Peter B
authors: PB
authors: Rupert
authors: Chemical Sciences Division, Lawrence Berkeley National Laboratory , Berkeley, California 94720, United States.
authors: Dahlia D
authors: DD
authors: An
authors: Chemical Sciences Division, Lawrence Berkeley National Laboratory , Berkeley, California 94720, United States.
authors: Marie-Claire
authors: MC
authors: Illy
authors: Chemical Sciences Division, Lawrence Berkeley National Laboratory , Berkeley, California 94720, United States.
authors: Emeline
authors: E
authors: Rostan
authors: Berkeley Center for Structural Biology, Lawrence Berkeley National Laboratory , Berkeley, California 94720, United States.
authors: Corie Y
authors: CY
authors: Ralston
authors: Division of Basic Sciences, Fred Hutchinson Cancer Research Center , Seattle, Washington 98109, United States.
authors: Roland K
authors: RK
authors: Strong
authors: Chemical Sciences Division, Lawrence Berkeley National Laboratory , Berkeley, California 94720, United States.
authors: Rebecca J
authors: RJ
authors: Abergel
mesh_terms: D000818:Animals; D002614:Chelating Agents / Q000737:chemistry*; D056831:Coordination Complexes / Q000737:chemistry* / Q000493:pharmacokinetics; D005260:Female; D008024:Ligands; D051379:Mice; D008956:Models, Chemical; D011506:Proteins / Q000737:chemistry*; D011878:Radiotherapy / Q000379:methods*; D013910:Thorium / Q000737:chemistry*; D014018:Tissue Distribution; D015040:Zirconium / Q000737:chemistry*
chemical_list: D002614:Chelating Agents; D056831:Coordination Complexes; D008024:Ligands; D011506:Proteins; D013910:Thorium; D015040:Zirconium