Engineered Recognition of Tetravalent Zirconium and Thorium by Chelator–Protein Systems: Toward Flexible Radiotherapy and Imaging Platforms
journal contributionposted on 01.11.2016, 17:49 by Ilya Captain, Gauthier J.-P. Deblonde, Peter B. Rupert, Dahlia D. An, Marie-Claire Illy, Emeline Rostan, Corie Y. Ralston, Roland K. Strong, Rebecca J. Abergel
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 radioisotopes 225Ac and 227Th 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 ThIV complexes 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 ZrIV and ThIV. Finally, differences in biodistribution profiles between free and siderocalin-bound 238PuIV-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 therapeutic 225Ac and 227Th isotopes or to the positron emission tomography emitter 89Zr, independent of metal valence state.
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metal valence stateligandprotein siderocalinTh IVRespective stability constants log β 110Tetravalent ZirconiumX-ray structurestetravalent metal ionsTh IV complexespositron emission tomography emitter 89 Zr225 Acchelating platformradioisotopes 225 Acvivo stabilitycytotoxic dosebiodistribution profilesEu IIIFlexible Radiotherapysiderophore-binding protein siderocalinZr IVLI227 Th isotopesImaging Platforms Targeted α therapyEngineered Recognitioncancer treatment40 nMdissociation constants227 Th