Engineered Recognition of Tetravalent Zirconium and Thorium by Chelator-Protein Systems: Toward Flexible Radiotherapy and Imaging Platforms.
Inorg Chem
; 55(22): 11930-11936, 2016 Nov 21.
Article
en En
| MEDLINE
| ID: mdl-27802058
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 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 ß110 = 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 proteinligandmetal 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 siderocalin3,4,3-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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Base de datos:
MEDLINE
Asunto principal:
Radioterapia
/
Circonio
/
Proteínas
/
Quelantes
/
Torio
/
Complejos de Coordinación
Límite:
Animals
Idioma:
En
Revista:
Inorg Chem
Año:
2016
Tipo del documento:
Article
País de afiliación:
Estados Unidos