Engineered Recognition of Tetravalent Zirconium and Thorium by Chelator–Protein Systems: Toward Flexible Radiotherapy and Imaging Platforms

Captain, Ilya; Deblonde, Gauthier J. -P.; Rupert, Peter B.; An, Dahlia D.; Illy, Marie-Claire; Rostan, Emeline; Ralston, Corie Y.; Strong, Roland K.; Abergel, Rebecca J.

doi:10.1021/acs.inorgchem.6b02041

Engineered Recognition of Tetravalent Zirconium and Thorium by Chelator–Protein Systems: Toward Flexible Radiotherapy and Imaging Platforms

Journal Article · Tue Nov 01 00:00:00 EDT 2016 · Inorganic Chemistry

DOI:https://doi.org/10.1021/acs.inorgchem.6b02041· OSTI ID:1458481

Captain, Ilya ^[1]; Deblonde, Gauthier J. -P. ^[1]; Rupert, Peter B. ^[2]; An, Dahlia D. ^[1]; Illy, Marie-Claire ^[1]; Rostan, Emeline ^[1]; Ralston, Corie Y. ^[3]; Strong, Roland K. ^[2]; Abergel, Rebecca J. ^[1]

Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Chemical Sciences Division
Fred Hutchinson Cancer Research Center, Seattle, WA (United States). Division of Basic Sciences
Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Berkeley Center for Structural Biology

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. In this work, 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 Eu^III(a lanthanide surrogate for Ac^III), Zr^IV, and Th^IVcomplexes 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 Zr^IV and Th^IV. Finally, differences in biodistribution profiles between free and siderocalin-bound ²³⁸Pu^IV-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.

View Accepted Manuscript (DOE)

Research Organization:: Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22). Chemical Sciences, Geosciences & Biosciences Division; National Inst. of Health (NIH); ParisTech, Paris (France); Orano, Paris (France)

Grant/Contract Number:: AC02-05CH11231

OSTI ID:: 1458481

Journal Information:: Inorganic Chemistry, Journal Name: Inorganic Chemistry Journal Issue: 22 Vol. 55; ISSN 0020-1669

Publisher:: American Chemical Society (ACS)Copyright Statement

Country of Publication:: United States

Language:: English

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