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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 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 β 110= 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 consolidatemore » binding to the therapeutic 225Ac and 227Th isotopes or to the positron emission tomography emitter 89Zr, independent of metal valence state.« less

Authors:
 [1];  [1];  [2];  [1];  [1];  [1];  [3];  [2];  [1]
  1. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Chemical Sciences Division
  2. Fred Hutchinson Cancer Research Center, Seattle, WA (United States). Division of Basic Sciences
  3. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Berkeley Center for Structural Biology
Publication Date:
Research Org.:
Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22). Chemical Sciences, Geosciences & Biosciences Division; National Institutes of Health (NIH); ParisTech, Paris (France); Orano, Paris (France)
OSTI Identifier:
1458481
Grant/Contract Number:  
AC02-05CH11231; R01DK073462
Resource Type:
Accepted Manuscript
Journal Name:
Inorganic Chemistry
Additional Journal Information:
Journal Volume: 55; Journal Issue: 22; Related Information: © 2016 American Chemical Society.; Journal ID: ISSN 0020-1669
Publisher:
American Chemical Society (ACS)
Country of Publication:
United States
Language:
English
Subject:
62 RADIOLOGY AND NUCLEAR MEDICINE

Citation Formats

Captain, Ilya, Deblonde, Gauthier J. -P., Rupert, Peter B., An, Dahlia D., Illy, Marie-Claire, Rostan, Emeline, Ralston, Corie Y., Strong, Roland K., and Abergel, Rebecca J. Engineered Recognition of Tetravalent Zirconium and Thorium by Chelator–Protein Systems: Toward Flexible Radiotherapy and Imaging Platforms. United States: N. p., 2016. Web. doi:10.1021/acs.inorgchem.6b02041.
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. Engineered Recognition of Tetravalent Zirconium and Thorium by Chelator–Protein Systems: Toward Flexible Radiotherapy and Imaging Platforms. United States. doi:10.1021/acs.inorgchem.6b02041.
Captain, Ilya, Deblonde, Gauthier J. -P., Rupert, Peter B., An, Dahlia D., Illy, Marie-Claire, Rostan, Emeline, Ralston, Corie Y., Strong, Roland K., and Abergel, Rebecca J. Tue . "Engineered Recognition of Tetravalent Zirconium and Thorium by Chelator–Protein Systems: Toward Flexible Radiotherapy and Imaging Platforms". United States. doi:10.1021/acs.inorgchem.6b02041. https://www.osti.gov/servlets/purl/1458481.
@article{osti_1458481,
title = {Engineered Recognition of Tetravalent Zirconium and Thorium by Chelator–Protein Systems: Toward Flexible Radiotherapy and Imaging Platforms},
author = {Captain, Ilya and Deblonde, Gauthier J. -P. and Rupert, Peter B. and An, Dahlia D. and Illy, Marie-Claire and Rostan, Emeline and Ralston, Corie Y. and Strong, Roland K. and Abergel, Rebecca J.},
abstractNote = {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 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 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.},
doi = {10.1021/acs.inorgchem.6b02041},
journal = {Inorganic Chemistry},
number = 22,
volume = 55,
place = {United States},
year = {2016},
month = {11}
}

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Cited by: 9 works
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Figures / Tables:

Figure 1 Figure 1: Complexation of MIII and MIV by the hexadentate siderophore enterobactin or the octadentate synthetic analogues 3,4,3-LI(CAM) or 3,4,3-LI(1,2-HOPO), when deprotonated. Polyamine scaffolds and metal-binding oxygen atoms are highlighted in blue and red, respectively.

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    Figures/Tables have been extracted from DOE-funded journal article accepted manuscripts.