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 Ac andTh 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 β = 29.65 ± 0.65, 57.26 ± 0.20, and 47.71 ± 0.08, determined for the Eu (a lanthanide surrogate for Ac), Zr, and Th 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 Zr and Th. Finally, differences in biodistribution profiles between free and siderocalin-bound Pu-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 Ac andTh isotopes or to the positron emission tomography emitter Zr, independent of metal valence state.

The Iron Tug-of-War between Bacterial Siderophores and Innate Immunity

“…lanthanide and actinide, and act in concert with Lcn2 to facilitate transport and elimination of such toxic elements [88]. Intriguingly, one study demonstrates that the siderophore-Lcn2 complex could be engineered as a vehicle to deliver radioisotopes into tumors for imaging and radiotherapy [89]. Such findings herald the prospect of engineering siderophores and Lcn2 into multi-target therapeutics capable of treating diseases associated with iron, zinc, copper or heavy metal poisoning, and also cancers.…”

Investigation of the complexation of natZr(iv) and 89Zr(iv) by hydroxypyridinones for the development of chelators for PET imaging applications

“…24 These recent advances have led to the first hydroxamate based bifunctional chelators that provide 89 Zr complexes with improved in vivo stability compared to DFB 25,26 . Alternatively, chelators bearing catechols, 27,28 phosphonates 29 or 3,2-HOPOs 30 have also been proposed. The development of HOPO based chelators for nuclear imaging application is not new and several examples of chelators for 67 Ga or 68 Ga complexation have been reported over the recent years.…”

211At-labeled immunoconjugate via a one-pot three-component double click strategy: practical access to α-emission cancer radiotherapeutics

“…α-Emitters, including 225 Ac, with a half-life of 10 days, 223 Ra, with a half-life of 11.4 days, and 227 Th, with a half-life of 18.7 days, are favored for use in radiotherapy techniques involving targeted molecules, such as radioimmunoconjugates, because of their long half-lives 11. Efficient chelators of these radionuclides must be developed before such applications may be realized 12,1314,15 and several approaches to preparing 211 At-labeled molecules for cancer targeting have been explored.…”