Dahlia D. An

Actinide chelation: biodistribution and in vivo complex stability of the targeted metal ions.

Because of the continuing use of nuclear fuel sources and heightened threats of nuclear weapon use, the amount of produced and released radionuclides is increasing daily, as is the risk of larger human exposure to fission product actinides. A rodent model was used to follow the in vivo distribution of representative actinides, administered as free metal ions or complexed with chelating agents including diethylenetriamine pentaacetic acid (DTPA) and the hydroxypyridinonate ligands 3,4,3-LI(1,2-HOPO) and 5-LIO(Me-3,2-HOPO). Different metabolic pathways for the different metal ions were evidenced, resulting in intricate ligand- and metal-dependent decorporation mechanisms. While the three studied chelators are known for their unrivaled actinide decorporation efficiency, the corresponding metal complexes may undergo in vivo decomposition and release metal ions in various biological pools. This study sets the basis to further explore the metabolism and in vivo coordination properties of internalized actinides for the future development of viable therapeutic chelating agents.

Siderocalin-mediated recognition, sensitization, and cellular uptake of actinides.

Significance The release of actinides in the environment, particularly after a nuclear power plant accident or the potential use of a radiological dispersal device, is a public health threat, as all actinides are radioactive and will trigger damage once internalized by the human body. The biological chemistry of actinide metal ions is largely unknown and new approaches to the understanding of pathways underlying contamination are needed. This work identifies a new mammalian pathway for the intracellular delivery of the radioactive toxic metal ions that are actinides, through the protein siderocalin. Spectroscopic tools, including X-ray diffraction and luminescence, provided insights on the coordination of these metal ions, which is crucial to devise new strategies for decontamination. Synthetic radionuclides, such as the transuranic actinides plutonium, americium, and curium, present severe health threats as contaminants, and understanding the scope of the biochemical interactions involved in actinide transport is instrumental in managing human contamination. Here we show that siderocalin, a mammalian siderophore-binding protein from the lipocalin family, specifically binds lanthanide and actinide complexes through molecular recognition of the ligands chelating the metal ions. Using crystallography, we structurally characterized the resulting siderocalin–transuranic actinide complexes, providing unprecedented insights into the biological coordination of heavy radioelements. In controlled in vitro assays, we found that intracellular plutonium uptake can occur through siderocalin-mediated endocytosis. We also demonstrated that siderocalin can act as a synergistic antenna to sensitize the luminescence of trivalent lanthanide and actinide ions in ternary protein–ligand complexes, dramatically increasing the brightness and efficiency of intramolecular energy transfer processes that give rise to metal luminescence. Our results identify siderocalin as a potential player in the biological trafficking of f elements, but through a secondary ligand-based metal sequestration mechanism. Beyond elucidating contamination pathways, this work is a starting point for the design of two-stage biomimetic platforms for photoluminescence, separation, and transport applications.

Chelation and stabilization of berkelium in oxidation state + IV

Berkelium (Bk) has been predicted to be the only transplutonium element able to exhibit both +III and +IV oxidation states in solution, but evidence of a stable oxidized Bk chelate has so far remained elusive. Here we describe the stabilization of the heaviest 4+ ion of the periodic table, under mild aqueous conditions, using a siderophore derivative. The resulting Bk(IV) complex exhibits luminescence via sensitization through an intramolecular antenna effect. This neutral Bk(IV) coordination compound is not sequestered by the protein siderocalin-a mammalian metal transporter-in contrast to the negatively charged species obtained with neighbouring trivalent actinides americium, curium and californium (Cf). The corresponding Cf(III)-ligand-protein ternary adduct was characterized by X-ray diffraction analysis. Combined with theoretical predictions, these data add significant insight to the field of transplutonium chemistry, and may lead to innovative Bk separation and purification processes.

Highly Luminescent and Stable Hydroxypyridinonate Complexes: A Step Towards New Curium Decontamination Strategies

The photophysical properties, solution thermodynamics, and in vivo complex stabilities of Cm(III) complexes formed with multidentate hydroxypyridinonate ligands, 3,4,3-LI(1,2-HOPO) and 5-LIO(Me-3,2-HOPO), are reported. Both chelators were investigated for their ability to act as antenna chromophores for Cm(III), leading to highly sensitized luminescence emission of the metal upon complexation, with long lifetimes (383 and 196 μs for 3,4,3-LI(1,2-HOPO) and 5-LIO(Me-3,2-HOPO), respectively) and remarkable quantum yields (45 % and 16 %, respectively) in aqueous solution. The bright emission peaks were used to probe the electronic structure of the 5f complexes and gain insight into ligand field effects; they were also exploited to determine the high (and proton-independent) stabilities of the corresponding Cm(III) complexes (log β110 = 21.8(4) for 3,4,3-LI(1,2-HOPO) and log β120 = 24.5(5) for 5-LIO(Me-3,2-HOPO)). The in vivo complex stability for both ligands was assessed by using (248) Cm as a tracer in a rodent model, which provided a direct comparison with the in vitro thermodynamic results and demonstrated the great potential of 3,4,3-LI(1,2-HOPO) as a therapeutic Cm(III) decontamination agent.

Significance of Single Variables in Defining Adequate Animal Models to Assess the Efficacy of New Radionuclide Decorporation Agents: Using the Contamination Dose as an Example

Strategy, Management and Health Policy Enabling Technology, Genomics, Proteomics Preclinical Research Preclinical Development Toxicology, Formulation Drug Delivery, Pharmacokinetics Clinical Development Phases I‐III Regulatory, Quality, Manufacturing Postmarketing Phase IV

238Pu elimination profiles after delayed treatment with 3,4,3LI(1,2HOPO) in female and male Swiss-Webster mice

Abstract Purpose: To characterize the dose-dependent and sex-related efficacy of the hydroxypyridinonate decorporation agent 3,4,3-LI(1,2-HOPO) at enhancing plutonium elimination when post-exposure treatment is delayed. Materials and methods: Six parenteral dose levels of 3,4,3-LI(1,2-HOPO) from 1–300 μmol/kg were evaluated for decorporating plutonium in female and male Swiss-Webster mice administered a soluble citrate complex of 238Pu and treated 24 hours later. Necropsies were scheduled at four time-points (2, 4, 8, and 15 days post-contamination) for the female groups and at three time-points (2, 4, and 8 days post-contamination) for the male groups. Results: Elimination enhancement was dose-dependent in the 1–100 μmol/kg dose range at all necropsy time-points, with some significant reductions in full body and tissue content for both female and male animals. The highest dose level resulted in slight toxicity, with a short recovery period, which delayed excretion of the radionuclide. Conclusions: While differences were noted between the female and male cohorts in efficacy range and recovery times, all groups displayed sustained dose-dependent 238Pu elimination enhancement after delayed parenteral treatment with 3,4,3-LI(1,2-HOPO), the actinide decorporation agent under development.

Biodistribution of the Multidentate Hydroxypyridinonate Ligand [14C]‐3,4,3‐LI(1,2‐HOPO), a Potent Actinide Decorporation Agent

Preclinical Research

Evaluating the potential of chelation therapy to prevent and treat gadolinium deposition from MRI contrast agents

Several MRI contrast agent clinical formulations are now known to leave deposits of the heavy metal gadolinium in the brain, bones, and other organs of patients. This persistent biological accumulation of gadolinium has been recently recognized as a deleterious outcome in patients administered Gd-based contrast agents (GBCAs) for MRI, prompting the European Medicines Agency to recommend discontinuing the use of over half of the GBCAs currently approved for clinical applications. To address this problem, we find that the orally-available metal decorporation agent 3,4,3-LI(1,2-HOPO) demonstrates superior efficacy at chelating and removing Gd from the body compared to diethylenetriaminepentaacetic acid, a ligand commonly used in the United States in the GBCA Gadopentetate (Magnevist). Using the radiotracer 153Gd to obtain precise biodistribution data, the results herein, supported by speciation simulations, suggest that the prophylactic or post-hoc therapeutic use of 3,4,3-LI(1,2-HOPO) may provide a means to mitigate Gd retention in patients requiring contrast-enhanced MRI.