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 ß110 = 21.8(4) for 3,4,3-LI(1,2-HOPO) and log ß120 = 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.

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.

Efficient discrimination of transplutonium actinides by in vivo models.

Transplutonium actinides are among the heaviest elements whose macroscale chemical properties can be experimentally tested. Being scarce and hazardous, their chemistry is rather unexplored, and they have traditionally been considered a rather homogeneous group, with most of their characteristics extrapolated from lanthanide surrogates. Newly emerged applications for these elements, combined with their persistent presence in nuclear waste, however, call for a better understanding of their behavior in complex living systems. In this work, we explored the biodistribution and excretion profiles of four transplutonium actinides (248Cm, 249Bk, 249Cf and 253Es) in a small animal model, and evaluated their in vivo sequestration and decorporation by two therapeutic chelators, diethylenetriamine pentaacetic acid and 3,4,3-LI(1,2-HOPO). Notably, the organ deposition patterns of those transplutonium actinides were element-dependent, particularly in the liver and skeleton, where lower atomic number radionuclides showed up to 7-fold larger liver/skeleton accumulation ratios. Nevertheless, the metal content in multiple organs was significantly decreased for all tested actinides, particularly in the liver, after administering the therapeutic agent 3,4,3-LI(1,2-HOPO) post-contamination. Lastly, the systematic comparison of the radionuclide biodistributions showed discernibly element-dependent organ depositions, which may provide insights into design rules for new bio-inspired chelating systems with high sequestration and separation performance.

From early prophylaxis to delayed treatment: Establishing the plutonium decorporation activity window of hydroxypyridinonate chelating agents.

The potential consequences of a major radiological event are not only large-scale external radiation exposure of the population, but also uncontrolled dissemination of, and internal contamination with, radionuclides. When planning an emergency response to radiological and nuclear incidents, one must consider the need for not only post-exposure treatment for contaminated individuals, but also prophylactic measures to protect the workforce facing contaminated areas and patients in the aftermath of such events. In addition to meeting the desired criteria for post-exposure treatments such as safety, ease of administration, and broad-spectrum efficacy against multiple radionuclides and levels of challenge, ideal prophylactic countermeasures must include rapid onset; induce minimal to no performance-decrementing side effects; be compatible with current military Chemical, Biological, Radiological, Nuclear, and Explosive countermeasures; and require minimal logistical burdens. Hydroxypyridinone-based actinide decorporation agents have shown the most promise as decorporation strategies for various radionuclides of concern, including the actinides plutonium and americium. The studies presented here probe the extent of plutonium decorporation efficacy for two chelating agents, 3,4,3-LI(1,2-HOPO) and 5-LIO(Me-3,2-HOPO), from early pre-exposure time points to a delay of up to 7 days in parenteral or oral treatment administration, i.e., well beyond the initial hours of emergency response. Despite delayed treatment after a contamination event, both ligands clearly enhanced plutonium elimination through the investigated 7-day post-treatment period. In addition, a remarkable prophylactic efficacy was revealed for 3,4,3-LI(1,2-HOPO) with treatment as early as 48 h before the plutonium challenge. This work provides new perspectives in the indication and use of experimental actinide decorporation treatments.

Synthesis and initial evaluation for in vivo chelation of Pu(IV) of a mixed octadentate spermine-based ligand containing 4-carbamoyl-3-hydroxy-1-methyl-2(1H)-pyridinone and 6-carbamoyl-1-hydroxy-2(1H)-pyridinone.

An improved synthesis for a series of 1-hydroxy-2(1H)-pyridinone-based octadentate ligands is reported. The mixed chelate, octadentate ligand, 3,4,3-LI(1,2-Me-3,2-HOPO), was designed, synthesized, and tested for in vivo chelation of Pu in a mouse model. This ligand incorporates both 1,2-HOPO and Me-3,2-HOPO metal chelating units; the latter has higher affinity toward actinide ions than does 1,2-HOPO at physiological pH. Injected or administered orally to fasted or normally fed mice at the standard clinical dose 30 micromol/kg, both 3,4,3-LI(1,2-HOPO) and 3,4,3-LI(1,2-Me-3,2-HOPO) remove significantly more Pu than injected CaNa(3)DTPA. Injected doses of 0.1 micromol/kg of these HOPO ligands are as effective as 30 micromol/kg of injected CaNa(3)DTPA. Ten daily injections of 30 micromol/kg of a HOPO ligand did not induce detectable acute toxicity in mice. The mixed HOPO ligand is somewhat more effective than 3,4,3-LI(1,2-HOPO) when given orally, and the enhanced reduction of liver Pu by the mixed ligand is statistically significant. Thus, both octadentate HOPO ligands meet the criterion of low toxicity at doses that are more effective than the standard dose of CaNa(3)DTPA. Their improved effectiveness at low dose along with great oral activity (despite low gastrointestinal absorption) implies that new treatment regimens can be developed using the HOPO ligands alone or as adjuncts to CaNa(3)DTPA therapy, which will greatly exceed the amount of Pu excretion that is achievable with CaNa(3)DTPA alone.

Dose-dependent efficacy and safety toxicology of hydroxypyridinonate actinide decorporation agents in rodents: towards a safe and effective human dosing regimen.

Two hydroxypyridinone-containing actinide decorporation agents, 3,4,3-LI(1,2-HOPO) and 5-LIO(Me-3,2-HOPO), are being developed for the treatment of internal actinide contamination by chelation therapy. Dose-response efficacy profiles in mice were established for the removal of intravenously injected (238)Pu and (241)Am after parenteral and oral treatment with these chelators. In both cases, presumed efficacious doses promoted substantially greater actinide elimination rates than the currently approved agent, diethylenetriamine-pentaacetic acid, considering two different interspecies scaling methods for the conversion of human doses to equivalent rodent dose levels. In addition, genotoxicity of both ligands was assessed using the Salmonella/ Escherichia coli /microsome plate incorporation test and the Chinese hamster ovary cell chromosome aberration assay, showing that neither ligand is genotoxic, in the presence and absence of metabolic activation. Finally, maximum tolerated dose studies were performed in rats for seven consecutive daily oral administrations with the chelators, confirming the safety of the presumed efficacious doses for 3,4,3-LI(1,2-HOPO) and 5-LIO(Me-3,2-HOPO). The results of these studies add to the growing body of evidence that both decorporation agents have remarkable decorporation efficacy properties and promising safety toxicology profiles. These results are necessary components of the regulatory approval process and will help determine the optimal human dosing regimens for the treatment of internal radionuclide contamination.

3,4,3-LI(1,2-HOPO): in vitro formation of highly stable lanthanide complexes translates into efficacious in vivo europium decorporation.

The spermine-based hydroxypyridonate octadentate chelator 3,4,3-LI(1,2-HOPO) was investigated for its ability to act as an antenna that sensitizes the emission of Sm(III), Eu(III), and Tb(III) in the Visible range (Φ(tot) = 0.2-7%) and the emission of Pr(III), Nd(III), Sm(III), and Yb(III) in the Near Infra-Red range, with decay times varying from 1.78 µs to 805 µs at room temperature. The particular luminescence spectroscopic properties of these lanthanide complexes formed with 3,4,3-LI(1,2-HOPO) were used to characterize their respective solution thermodynamic stabilities as well as those of the corresponding La(III), Gd(III), Dy(III), Ho(III), Er(III), Tm(III), and Lu(III) complexes. The remarkably high affinity of 3,4,3-LI(1,2-HOPO) for lanthanide metal ions and the resulting high complex stabilities (pM values ranging from 17.2 for La(III) to 23.1 for Yb(III)) constitute a necessary but not sufficient criterion to consider this octadentate ligand an optimal candidate for in vivo metal decorporation. The in vivo lanthanide complex stability and decorporation capacity of the ligand were assessed, using the radioactive isotope (152)Eu 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 metal chelating agent.

Biomimetic actinide chelators: an update on the preclinical development of the orally active hydroxypyridonate decorporation agents 3,4,3-LI(1,2-HOPO) and 5-LIO(Me-3,2-HOPO).

The threat of a dirty bomb or other major radiological contamination presents a danger of large-scale radiation exposure of the population. Because major components of such contamination are likely to be actinides, actinide decorporation treatments that will reduce radiation exposure must be a priority. Current therapies for the treatment of radionuclide contamination are limited and extensive efforts must be dedicated to the development of therapeutic, orally bioavailable, actinide chelators for emergency medical use. Using a biomimetic approach based on the similar biochemical properties of plutonium(IV) and iron(III), siderophore-inspired multidentate hydroxypyridonate ligands have been designed and are unrivaled in terms of actinide-affinity, selectivity, and efficiency. A perspective on the preclinical development of two hydroxypyridonate actinide decorporation agents, 3,4,3-LI(1,2-HOPO) and 5-LIO(Me-3,2-HOPO), is presented. The chemical syntheses of both candidate compounds have been optimized for scale-up. Baseline preparation and analytical methods suitable for manufacturing large amounts have been established. Both ligands show much higher actinide-removal efficacy than the currently approved agent, diethylenetriaminepentaacetic acid (DTPA), with different selectivity for the tested isotopes of plutonium, americium, uranium and neptunium. No toxicity is observed in cells derived from three different human tissue sources treated in vitro up to ligand concentrations of 1 mM, and both ligands were well tolerated in rats when orally administered daily at high doses (>100 micromol kg d) over 28 d under good laboratory practice guidelines. Both compounds are on an accelerated development pathway towards clinical use.