Search Results (5)

Incorporation of lanthanide (Ln) and actinide (An) ions into the human body poses significant chemotoxic and radiotoxic risks, necessitating effective decorporation strategies. This study investigates the displacement of biologically relevant ligands from trivalent ions of europium, Eu(III), and curium, Cm(III), in artificial biofluids by various complexing agents, i.e., ethylenediaminetetraacetic acid (EDTA), ethylene glycol-bis(β-aminoethyl ether)-N,N,N′,N′-tetraacetic acid (EGTA), diethylenetriaminepentaacetic acid (DTPA), and spermine-based hydroxypyridonate chelator 3,4,3-LI(1,2-HOPO) (HOPO). Utilizing a modified unified bioaccessibility method (UBM) to simulate gastrointestinal conditions, we conducted concentration-dependent displacement experiments at both room and body temperatures. Time-resolved laser-induced fluorescence spectroscopy (TRLFS) supported by ²H nuclear magnetic resonance (NMR) spectroscopy and thermodynamic modelling revealed the complexation efficacy of the agents under physiological conditions. Results demonstrate that high affinity, governed by complex stability constants and ligand pK_a values, is critical to overcome cation and anion competition and leads to effective decorporation. Additionally, there is evidence that cyclic ligands are inferior to linear ligands for this application. HOPO and DTPA exhibited superior displacement efficacy, particularly in the complete gastrointestinal tract simulation. This study highlights the utility of in vitro workflows for evaluating decorporation agents and emphasizes the need for ligands with optimal binding characteristics for enhanced chelation therapies. Full article

Inhalation of aerosolized uranium is recognized as a principal mode of exposure, posing significant risks of damage to the lungs, kidneys, and other vital organs. To enhance nuclide elimination from the body, chelating agents are employed; however, single-component chelators often exhibit limited spectral activity and low effectiveness, resulting in toxicologically relevant concentrations. We have developed a composite chelating agent composed of 3,4,3-Li(1,2-HOPO), DFP, and HEDP in optimized ratios, demonstrating marked improvements in eliminating inhaled uranium. The selection of these components was initially guided by an agarose gel dynamics method, focusing on uranium binding and removal efficacy. Optimization of the formula was conducted through response surface methodology in a cellular model. The compound’s ability to enhance survival rates in mice subjected to acute uranium inhalation was confirmed, showing a dose-dependent improvement in survival in severely affected mice. Comparative assessments indicated that this multifaceted chelating agent substantially surpasses the uranium tissue clearance achieved by individual chelating agents. Full article

The octadentate hydroxypyridonate ligand 3,4,3-LI(1,2-HOPO) (t-HOPO) shows strong binding affinity with actinide cations and is considered as a promising decorporation agent used to eliminate in vivo actinides, while its dynamics in its unbound and bound states in the condensed phase remain unclear. In this work, by means of MD simulations, the folding dynamics of intact t-HOP^O in its neutral (t-HOPO0) and in its deprotonated state (t-HOPO⁴⁻) were studied. The results indicated that the deprotonation of t-HOPO in the aqueous phase significantly narrowed the accessible conformational space under the simulated conditions, and it was prepared in a conformation that could conveniently clamp the cations. The simulation of U^IV-t-HOPO showed that the tetravalent uranium ion was deca-coordinated with eight ligating O atoms from the t-HOPO⁴⁻ ligand, and two from aqua ligands. The strong electrostatic interaction between the U⁴⁺ ion and t-HOPO⁴⁻ further diminished the flexibility of t-HOPO⁴⁻ and confined it in a limited conformational space. The strong interaction between the U4+ ion and t-HOPO⁴⁻ was also implicated in the shortened residence time of water molecules. Full article

⁸⁹Zr represents a highly favorable positron emitter for application in immuno-PET (Positron Emission Tomography) imaging. Clinically, the ⁸⁹Zr⁴⁺ ion is introduced into antibodies by complexation with desferrioxamine B. However, producing complexes of limited kinetic inertness. Therefore, several new chelators for ⁸⁹Zr introduction have been developed over the last years. Of these, the direct comparison of the most relevant ones for clinical translation, DFO* and 3,4,3-(LI-1,2-HOPO), is still missing. Thus, we directly compared DFO with DFO* and 3,4,3-(LI-1,2-HOPO) immunoconjugates to identify the most suitable agent stable ⁸⁹Zr-complexation. The chelators were introduced into cetuximab, and an optical analysis method was developed, enabling the efficient quantification of derivatization sites per protein. The cetuximab conjugates were efficiently obtained and radiolabeled with ⁸⁹Zr at 37 °C within 30 min, giving the [⁸⁹Zr]Zr-cetuximab derivatives in high radiochemical yields and purities of >99% as well as specific activities of 50 MBq/mg. The immunoreactive fraction of all ⁸⁹Zr-labeled cetuximab derivatives was determined to be in the range of 86.5–88.1%. In vivo PET imaging and ex vivo biodistribution studies in tumor-bearing animals revealed a comparable and significantly higher kinetic inertness for both [⁸⁹Zr]Zr-3,4,3-(LI-1,2-HOPO)-cetuximab and [⁸⁹Zr]Zr-DFO*-cetuximab, compared to [⁸⁹Zr]Zr-DFO-cetuximab. Of these, [⁸⁹Zr]Zr-DFO*-cetuximab showed a considerably more favorable pharmacokinetic profile with significantly lower liver and spleen retention than [⁸⁹Zr]Zr-3,4,3-(LI-1,2-HOPO)-cetuximab. Since [⁸⁹Zr]Zr-DFO* demonstrates a very high kinetic inertness, paired with a highly favorable pharmacokinetic profile of the resulting antibody conjugate, DFO* currently represents the most suitable chelator candidate for stable ⁸⁹Zr-radiolabeling of antibodies and clinical translation. Full article

In this work, five different chelating agents, namely DFO, CTH-36, DFO*, 3,4,3-(LI-1,2-HOPO) and DOTA-GA, were compared with regard to the relative kinetic inertness of their corresponding ⁸⁹Zr complexes to evaluate their potential for in vivo application and stable ⁸⁹Zr complexation. The chelators were identically functionalized with tetrazines, enabling a fully comparable, efficient, chemoselective and biorthogonal conjugation chemistry for the modification of any complementarily derivatized biomolecules of interest. A small model peptide of clinical relevance (TCO-c(RGDfK)) was derivatized via iEDDA click reaction with the developed chelating agents (TCO = trans-cyclooctene and iEDDA = inverse electron demand Diels-Alder). The bioconjugates were labeled with ⁸⁹Zr⁴⁺, and their radiochemical properties (labeling conditions and efficiency), logD_(7.4), as well as the relative kinetic inertness of the formed complexes, were compared. Furthermore, density functional theory (DFT) calculations were conducted to identify potential influences of chelator modification on complex formation and geometry. The results of the DFT studies showed—apart from the DOTA-GA derivative—no significant influence of chelator backbone functionalization or the conjugation of the chelator tetrazines by iEDDA. All tetrazines could be efficiently introduced into c(RGDfK), demonstrating the high suitability of the agents for efficient and chemoselective bioconjugation. The DFO-, CTH-36- and DFO*-modified c(RGDfK) peptides showed a high radiolabeling efficiency under mild reaction conditions and complete ⁸⁹Zr incorporation within 1 h, yielding the ⁸⁹Zr-labeled analogs as homogenous products. In contrast, 3,4,3-(LI-1,2-HOPO)-c(RGDfK) required considerably prolonged reaction times of 5 h for complete radiometal incorporation and yielded several different ⁸⁹Zr-labeled species. The labeling of the DOTA-GA-modified peptide was not successful at all. Compared to [⁸⁹Zr]Zr-DFO-, [⁸⁹Zr]Zr-CTH-36- and [⁸⁹Zr]Zr-DFO*-c(RGDfK), the corresponding [⁸⁹Zr]Zr-3,4,3-(LI-1,2-HOPO) peptide showed a strongly increased lipophilicity. Finally, the relative stability of the ⁸⁹Zr complexes against the EDTA challenge was investigated. The [⁸⁹Zr]Zr-DFO complex showed—as expected—a low kinetic inertness. Unexpectedly, also, the [⁸⁹Zr]Zr-CTH-36 complex demonstrated a high susceptibility against the challenge, limiting the usefulness of CTH-36 for stable ⁸⁹Zr complexation. Only the [⁸⁹Zr]Zr-DFO* and the [⁸⁹Zr]Zr-3,4,3-(LI-1,2-HOPO) complexes demonstrated a high inertness, qualifying them for further comparative in vivo investigation to determine the most appropriate alternative to DFO for clinical application. Full article