Actinium chelation and crystallization in a macromolecular scaffold.

Targeted alpha therapy (TAT) pairs the specificity of antigen targeting with the lethality of alpha particles to eradicate cancerous cells. Actinium-225 [225Ac; t1/2 = 9.920(3) days] is an alpha-emitting radioisotope driving the next generation of TAT radiopharmaceuticals. Despite promising clinical results, a fundamental understanding of Ac coordination chemistry lags behind the rest of the Periodic Table due to its limited availability, lack of stable isotopes, and inadequate systems poised to probe the chemical behavior of this radionuclide. In this work, we demonstrate a platform that combines an 8-coordinate synthetic ligand and a mammalian protein to characterize the solution and solid-state behavior of the longest-lived Ac isotope, 227Ac [t1/2 = 21.772(3) years]. We expect these results to direct renewed efforts for 225Ac-TAT development, aid in understanding Ac coordination behavior relative to other +3 lanthanides and actinides, and more broadly inform this element's position on the Periodic Table.

Characterization of two affinity matured Anti-Yersinia pestis F1 human antibodies with medical countermeasure potential.

Yersinia pestis, the causative agent of plague and a biological threat agent, presents an urgent need for novel medical countermeasures due to documented cases of naturally acquired antibiotic resistance and potential person-to-person spread during a pneumonic infection. Immunotherapy has been proposed as a way to circumvent current and future antibiotic resistance. Here, we describe the development and characterization of two affinity matured human antibodies (αF1Ig AM2 and αF1Ig AM8) that promote survival of mice after exposure to aerosolized Y. pestis. We share details of the error prone PCR and yeast display technology-based affinity maturation process that we used. The resultant matured antibodies have nanomolar affinity for Y. pestis F1 antigen, are produced in high yield, and are resilient to 37°C stress for up to 6 months. Importantly, in vitro assays using a murine macrophage cell line demonstrated that αF1Ig AM2 and αF1Ig AM8 are opsonic. Even more importantly, in vivo studies using pneumonic plague mouse models showed that 100% of the mice receiving 500 µg of IgGs αF1Ig AM2 and αF1Ig AM8 survived lethal challenge with aerosolized Y. pestis CO92. Combined, these results provide evidence of the quality and robustness of αF1Ig AM2 and αF1Ig AM8 and support their development as potential medical countermeasures against plague.

Fitting Monte Carlo simulation results with an empirical model of megavoltage x-ray beams for rapid depth dose calculations in water.

Objective. The purpose of this study was to assess a method of accelerating Monte Carlo simulations for modeling depth dose distributions from megavoltage x-ray beams by fitting them to an empirically-derived function.Approach. Using Geant4, multiple simulations of a typical medical linear accelerator beam in water and in water with an air cavity were conducted with varying numbers of initial electrons. The resulting percent depth dose curves were compared to published data from actual linear accelerator measurements. Two methods were employed to reduce computation time for this modeling process. First, an empirical function derived from measurements at a particular linear accelerator energy, source-to-surface distance, and field size was used to directly fit the simulated data. Second, a linear regression was performed to predict the empirical function's parameters for simulations with more initial electrons.Main results. Fitting simulated depth dose curves with the empirical function yielded significant improvements in either accuracy or computation time, corresponding to the two methods described. When compared to published measurements, the maximum error for the largest simulation was 5.58%, which was reduced to 2.01% with the best fit of the function. Fitting the empirical function around the air cavity heterogeneity resulted in errors less than 2.5% at the interfaces. The linear regression prediction modestly improved the same simulation with a maximum error of 4.22%, while reducing the required computation time from 66.53 h to 43.75 h.Significance. This study demonstrates the effective use of empirical functions to expedite Monte Carlo simulations for a range of applications from radiation protection to food sterilization. These results are particularly impactful in radiation therapy treatment planning, where time and accuracy are especially valuable. Employing these methods may improve patient outcomes by ensuring that dose delivery more accurately matches the prescription or by shortening the preparation time before treatment in Monte Carlo-based treatment planning systems.

Ligand-Assisted Direct Lithography of Upconverting and Avalanching Nanoparticles for Nonlinear Photonics.

Upconverting nanoparticles (UCNPs) exhibit unique nonlinear optical properties that can be harnessed in microscopy, sensing, and photonics. However, forming high-resolution nano- and micropatterns of UCNPs with large packing fractions is still challenging. Additionally, there is limited understanding of how nanoparticle patterning chemistries are affected by the particle size. Here, we explore direct patterning chemistries for 6-18 nm Tm3+-, Yb3+/Tm3+-, and Yb3+/Er3+-based UCNPs using ligands that form either new ionic linkages or covalent bonds between UCNPs under ultraviolet (UV), electron-beam (e-beam), and near-infrared (NIR) exposure. We study the effect of UCNP size on these patterning approaches and find that 6 nm UCNPs can be patterned with compact ionic-based ligands. In contrast, patterning larger UCNPs requires long-chain, cross-linkable ligands that provide sufficient interparticle spacing to prevent irreversible aggregation upon film casting. Compared to approaches that use a cross-linkable liquid monomer, our patterning method limits the cross-linking reaction to the ligands bound on UCNPs deposited as a thin film. This highly localized photo-/electron-initiated chemistry enables the fabrication of densely packed UCNP patterns with high resolutions (∼1 µm with UV and NIR exposure; <100 nm with e-beam). Our upconversion NIR lithography approach demonstrates the potential to use inexpensive continuous-wave lasers for high-resolution 2D and 3D lithography of colloidal materials. The deposited UCNP patterns retain their upconverting, avalanching, and photoswitching behaviors, which can be exploited in patterned optical devices for next-generation UCNP applications.

Macrocyclic 1,2-Hydroxypyridinone-Based Chelators as Potential Ligands for Thorium-227 and Zirconium-89 Radiopharmaceuticals.

Thorium-227 (227Th) is an α-emitting radionuclide that has shown preclinical and clinical promise for use in targeted α-therapy (TAT), a type of molecular radiopharmaceutical treatment that harnesses high energy α particles to eradicate cancerous lesions. Despite these initial successes, there still exists a need for bifunctional chelators that can stably bind thorium in vivo. Toward this goal, we have prepared two macrocyclic chelators bearing 1,2-hydroxypyridinone groups. Both chelators can be synthesized in less than six steps from readily available starting materials, which is an advantage over currently available platforms. The complex formation constants (log ßmlh) of these ligands with Zr4+ and Th4+, measured by spectrophotometric titrations, are greater than 34 for both chelators, indicating the formation of exceedingly stable complexes. Radiolabeling studies were performed to show that these ligands can bind [227Th]Th4+ at concentrations as low as 10-6 M, and serum stability experiments demonstrate the high kinetic stability of the formed complexes under biological conditions. Identical experiments with zirconium-89 (89Zr), a positron-emitting radioisotope used for positron emission tomography (PET) imaging, demonstrate that these chelators can also effectively bind Zr4+ with high thermodynamic and kinetic stability. Collectively, the data reported herein highlight the suitability of these ligands for use in 89Zr/227Th paired radioimmunotheranostics.

Siderocalin fusion proteins enable a new 86Y/90Y theranostic approach.

The mammalian protein siderocalin binds bacterial siderophores and their iron complexes through cation-π and electrostatic interactions, but also displays high affinity for hydroxypyridinone complexes of trivalent lanthanides and actinides. In order to circumvent synthetic challenges, the use of siderocalin-antibody fusion proteins is explored herein as an alternative targeting approach for precision delivery of trivalent radiometals. We demonstrate the viability of this approach in vivo, using the theranostic pair 90Y (ß-, t1/2 = 64 h)/86Y (ß+, t1/2 = 14.7 h) in a SKOV-3 xenograft mouse model. Ligand radiolabeling with octadentate hydroxypyridinonate 3,4,3-LI(1,2-HOPO) and subsequent protein binding were achieved at room temperature. The results reported here suggest that the rapid non-covalent binding interaction between siderocalin fusion proteins and the negatively charged Y(iii)-3,4,3-LI(1,2-HOPO) complexes could enable purification-free, cold-kit labeling strategies for the application of therapeutically relevant radiometals in the clinic.

Screening the complex biological behavior of late lanthanides through genome-wide interactions.

Despite their similar physicochemical properties, recent studies have demonstrated that lanthanides can display different biological behaviors. Hence, the lanthanide series can be divided into three parts, namely early, mid, and late lanthanides, based on their interactions with biological systems. In particular, the late lanthanides demonstrate distinct, but poorly understood biological activity. In the current study, we employed genome-wide functional screening to help understand biological effects of exposure to Yb(III) and Lu(III), which were selected as representatives of the late lanthanides. As a model organism, we used Saccharomyces cerevisiae, since it shares many biological functions with humans. Analysis of the functional screening results indicated toxicity of late lanthanides is consistent with disruption of vesicle-mediated transport, and further supported a role for calcium transport processes and mitophagy in mitigating toxicity. Unexpectedly, our analysis suggested that late lanthanides target proteins with SH3 domains, which may underlie the observed toxicity. This study provides fundamental insights into the unique biological chemistry of late lanthanides, which may help devise new avenues toward the development of decorporation strategies and bio-inspired separation processes.

Relative Effects of Radiation-Induced Changes in Bone Mass, Structure, and Tissue Material on Vertebral Strength in a Rat Model.

The observed increased risk of fracture after cancer radiation therapy is presumably due to a radiation-induced reduction in whole-bone strength. However, the mechanisms for impaired strength remain unclear, as the increased fracture risk is not fully explained by changes in bone mass. To provide insight, a small animal model was used to determine how much of this whole-bone weakening effect for the spine is attributable to changes in bone mass, structure, and material properties of the bone tissue and their relative effects. Further, because women have a greater risk of fracture after radiation therapy than men, we investigated if sex had a significant influence on bone's response to irradiation. Fractionated in vivo irradiation (10 × 3 Gy) or sham irradiation (0 Gy) was administered daily to the lumbar spine in twenty-seven 17-week-old Sprague-Dawley rats (n = 6-7/sex/group). Twelve weeks after final treatment, animals were euthanized, and lumbar vertebrae (L4 and L5 ) were isolated. Using a combination of biomechanical testing, micro-CT-based finite element analysis, and statistical regression analysis, we separated out the effect of mass, structural, and tissue material changes on vertebral strength. Compared with the sham group (mean ± SD strength = 420 ± 88 N), the mean strength of the irradiated group was lower by 28% (117 N/420 N, p < 0.0001). Overall, the response of treatment did not differ with sex. By combining results from both general linear regression and finite element analyses, we calculated that mean changes in bone mass, structure, and material properties of the bone tissue accounted for 56% (66 N/117 N), 20% (23 N/117 N), and 24% (28 N/117 N), respectively, of the overall change in strength. As such, these results provide insight into why an elevated clinical fracture risk for patients undergoing radiation therapy is not well explained by changes in bone mass alone. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Radiolytic Evaluation of 3,4,3-LI(1,2-HOPO) in Aqueous Solutions.

The octadentate hydroxypyridinone ligand 3,4,3-LI(1,2-HOPO) (abbreviated as HOPO) has been identified as a promising candidate for both chelation and f-element separation technologies, two applications that require optimal performance in radiation environments. However, the radiation robustness of HOPO is currently unknown. Here, we employ a combination of time-resolved (electron pulse) and steady-state (alpha self-radiolysis) irradiation techniques to elucidate the basic chemistry of HOPO and its f-element complexes in aqueous radiation environments. Chemical kinetics were measured for the reaction of HOPO and its Nd(III) ion complex ([NdIII(HOPO)]-) with key aqueous radiation-induced radical transients (eaq-, H• atom, and •OH and NO3• radicals). The reaction of HOPO with the eaq- is believed to proceed via reduction of the hydroxypyridinone moiety, while transient adduct spectra indicate that reactions with the H• atom and •OH and NO3• radicals proceeded by addition to HOPO's hydroxypyridinone rings, potentially allowing for the generation of an extensive suite of addition products. Complementary steady-state 241Am(III)-HOPO complex ([241AmIII(HOPO)]-) irradiations showed the gradual release of 241Am(III) ions with increasing alpha dose up to 100 kGy, although complete ligand destruction was not observed.

Identifying Toxicity Mechanisms Associated with Early Lanthanide Exposure through Multidimensional Genome-Wide Screening.

Lanthanides are a series of elements essential to a wide range of applications, from clean energy production to healthcare. Despite their presence in multiple products and technologies, their toxicological characteristics have been only partly studied. Recently, our group has employed a genomic approach to extensively characterize the toxicity mechanisms of lanthanides. Even though we identified substantially different behaviors for mid and late lanthanides, the toxicological profiles of early lanthanides remained elusive. Here, we overcome this gap by describing a multidimensional genome-wide toxicogenomic study for two early lanthanides, namely, lanthanum and praseodymium. We used Saccharomyces cerevisiae as a model system since its genome shares many biological pathways with humans. By performing functional analysis and protein-protein interaction network analysis, we identified the main genes and proteins that participate in the yeast response to counter metal harmful effects. Moreover, our analysis also highlighted key enzymes that are dysregulated by early lanthanides, inducing cytotoxicity. Several of these genes and proteins have human orthologues, indicating that they may also participate in the human response against the metals. By highlighting the key genes and proteins in lanthanide-induced toxicity, this work may contribute to the development of new prophylactic and therapeutic strategies against lanthanide harmful exposures.

Evaluation of 134Ce as a PET imaging surrogate for antibody drug conjugates incorporating 225Ac.

INTRODUCTION: The in vivo generator 134Ce/134La has the potential to serve as a PET imaging surrogate for both alpha-emitting 225Ac and 227Th radionuclides due to the unique CeIII/CeIV redox couple and the relatively long half-life of 134Ce. The purpose of this study was to demonstrate the compatibility of 134Ce with DOTA-based antibody drug conjugates, which would act as therapeutic agents when incorporating 225Ac. METHODS: The in vivo biodistributions of [134Ce]Ce-DOTA and [134Ce]Ce-citrate were assayed by microPET imaging over 25 h in Swiss Webster mice to determine the in vivo stability of the [134Ce]Ce-DOTA complex. L3-edge X-ray absorption spectroscopy measurements were used to confirm the Ce oxidation state and the formation of a fully coordinated Ce-DOTA complex. The in vivo biodistribution of [134Ce]Ce-DOTA-Trastuzumab was assayed over 147 h by microPET imaging in SK-OV-3 tumor-bearing NOD SCID mice to evaluate tumor uptake and in vivo stability. Mice were euthanized at 214 h after administration of the radiolabeled antibody conjugate, and imaged 1 h later. An ex vivo biodistribution experiment was then performed in order to corroborate the PET images. RESULTS: [134Ce]Ce-DOTA displayed rapid renal elimination and high in vivo stability over 25 h, with negligible bone and liver uptake, in comparison to [134Ce]Ce-citrate. L3-edge X-ray absorption spectroscopy experiments confirmed the 3+ oxidation state within the stable Ce-DOTA complex. MicroPET images of [134Ce]Ce-DOTA-Trastuzumab displayed elevated tumor uptake over 214 h, with minimal bone and liver uptake analogous to previously reported [225Ac]Ac-DOTA-Trastuzumab biodistribution results, and the ex vivo biodistribution of [134Ce]Ce-DOTA-Trastuzumab corroborated the final PET images. CONCLUSION: These results demonstrate that 134Ce allows for long-term tumor targeting with DOTA-based antibody drug conjugates and may therefore be used to trace antibody drug conjugates incorporating 225Ac.

In situ beam reduction of Pu(IV) and Bk(IV) as a route to trivalent transuranic coordination complexes with hydroxypyridinone chelators.

The solution-state interactions of plutonium and berkelium with the octadentate chelator 3,4,3-LI(1,2-HOPO) (343-HOPO) were investigated and characterized by X-ray absorption spectroscopy, which revealed in situ reductive decomposition of the tetravalent species of both actinide metals to yield Pu(III) and Bk(III) coordination complexes. X-ray absorption near-edge structure (XANES) measurements were the first indication of in situ synchrotron redox chemistry as the Pu threshold and white-line position energies for Pu-343-HOPO were in good agreement with known diagnostic Pu(III) species, whereas Bk-343-HOPO results were found to mirror the XANES behavior of Bk(III)-DTPA. Extended X-ray absorption fine structure results revealed An-OHOPO bond distances of 2.498 (5) and 2.415 (2) Šfor Pu and Bk, respectively, which match well with bond distances obtained for trivalent actinides and 343-HOPO via density functional theory calculations. Pu(III)- and Bk(III)-343-HOPO data also provide initial insight into actinide periodicity as they can be compared with previous results with Am(III)-, Cm(III)-, Cf(III)-, and Es(III)-343-HOPO, which indicate there is likely an increase in 5f covalency and heterogeneity across the actinide series.

Precision Engineering of 2D Protein Layers as Chelating Biogenic Scaffolds for Selective Recovery of Rare-Earth Elements.

Rare-earth elements, which include the lanthanide series, are key components of many clean energy technologies, including wind turbines and photovoltaics. Because most of these 4f metals are at high risk of supply chain disruption, the development of new recovery technologies is necessary to avoid future shortages, which may impact renewable energy production. This paper reports the synthesis of a non-natural biogenic material as a potential platform for bioinspired lanthanide extraction. The biogenic material takes advantage of the atomically precise structure of a 2D crystalline protein lattice with the high lanthanide binding affinity of hydroxypyridinonate chelators. Luminescence titration data demonstrated that the engineered protein layers have affinities for all tested lanthanides in the micromolar-range (dissociation constants) and a higher binding affinity for the lanthanide ions with a smaller ionic radius. Furthermore, competitive titrations confirmed the higher selectivity (up to several orders of magnitude) of the biogenic material for lanthanides compared to other cations commonly found in f-element sources. Lastly, the functionalized protein layers could be reused in several cycles by desorbing the bound metal with citrate solutions. Taken together, these results highlight biogenic materials as promising bioadsorption platforms for the selective binding of lanthanides, with potential applications in the recovery of these critical elements from waste.

Delineating toxicity mechanisms associated with MRI contrast enhancement through a multidimensional toxicogenomic profiling of gadolinium.

Gadolinium is a metal used in contrast agents for magnetic resonance imaging. Although gadolinium is widely used in clinical settings, many concerns regarding its toxicity and bioaccumulation after gadolinium-based contrast agent administration have been raised and published over the last decade. To date, most toxicological studies have focused on identifying acute effects following gadolinium exposure, rather than investigating associated toxicity mechanisms. In this study, we employ functional toxicogenomics to assess mechanistic interactions of gadolinium with Saccharomyces cerevisiae. Furthermore, we determine which mechanisms are conserved in humans, and their implications for diseases related to the use of gadolinium-based contrast agents in medicine. A homozygous deletion pool of 4291 strains were screened to identify biological functions and pathways disturbed by the metal. Gene ontology and pathway enrichment analyses showed endocytosis and vesicle-mediated transport as the main yeast response to gadolinium, while certain metabolic processes, such as glycosylation, were the primary disrupted functions after the metal treatments. Cluster and protein-protein interaction network analyses identified proteins mediating vesicle-mediated transport through the Golgi apparatus and the vacuole, and vesicle cargo exocytosis as key components to reduce the metal toxicity. Moreover, the metal seemed to induce cytotoxicity by disrupting the function of enzymes (e.g. transferases and proteases) and chaperones involved in metabolic processes. Several of the genes and proteins associated with gadolinium toxicity are conserved in humans, suggesting that they may participate in pathologies linked to gadolinium-based contrast agent exposures. We thereby discuss the potential role of these conserved genes and gene products in gadolinium-induced nephrogenic systemic fibrosis, and propose potential prophylactic strategies to prevent its adverse health effects.

The enduring legacy of Marie Curie: impacts of radium in 21st century radiological and medical sciences.

PURPOSE: This review is focused on radium and radionuclides in its decay chain in honor of Marie Curie, who discovered this element. MATERIALS AND METHODS: We conglomerated current knowledge regarding radium and its history predating our present understanding of this radionuclide. RESULTS: An overview of the properties of radium and its dose assessment is shown followed by discussions about both the negative detrimental and positive therapeutic applications of radium with this history and its evolution reflecting current innovations in medical science. CONCLUSIONS: We hope to remind all those who are interested in the progress of science about the vagaries of the process of scientific discovery. In addition, we raise the interesting question of whether Marie Curie's initial success was in part possible due to her tight alignment with her husband Pierre Curie who pushed the work along.

Development of radiopharmaceuticals for targeted alpha therapy: Where do we stand?

Targeted alpha therapy is an oncological treatment, where cytotoxic doses of alpha radiation are locally delivered to tumor cells, while the surrounding healthy tissue is minimally affected. This therapeutic strategy relies on radiopharmaceuticals made of medically relevant radionuclides chelated by ligands, and conjugated to targeting vectors, which promote the drug accumulation in tumor sites. This review discusses the state-of-the-art in the development of radiopharmaceuticals for targeted alpha therapy, breaking down their key structural components, such as radioisotope, targeting vector, and delivery formulation, and analyzing their pros and cons. Moreover, we discuss current drawbacks that are holding back targeted alpha therapy in the clinic, and identify ongoing strategies in field to overcome those issues, including radioisotope encapsulation in nanoformulations to prevent the release of the daughters. Lastly, we critically discuss potential opportunities the field holds, which may contribute to targeted alpha therapy becoming a gold standard treatment in oncology in the future.

Multidimensional genome-wide screening in yeast provides mechanistic insights into europium toxicity.

Europium is a lanthanide metal that is highly valued in optoelectronics. Even though europium is used in many commercial products, its toxicological profile has only been partially characterized, with most studies focusing on identifying lethal doses in different systems or bioaccumulation in vivo. This paper describes a genome-wide toxicogenomic study of europium in Saccharomyces cerevisiae, which shares many biological functions with humans. By using a multidimensional approach and functional and network analyses, we have identified a group of genes and proteins associated with the yeast responses to ameliorate metal toxicity, which include metal discharge paths through vesicle-mediated transport, paths to regulate biologically relevant cations, and processes to reduce metal-induced stress. Furthermore, the analyses indicated that europium promotes yeast toxicity by disrupting the function of chaperones and cochaperones, which have metal-binding sites. Several of the genes and proteins highlighted in our study have human orthologues, suggesting they may participate in europium-induced toxicity in humans. By identifying the endogenous targets of europium as well as the already existing paths that can decrease its toxicity, we can determine specific genes and proteins that may help to develop future therapeutic strategies.

ThIV-Desferrioxamine: characterization of a fluorescent bacterial probe.

Diversifying our ability to guard against emerging pathogenic threats is essential for keeping pace with global health challenges, including those presented by drug-resistant bacteria. Some modern diagnostic and therapeutic innovations to address this challenge focus on targeting methods that exploit bacterial nutrient sequestration pathways, such as the desferrioxamine (DFO) siderophore used by Staphylococcus aureus (S. aureus) to sequester FeIII. Building on recent studies that have shown DFO to be a versatile vehicle for chemical delivery, we show proof-of-principle that the FeIII sequestration pathway can be used to deliver a potential radiotherapeutic. Our approach replaces the FeIII nutrient sequestered by H4DFO+ with ThIV and made use of a common fluorophore, FITC, which we covalently bonded to DFO to provide a combinatorial probe for simultaneous chelation paired with imaging and spectroscopy, H3DFO_FITC. Combining insight provided from FITC-based imaging with characterization by NMR spectroscopy, we demonstrated that the fluorescent DFO_FITC conjugate retained the ThIV chelation properties of native H4DFO+. Fluorescence microscopy with both [Th(DFO_FITC)] and [Fe(DFO_FITC)] complexes showed similar uptake by S. aureus and increased intercellular accumulation as compared to the FITC and unchelated H3DFO_FITC controls. Collectively, these results demonstrate the potential for the newly developed H3DFO_FITC conjugate to be used as a targeting vector and bacterial imaging probe for S. aureus. The results presented within provide a framework to expand H4DFO+ and H3DFO_FITC to relevant radiotherapeutics (like 227Th).

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.