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PurposeMultiple myeloma is a plasma cell malignancy with an unmet clinical need for improved imaging methods and therapeutics. Recently, we identified CD46 as an overexpressed therapeutic target in multiple myeloma and developed the antibody YS5, which targets a cancer-specific epitope on this protein. We further developed the CD46-targeting PET probe [89Zr]Zr-DFO-YS5 for imaging and [225Ac]Ac-DOTA-YS5 for radiopharmaceutical therapy of prostate cancer. These prior studies suggested the feasibility of the CD46 antigen as a theranostic target in multiple myeloma. Herein, we validate [89Zr]Zr-DFO-YS5 for immunoPET imaging and [225Ac]Ac-DOTA-YS5 for radiopharmaceutical therapy of multiple myeloma in murine models.Experimental designIn vitro saturation binding was performed using the CD46 expressing MM.1S multiple myeloma cell line. ImmunoPET imaging using [89Zr]Zr-DFO-YS5 was performed in immunodeficient (NSG) mice bearing subcutaneous and systemic multiple myeloma xenografts. For radioligand therapy, [225Ac]Ac-DOTA-YS5 was prepared, and both dose escalation and fractionated dose treatment studies were performed in mice bearing MM1.S-Luc systemic xenografts. Tumor burden was analyzed using BLI, and body weight and overall survival were recorded to assess antitumor effect and toxicity.Results[89Zr]Zr-DFO-YS5 demonstrated high affinity for CD46 expressing MM.1S multiple myeloma cells (Kd = 16.3 nmol/L). In vitro assays in multiple myeloma cell lines demonstrated high binding, and bioinformatics analysis of human multiple myeloma samples revealed high CD46 expression. [89Zr]Zr-DFO-YS5 PET/CT specifically detected multiple myeloma lesions in a variety of models, with low uptake in controls, including CD46 knockout (KO) mice or multiple myeloma mice using a nontargeted antibody. In the MM.1S systemic model, localization of uptake on PET imaging correlated well with the luciferase expression from tumor cells. A treatment study using [225Ac]Ac-DOTA-YS5 in the MM.1S systemic model demonstrated a clear tumor volume and survival benefit in the treated groups.ConclusionsOur study showed that the CD46-targeted probe [89Zr]Zr-DFO-YS5 can successfully image CD46-expressing multiple myeloma xenografts in murine models, and [225Ac]Ac-DOTA-YS5 can effectively inhibit the growth of multiple myeloma. These results demonstrate that CD46 is a promising theranostic target for multiple myeloma, with the potential for clinical translation.

Radiopharmaceutical therapy using α -emitting 225 Ac is an emerging treatment for patients with advanced metastatic cancers. Measurement of the spatial dose distribution in organs and tumors is needed to inform treatment dose prescription and reduce off-target toxicity, at not only organ but also sub-organ scales. Digital autoradiography with α -sensitive detection devices can measure radioactivity distributions at 20-40 μm resolution, but anatomical characterization is typically limited to 2D. We collected digital autoradiographs across whole tissues to generate 3D dose volumes and used them to evaluate the simultaneous tumor control and regional kidney dosimetry of a novel therapeutic radiopharmaceutical for prostate cancer, [225Ac]Ac-Macropa-PEG4-YS5, in mice. 22Rv1 xenograft-bearing mice treated with 18.5 kBq of [225Ac]Ac-Macropa-PEG4-YS5 were sacrificed at 24 h and 168 h post-injection for quantitative α -particle digital autoradiography and hematoxylin and eosin staining. Gamma-ray spectroscopy of biodistribution data was used to determine temporal dynamics and 213 Bi redistribution. Tumor control probability and sub-kidney dosimetry were assessed. Heterogeneous 225 Ac spatial distribution was observed in both tumors and kidneys. Tumor control was maintained despite heterogeneity if cold spots coincided with necrotic regions. 225 Ac dose-rate was highest in the cortex and renal vasculature. Extrapolation of tumor control suggested that kidney absorbed dose could be reduced by 41% while maintaining 90% TCP. The 3D dosimetry methods described allow for whole tumor and organ dose measurements following 225 Ac radiopharmaceutical therapy, which correlate to tumor control and toxicity outcomes.

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.

Targeted alpha particle therapy (TAT) has emerged as a promising strategy for the treatment of prostate cancer (PCa). Actinium-225 (225Ac), a potent alpha-emitting radionuclide, may be incorporated into targeting vectors, causing robust and in some cases sustained antitumor responses. The development of radiolabeling techniques involving EDTA, DOTA, DOTPA, and Macropa chelators has laid the groundwork for advancements in this field. At the forefront of clinical trials with 225Ac in PCa are PSMA-targeted TAT agents, notably [225Ac]Ac-PSMA-617, [225Ac]Ac-PSMA-I&T and [225Ac]Ac-J591. Ongoing investigations spotlight [225Ac]Ac-hu11B6, [225Ac]Ac-YS5, and [225Ac]Ac-SibuDAB, targeting hK2, CD46, and PSMA, respectively. Despite these efforts, hurdles in 225Ac production, daughter redistribution, and a lack of suitable imaging techniques hinder the development of TAT. To address these challenges and additional advantages, researchers are exploring alpha-emitting isotopes including 227Th, 223Ra, 211At, 213Bi, 212Pb or 149Tb, providing viable alternatives for TAT.

PurposeRadiopharmaceutical therapy is changing the standard of care in prostate cancer and other malignancies. We previously reported high CD46 expression in prostate cancer and developed an antibody-drug conjugate and immunoPET agent based on the YS5 antibody, which targets a tumor-selective CD46 epitope. Here, we present the preparation, preclinical efficacy, and toxicity evaluation of [225Ac]DOTA-YS5, a radioimmunotherapy agent based on the YS5 antibody.Experimental design[225Ac]DOTA-YS5 was developed, and its therapeutic efficiency was tested on cell-derived (22Rv1, DU145), and patient-derived (LTL-545, LTL484) prostate cancer xenograft models. Biodistribution studies were carried out on 22Rv1 tumor xenograft models to confirm the targeting efficacy. Toxicity analysis of the [225Ac]DOTA-YS5 was carried out on nu/nu mice to study short-term (acute) and long-term (chronic) toxicity.ResultsBiodistribution study shows that [225Ac]DOTA-YS5 agent delivers high levels of radiation to the tumor tissue (11.64% ± 1.37%ID/g, 28.58% ± 10.88%ID/g, 29.35% ± 7.76%ID/g, and 31.78% ± 5.89%ID/g at 24, 96, 168, and 408 hours, respectively), compared with the healthy organs. [225Ac]DOTA-YS5 suppressed tumor size and prolonged survival in cell line-derived and patient-derived xenograft models. Toxicity analysis revealed that the 0.5 μCi activity levels showed toxicity to the kidneys, likely due to redistribution of daughter isotope 213Bi.Conclusions[225Ac]DOTA-YS5 suppressed the growth of cell-derived and patient-derived xenografts, including prostate-specific membrane antigen-positive and prostate-specific membrane antigen-deficient models. Overall, this preclinical study confirms that [225Ac]DOTA-YS5 is a highly effective treatment and suggests feasibility for clinical translation of CD46-targeted radioligand therapy in prostate cancer.

The behavior of 88Y, 152Eu, 228Ac, 241Am, and 244Cm was studied with 2-thenoyltrifluoroacetone resin with batch uptake, kinetics and column studies. Studies were performed in acetate buffer solutions (pH ~ 2 to ~ 6) and there was high uptake of all isotopes, except 228Ac, at pH > 4.5. The kinetics of uptake were reasonable, although slower for the actinides, and sufficient for column studies. The retention of 88Y, 152Eu, and 241Am on the resin in column studies was demonstrated as well as a reasonable separation of these isotopes from 228Ac. [ABSTRACT FROM AUTHOR]

Actinium-225 (225Ac) is one of the most promising radionuclides for targeted alpha therapy (TAT). With a half-life of 9.92 days and a decay chain that emits four high-energy α particles, 225Ac is well-suited for TAT when conjugated to macromolecular targeting vectors that exhibit extended in vivo circulation times. The implementation of 225Ac in these targeted constructs, however, requires a suitable chelator that can bind and retain this radionuclide in vivo. Previous work has demonstrated the suitability of a diaza-18-crown-6 macrocyclic chelator H2macropa for this application. Building upon these prior efforts, in this study, two rigid variants of H2macropa, which contain either one (H2BZmacropa) or two (H2BZ2macropa) benzene rings within the macrocyclic core, were synthesized and investigated for their potential use for 225Ac TAT. The coordination chemistry of these ligands with La3+, used as a nonradioactive model for Ac3+, was carried out. Both NMR spectroscopic and X-ray crystallographic studies of the La3+ complexes of these ligands revealed similar structural features to those found for the related complex of H2macropa. Thermodynamic stability constants of the La3+ complexes, however, were found to be 1 and 2 orders of magnitude lower than those of H2macropa for H2BZmacropa and H2BZ2macropa, respectively. The decrease in thermodynamic stability was rationalized via the use of density functional theory calculations. 225Ac radiolabeling and serum stability studies with H2BZmacropa showed that this chelator compares favorably with H2macropa. Based on these promising results, a bifunctional version of this chelator, H2BZmacropa-NCS, was synthesized and conjugated to the antibody codrituzumab (GC33), which targets the liver cancer biomarker glypican-3 (GPC3). The resulting GC33-BZmacropa conjugate and an analogous GC33-macropa conjugate were evaluated for their 225Ac radiolabeling efficiencies, antigen-binding affinities, and in vivo biodistribution in HepG2 liver cancer tumor-bearing mice. Although both conjugates were comparably effective in their radiolabeling efficiencies, [225Ac]Ac-GC33-BZmacropa showed slightly poorer serum stability and biodistribution than [225Ac]Ac-GC33-macropa. Together, these results establish H2BZmacropa-NCS as a new bifunctional chelator for the preparation of 225Ac radiopharmaceuticals.

By collinearly laser optical pumping of atoms and ions, the laser nuclear-spin-polarization beam facility at TRIUMF-ISAC has successfully provided highly nuclear-spin polarized radioactive isotope beams, such as 8 Li and 31Mg, to study material science, biochemistry, nuclear physics, and fundamental symmetries for over 20 years. In recent years with emerging research in all these fields using β -decay asymmetry of polarized nuclei, more novel/exotic species need to be laser-polarized, such as 230 , 232 Ac and 58 , 74 Cu. To develop optical pumping schemes and provide novel nuclear-spin polarized beams to meet these increasing demands the classical ISAC polarizer facility requires upgrades. In this paper, an overview of the polarizer facility is presented and recent, as well as ongoing, upgrades and development work are discussed. [ABSTRACT FROM AUTHOR]

The uptake behavior of 88Y, 140Ba, 140La, 141Ce, 152Eu, 228Ac, and 241Am was studied with batch uptake, kinetics and column studies in a synergistic extraction system with Pb resin and 2-thenoyltrifluoroacetone in acetate-ethanol solutions. The k′ values are very high (> 10,000) at near neutral pH (~ 5 to 6) for all of the radioisotopes studied. The kinetics are reasonably fast for column separations, though the uptake rate is dependent on the concentration of 2-thenoyltrifluoroacetone. Column studies were performed to demonstrate the separation of the trivalent actinides and lanthanides from barium and common fission products (99Mo, 103Ru). [ABSTRACT FROM AUTHOR]

Radioimmunotherapy, an approach using radiolabeled antibodies, has had minimal success in the clinic with several β-emitting radionuclides for the treatment of ovarian cancer. Alternatively, radioimmunotherapy with α-emitters offers the advantage of depositing much higher energy over shorter distances but was thought to be inappropriate for the treatment of solid tumors, for which antibody penetration is limited to a few cell diameters around the vascular system. However, the deposition of high-energy α-emitters to tumor markers adjacent to a typical leaky tumor vascular system may have large antitumor effects at the tumor vascular level, and their reduced penetration in normal tissue would be expected to lower off-target toxicity. Methods: To evaluate this concept, DOTAylated-huCC49 was labeled with the α-emitter 225Ac to target tumor-associated glycoprotein 72-positive xenografts in a murine model of ovarian cancer. Results:225Ac-labeled DOTAylated-huCC49 radioimmunotherapy significantly reduced tumor growth in a dose-dependent manner (1.85, 3.7, and 7.4 kBq), with the 7.4-kBq dose extending survival by more than 3-fold compared with the untreated control. Additionally, a multitreatment regime (1.85 kBq followed by 5 weekly doses of 0.70 kBq for a total of 5.4 kBq) extended survival almost 3-fold compared with the untreated control group, without significant off-target toxicity. Conclusion: These results establish the potential for antibody-targeted α-radionuclide therapy for ovarian cancer, which may be generalized to α-radioimmunotherapy in other solid tumors.

Interest in the use of 225Ac for targeted alpha therapies has increased dramatically over the past few years, resulting in a multitude of new isotope production and translational research efforts. However, 225Ac radioimmunoconjugate (RIC) research is still in its infancy, with most prior experience in hematologic malignancies and only one reported preclinical solid tumor study using 225Ac RICs. In an effort to compare 225Ac RICs to other current antibody conjugates, a variety of RICs are tested against intractable small-cell lung cancer (SCLC). We directly compare, in vitro and in vivo, two promising candidates of each α or β- category, 225Ac and 177Lu, versus pyrrolobenzodiazepine (PBD) nonradioactive benchmarks. The monoclonal antibody constructs are targeted to either delta like 3 protein (DLL3), a recently discovered SCLC target, or CD46 as a positive control. An immunocompromised maximum tolerated dose assay is performed on NOD SCID mice, along with tumor efficacy proof-of-concept studies in vivo. We overview the conjugation techniques required to create serum-stable RICs and characterize and compare in vitro cell killing with RICs conjugated to nonspecific antibodies (huIgG1) with either native or site-specific thiol loci against tumor antigen DLL3-expressing and nonexpressing cell lines. Using patient-derived xenografts of SCLC onto NOD SCID mice, solid tumor growth was controlled throughout 3 weeks before growth appeared, in comparison to PBD conjugate controls. NOD SCID mice showed lengthened survival using 225Ac compared to 177Lu RICs, and PBD dimers showed full tumor suppression with nine out of ten mice. The exploration of RICs on a variety of antibody-antigen systems is necessary to direct efforts in cancer research toward promising candidates. However, the anti-DLL3-RIC system with 225Ac and 177Lu appears to be not as effective as the anti-DLL3-PBD counterpart in SCLC therapy with matched antibodies and portrays the challenges in both SCLC therapy as well as the specialized utility of RICs in cancer treatment.

Hu11B6 is a monoclonal antibody that internalizes in cells expressing androgen receptor (AR)-regulated prostate-specific enzyme human kallikrein-related peptidase 2 (hK2; KLK2). In multiple rodent models, Actinium-225-labeled hu11B6-IgG1 ([225Ac]hu11B6-IgG1) has shown promising treatment efficacy. In the present study, we investigated options to enhance and optimize [225Ac]hu11B6 treatment. First, we evaluated the possibility of exploiting IgG3, the IgG subclass with superior activation of complement and ability to mediate FC-γ-receptor binding, for immunotherapeutically enhanced hK2 targeted α-radioimmunotherapy. Second, we compared the therapeutic efficacy of a single high activity vs. fractionated activity. Finally, we used RNA sequencing to analyze the genomic signatures of prostate cancer that progressed after targeted α-therapy. [225Ac]hu11B6-IgG3 was a functionally enhanced alternative to [225Ac]hu11B6-IgG1 but offered no improvement of therapeutic efficacy. Progression-free survival was slightly increased with a single high activity compared to fractionated activity. Tumor-free animals succumbing after treatment revealed no evidence of treatment-associated toxicity. In addition to up-regulation of canonical aggressive prostate cancer genes, such as MMP7, ETV1, NTS, and SCHLAP1, we also noted a significant decrease in both KLK3 (prostate-specific antigen ) and FOLH1 (prostate-specific membrane antigen) but not in AR and KLK2, demonstrating efficacy of sequential [225Ac]hu11B6 in a mouse model.

225Ac-PSMA-617 targeted-therapy has demonstrated efficacy in 75-85% of patients; however, responses are not durable. We aimed to establish translatable mouse models of disseminated prostate cancer (PCa) to evaluate effectiveness of 225Ac-PSMA-617 at various disease stages. Methods: C4-2, C4-2B, or 22Rv1 cells were injected into the left ventricle of male NSG mice. Disease progression was monitored using bioluminescence imaging (BLI). For treatment, mice were injected with 40 kBq 225Ac-PSMA-617 at one (early treatment cohort) or three weeks (late treatment cohort) post-inoculation. Treatment efficacy was monitored by BLI of whole-body tumor burden. Mice were sacrificed based on body conditioning score. Results: C4-2 cells yielded metastases in liver, lungs, spleen, stomach, bones, and brain - achieving a clinically relevant model of widespread metastatic disease. The disease burden in the early treatment cohort was stable over 27 weeks in 5/9 mice and progressive in 4/9 mice. These mice were sacrificed due to brain metastases. Median survival of the late treatment cohort was superior to controls (13 vs. 7 weeks; p

In the current study, the coordination chemistry of nine‐coordinate Ac(III) complexes with 35 monodentate and bidentate ligands was investigated using density functional theory (DFT) in terms of their geometries, charges, reaction energies, and bonding interactions. The energy decomposition analysis with naturals orbitals for chemical valence (EDA‐NOCV) and the quantum theory of atoms in molecules (QTAIM) were employed as analysis methods. Trivalent Ac exhibits the highest affinities toward hard acids (such as charged oxophilic donors, fluoride), so its classification as a hard acid is justified. Natural population analysis quantified the involvement of 5f orbitals on Ac to be about 30% of total valence electron natural configuration indicating that Ac is a member of the actinide series. Pearson correlation coefficients were used to study the pairwise correlations among the bond lengths, ΔG reaction energies, charges on Ac and donor atoms, and data from EDA‐NOCV and QTAIM. Strong correlations and anticorrelations were found between Voronoi charges on donor atoms with ΔG, EDA‐NOCV interaction energies and QTAIM bond critical point densities. [ABSTRACT FROM AUTHOR]

Optimization of separations for selective binding of rare earth elements and actinides is critical to guarantee a supply of materials essential to needs including national security and defense, technology, medicine, and communications. Computational modeling is key to accelerate solutions for selective separations; however, tools to predict accurate representations of the physical systems of interest require high performance computing resources to be developed to facilitate robust modeling. This study evaluates computational molecular modeling and machine learning applications on property analysis relevant to the binding of lanthanum and actinium with carboxylic acids. It focuses on assessing accuracy of computational predictions based on benchmark computational results due to lack of experimental information. Properties evaluated include Gibbs free energies of reaction, relativistic effects, diagnostics, partial charges, structural characteristics, and coordination sphere and equivalent volume. [ABSTRACT FROM AUTHOR]

A new routine method to measure 227Ac in water samples was developed. Actinium-227 was separated from potential radioactive and matrix interferences using a DGA resin (Eichrom) at optimal extraction and elution conditions (2 M and 15.7 M HNO3, respectively). This was possible because Ac was pre-concentrated and separated from Ca using titanium phosphate co-precipitation at pH 3.5. Finally, 227Ac was counted by alpha spectrometry for 48 h after a cerium fluoride micro-precipitation. A minimal detection limit of 0.03 ± 0.01 Bq l−1 was obtained. The method was validated using spiked water samples. [ABSTRACT FROM AUTHOR]

Cross sections for production of the medical isotope 225Ac by the 226Ra(p,2n) reaction have not previously been measured in fine steps over the relevant energy region, and no measurements are presently available in the literature for the actinium contaminant isotopes created by the adjacent 226Ra(p,n)226Ac and 226Ra(p,3n)224Ac reactions. We report thin-target cross-section measurements for production of 224Ac and 225Ac by protons of 15.1–16.8 MeV incident on radium. An upper limit for the 226Ac cross section is also reported. • Optimal cyclotron-based production of the medical isotope 225Ac requires knowledge of the 226Ra(p,xn) reactions. • We report thin-target cross-sections for production of 224Ac and 225Ac by protons of 15.1–16.8 MeV on radium. • An upper limit for the 226Ac cross section is also reported. • Production of 225Ac is observed to peak for a higher proton energy than predicted by commonly used simulation codes. [ABSTRACT FROM AUTHOR]

Actinium-225 is one of the most promising radionuclides for targeted alpha therapy. Its limited availability significantly restricts clinical trials and potential applications of 225Ac-based radiopharmaceuticals. In this work, we examine the possibility of 225Ac production from the thermal neutron flux of a nuclear reactor. For this purpose, a target consisting of 1.4 mg of 226Ra(NO 3) 2 (T 1/2 = 1600 years) and 115.5 mg of 90 % enriched, stable 157Gd 2 O 3 was irradiated for 48 h in the Breazeale Nuclear Reactor with an average neutron flux of 1.7·1013 cm−2·s−1. Gadolinium-157 has one of the highest thermal neutron capture cross sections of 0.25 Mb, and its neutron capture results in emission of high-energy, prompt γ-photons. Emitted γ-photons interact with 226Ra to produce 225Ra according to the 226Ra(γ, n)225Ra reaction. Gadolinium debulking and separation of undesirable, co-produced 227Ac from 225Ra was achieved in one step by using 60 g of branched DGA resin. After 225Ac ingrowth from 225Ra (T 1/2 = 14.8 d), 225Ac was extracted from the 226Ra and 225Ra fraction using 5 g of bDGA resin and then eluted using 5 mM HNO 3. Measured activity of 225Ac showed that 6(1) kBq or 0.16(3) μCi (1σ) of 225Ra was produced at the end of bombardment from 0.9 mg of 226Ra. The developed 225Ac separation is a waste-free process which can be used to obtain pure 225Ac in a nuclear reactor. [Display omitted] [ABSTRACT FROM AUTHOR]

According to the 2021 World Health Organization Classification of Tumors of the Central Nervous System, glioblastoma (GB) is a primary brain tumor and presents with the worst prognosis. Due to its infiltrating characteristic, molecular heterogeneity, and only partly preserved function of the blood-brain barrier, the median overall survival time is short (9–15 months), regardless of comprehensive treatment including surgery, radiotherapy, and chemotherapy. Several novel treatment strategies are under investigation. Unfortunately, none of them produced successful results; 90% of patients have a recurrence of the disease within 6 months. Local administration of the drug could be a promising approach to delivering treatment with minimized side effects, due to the recurrence of 95% glioblastomas in a margin of 2 cm at the primary site. Several ligand-receptor systems have been evaluated, such as targeting tenascin, the extracellular matrix protein, or radiolabeled somatostatin analogs, as it is overexpressed with the SSTR-2 receptor system in around 80% of gliomas. Moreover, this study revealed that the NK-1 receptor is overexpressed in GB, suggesting that substance P (SP) may serve as a ligand. A variety of radioisotopes, beta- (131I, 90Y, or 177 Lu) and alpha emitters (213Bi, 225Ac, or 211At), with different physical properties were tested for treatment. Alpha particles have many advantages over beta radiation such as short range with higher linear energy transfer. According to that characteristic, it is extremely dose delivered to the targeted cells, while reducing harm to nearby healthy tissue. Additionally, the biological effect of alpha radiation is independent of the cell cycle phase, cell oxygenation and O-6-methylguanine-DNA methyltransferase (MGMT) gene promoter methylation status. In this article, we summarize the experience with local treatment of primary and secondary GBs with locally used radioisotopes such as [213Bi]Bi-DOTA-SP or [225Ac]Ac-DOTA-SP.

Purpose: The spatial distribution of radiopharmaceuticals within multicellular clusters is known to have a significant effect on their biological response. Most therapeutic radiopharmaceuticals distribute nonuniformly in tissues which makes predicting responses of micrometastases challenging. The work presented here analyzes published temporally dependent nonuniform activity distributions within tumor spheroids treated with actinium-225-DOTA encapsulating liposomes (225Ac-liposomes) and uses these data in MIRDcell V3.11 to calculate absorbed dose distributions and predict biological response. The predicted responses are compared with experimental responses. Methods: Four types of liposomes were prepared having membranes with different combinations of release (R) and adhesion (A) properties. The combinations were R−A−, R−A+, R+A−, and R+A+. These afford different penetrating properties into tissue. The liposomes were loaded with either carboxyfluorescein diacetate succinimidyl ester (CFDA-SE) or 225Ac. MDA-MB-231 spheroids were treated with the CFDA-SE-liposomes, harvested at different times, and the time-integrated CFDA-SE concentration at each radial position within the spheroid was determined. This was translated into mean 225Ac decays/cell versus radial position, uploaded to MIRDcell, and the surviving fraction of cells in spherical multicellular clusters was simulated. The MIRDcell-predicted surviving fractions were compared with experimental fractional-outgrowths of the spheroids following treatment with 225Ac-liposomes. Results: The biological responses of the multicellular clusters treated with 225Ac-liposomes with physicochemical properties R+A+, R−A+, and R−A− were predicted by MIRDcell with statistically significant accuracy. The prediction for R+A− was not predicted accurately. Conclusion: In most instances, MIRDcell predicts responses of spheroids treated with 225Ac-liposomes that result in different tissue-penetrating profiles of the delivered radionuclides. [ABSTRACT FROM AUTHOR]

Precision laser spectroscopy of the 229-thorium nuclear isomer transition in a solid-state environment would represent a significant milestone in the field of metrology, opening the door to the realization of a nuclear clock. Working toward this goal, experimental methods require knowledge of various properties of a large band-gap material, such as calcium fluoride doped with specific isotopes of the heavy elements thorium, actinium, cerium, neptunium, and uranium. By accurately determining the atomic structure of potential charge compensation schemes by using a generalized gradient approximation within the ab-initio framework of density functional theory, calculations of electric field gradients on the dopants become accessible, which cause a quadrupole splitting of the nuclear-level structure that can be probed experimentally. Band gaps and absorption coefficients in the range of the 229-thorium nuclear transition are estimated by using the G 0 W 0 method and by solving the Bethe–Salpeter equation. [ABSTRACT FROM AUTHOR]

Radiopharmaceutical therapy using α -emitting 225 Ac is an emerging treatment for patients with advanced metastatic cancers. Measurement of the spatial dose distribution in organs and tumors is needed to inform treatment dose prescription and reduce off-target toxicity, at not only organ but also sub-organ scales. Digital autoradiography with α -sensitive detection devices can measure radioactivity distributions at 20-40 μ m resolution, but anatomical characterization is typically limited to 2D. We collected digital autoradiographs across whole tissues to generate 3D dose volumes and used them to evaluate the simultaneous tumor control and regional kidney dosimetry of a novel therapeutic radiopharmaceutical for prostate cancer, [ 225 Ac]Ac-Macropa-PEG 4 -YS5, in mice. 22Rv1 xenograft-bearing mice treated with 18.5 kBq of [ 225 Ac]Ac-Macropa-PEG 4 -YS5 were sacrificed at 24 h and 168 h post-injection for quantitative α -particle digital autoradiography and hematoxylin and eosin staining. Gamma-ray spectroscopy of biodistribution data was used to determine temporal dynamics and 213 Bi redistribution. Tumor control probability and sub-kidney dosimetry were assessed. Heterogeneous 225 Ac spatial distribution was observed in both tumors and kidneys. Tumor control was maintained despite heterogeneity if cold spots coincided with necrotic regions. 225 Ac dose-rate was highest in the cortex and renal vasculature. Extrapolation of tumor control suggested that kidney absorbed dose could be reduced by 41% while maintaining 90% TCP. The 3D dosimetry methods described allow for whole tumor and organ dose measurements following 225 Ac radiopharmaceutical therapy, which correlate to tumor control and toxicity outcomes., (© 2024. The Author(s).)

Monitoring of internal exposure to short-lived alpha-emitting radionuclides such as actinium-225 ( 225 Ac), which are becoming increasingly important in nuclear medicine, plays an important role in the radiation protection of occupationally exposed persons. After having tested gamma spectrometry, liquid scintillation counting and alpha spectrometry for monitoring of internal exposure, the focus of the present study was on solid phase extraction of 225 Ac from urine in combination with alpha spectrometry. The development of the method was based on recent findings from the literature on this topic. The method was used in a pilot phase to monitor internal exposure of four workers who were directly or indirectly involved in the manufacture and/or use of 225 Ac. The monitoring protocol allowed a relatively short 24-hour urine sample analysis with excellent recovery of the internal standard, but it did not allow for a detection limit of less than 1 mBq nor a sufficient yield of 225 Ac. Based on these results it is concluded that an in vitro excretion analysis alone is not appropriate for monitoring internal exposure to 225 Ac. Instead, different radiation monitoring techniques have to be combined to ensure the radiation protection of employees., (© 2024. The Author(s).)

The extraction of 224Ra and 228Ac with dibenzo-21-crown-7 resin was studied in solutions with Rose Bengal and identical solutions without Rose Bengal (blanks) from pH 3 to 12. Batch studies demonstrated that actinium is extracted at high pH (> 10) from both solutions but with a significantly higher extraction from the Rose Bengal solutions (maximum extraction ~ 60,000) than the blank solutions (maximum extraction ~ 2,000). In the Rose Bengal solutions, there was a weak extraction of actinium at lower pH (4–10) as well. There was no uptake of radium from the blank solutions, and a weak extraction at all pH levels from the Rose Bengal solutions. Kinetics studies were performed for actinium only, as radium had no significant extraction. Two column studies are demonstrated for the separation of radium from actinium. These separations are moderately effective with ~ 78% of the actinium recovered with no detectable radium. [ABSTRACT FROM AUTHOR]

Background: Alpha-particle-emitting radiotherapies are of great interest for the treatment of disseminated cancer. Actinium-225 (225Ac) produces four α-particles through its decay and is among the most attractive radionuclides for use in targeted radiotherapy applications. However, supply issues for this isotope have limited availability and increased cost for research and translation. Efforts have focused on accelerator-based methods that produce 225Ac in addition to long-lived 227Ac. Objective: The authors investigated the impact of 225Ac/227Ac material in the radiolabeling and radiopharmaceutical quality control evaluation of a DOTA chelate-conjugated peptide under good manufacturing practices. The authors use an automated module under identical conditions with either generator or accelerator-produced actinium radiolabeling. Methods: The authors have performed characterization of the radiolabeled products, including thin-layer chromatography, high-pressure liquid chromatography, gamma counting, and high-energy resolution gamma spectroscopy. Results: Peptide was radiolabeled and assessed at >95% radiochemical purity with high yields for generator produced 225Ac. The radiolabeling results produced material with subtle but detectable differences when using 225Ac/227Ac. Gamma spectroscopy was able to identify peptide initially labeled with 227Th, and at 100 d for quantification of 225Ac-bearing peptide. Conclusion: Peptides produced using 225Ac/227Ac material may be suitable for translation, but raise new issues that include processing times, logistics, and contaminant detection. [ABSTRACT FROM AUTHOR]

The present article describes a complete reanalysis of all published data on observed spectral lines and energy levels of the first three spectra of actinium (Ac I–III). In Ac I, three previously determined energy levels have been rejected, 12 new energy levels have been found; for six previously known levels, either the J values or the energies have been revised, and the ionization energy has been redetermined with an improved accuracy. In the line list of Ac I, three previous classifications have been discarded, 16 new ones have been found, and three have been revised. In Ac II, 16 new energy levels have been established, and 36 new identifications have been found for previously observed but unclassified lines. In both Ac I and Ac II, new sets of transition probabilities have been calculated. For all three spectra, complete datasets of critically evaluated energy levels, observed lines, and transition probabilities have been constructed to serve as recommended data on these spectra. [ABSTRACT FROM AUTHOR]

Glioblastoma (GBM) is the most common primary malignant astrocytoma characterized by extensive invasion, angiogenesis, hypoxia, and micrometastasis. Despite the relatively leaky nature of GBM blood vessels, effective delivery of antitumor therapeutics has been a major challenge due to the complications caused by the blood-brain barrier (BBB) and the highly torturous nature of newly formed tumor vasculature (blood tumor barrier-BTB). External beam radiotherapy was previously shown to be an effective means of permeabilizing central nervous system (CNS) barriers. By using targeted short-ranged radionuclides, we show for the first time that our targeted actinium-225-labeled αvβ3-specific liposomes (225Ac-IA-TLs) caused catastrophic double stranded DNA breaks and significantly enhanced the permeability of BBB and BTB in mice bearing orthotopic GBMs. Histologic studies revealed characteristic α-particle induced double strand breaks within tumors but was not significantly present in normal brain regions away from the tumor where BBB permeability was observed. These findings indicate that the enhanced vascular permeability in these distal regions did not result from direct α-particle-induced DNA damage. On the basis of these results, in addition to their direct antitumor effects, 225Ac-IA-TLs can potentially be used to enhance the permeability of BBB and BTB for effective delivery of systemically administered antitumor therapeutics. Mol Cancer Ther; 16(10); 2191-200. ©2017 AACR.

[Display omitted] Currently, alpha-emitting radionuclide 225Ac is one of the most promising isotopes in alpha therapy due to its high linear energy transfer during four sequential alpha decays. However, the main obstacle preventing the full introduction of 225Ac into clinical practice is the lack of stable retention of radionuclides, leading to free circulation of toxic isotopes in the body. In this work, the surface of silica nanoparticles (SiO 2 NPs) has been modified with metallic shells composed of titanium dioxide (TiO 2) and gold (Au) nanostructures to improve the retention of 225Ac and its decay products within the developed nanocarriers. In vitro and in vivo studies in healthy mice show that the metallic surface coating of SiO 2 NPs promotes an enhanced sequestering of radionuclides (225Ac and its daughter isotopes) compared to non-modified SiO 2 NPs for a prolonged period of time. Histological analysis reveals that for the period of 3–10 d after the injections, the developed nanocarriers have no significant toxic effects in mice. At the same time, almost no accumulation of leaked radionuclides can be detected in non-target organs (e.g., in the kidneys). In contrast, non-modified carriers (SiO 2 NPs) demonstrate the release of free radionuclides, which are distributed over the whole animal body with the consequent morphological changes in the lung, liver and kidney tissues. These results highlight the potential of the developed nanocarriers to be utilized as radionuclide delivery systems and offer an insight into design rules for the fabrication of new nanotherapeutic agents. [ABSTRACT FROM AUTHOR]

Purpose: Fibroblast activation protein (FAP), which has high expression in cancer-associated fibroblasts of epithelial cancers, can be used as a theranostic target. Our previous study used 64Cu and 225Ac-labelled FAP inhibitors (FAPI-04) for a FAP-expressing pancreatic cancer xenograft imaging and therapy. However, the optimal therapeutic radionuclide for FAPI needs to be investigated further. In this study, we evaluated the therapeutic effects of beta-emitter (177Lu)-labelled FAPI-46 and alpha-emitter (225Ac)-labelled FAPI-46 in pancreatic cancer models. Methods: PET scans (1 h post injection) were acquired in PANC-1 xenograft mice (n = 9) after the administration of [18F]FAPI-74 (12.4 ± 1.7 MBq) for the companion imaging. The biodistribution of [177Lu]FAPI-46 and [225Ac]FAPI-46 were evaluated in the xenograft model (total n = 12). For the determination of treatment effects, [177Lu]FAPI-46 and [225Ac]FAPI-46 were injected into PANC-1 xenograft mice at different doses: 3 MBq (n = 6), 10 MBq (n = 6), 30 MBq (n = 6), control (n = 4) for [177Lu]FAPI-46, and 3 kBq (n = 3), 10 kBq (n = 2), 30 kBq (n = 6), control (n = 7) for [225Ac]FAPI-46. Tumour sizes and body weights were followed. Results: [18F]FAPI-74 showed rapid clearance by the kidneys and high accumulation in the tumour and intestine 1 h after administration. [177Lu]FAPI-46 and [225Ac]FAPI-46 also showed rapid clearance by the kidneys and relatively high accumulation in the tumour at 3 h. Both [177Lu]FAPI-46 and [225Ac]FAPI-46 showed tumour-suppressive effects, with a mild decrease in body weight. The treatment effects of [177Lu]FAPI-46 were relatively slow but lasted longer than those of [225Ac]FAPI-46. Conclusion: This study suggested the possible application of FAPI radioligand therapy in FAP-expressing pancreatic cancer. Further evaluation is necessary to find the best radionuclide with shorter half-life, as well as the combination with therapies targeting tumour cells directly. [ABSTRACT FROM AUTHOR]

Actinium-225 is a promising isotope for targeted-α therapy. Unfortunately, progress in developing chelators for medicinal applications has been hindered by a limited understanding of actinium chemistry. This knowledge gap is primarily associated with handling actinium, as it is highly radioactive and in short supply. Hence, Ac(III) reactivity is often inferred from the lanthanides and minor actinides (that is, Am, Cm), with limited success. Here we overcome these challenges and characterize actinium in HCl solutions using X-ray absorption spectroscopy and molecular dynamics density functional theory. The Ac-Cl and Ac-OH2O distances are measured to be 2.95(3) and 2.59(3) Å, respectively. The X-ray absorption spectroscopy comparisons between Ac(III) and Am(III) in HCl solutions indicate Ac(III) coordinates more inner-sphere Cl(1-) ligands (3.2±1.1) than Am(III) (0.8±0.3). These results imply diverse reactivity for the +3 actinides and highlight the unexpected and unique Ac(III) chemical behaviour.

Purpose: We demonstrate cyclotron production of high-quality 225Ac using an electroplated 226Ra target. Methods: 226Ra was extracted from legacy Ra sources using a chelating resin. Subsequent ion-exchange purification gave pure 226Ra with a certain amount of carrier Ba. The radium target was prepared by electroplating. We successfully deposited about 37 MBq of 226Ra on a target box. Maximum activation was achieved using 15.6 MeV protons on the target at 20 µA for 5 h. Two functional resins with various concentrations of nitric acid purified 225Ac and recovered 226Ra. Cooling the intermediate 225Ac for 2–3 weeks decayed the major byproduct of 226Ac and increased the radionuclidic purity of 225Ac. Repeating the same separation protocol provided high-quality 225Ac. Results: We obtained 225Ac at a yield of about 2.4 MBq at the end of bombardment (EOB), and the subsequent initial purification gave 1.7 MBq of 225Ac with 226Ac/225Ac ratio of < 3% at 4 days from EOB. Additional cooling time coupled with the separation procedure (secondary purification) effectively increased the 225Ac (4n + 1 series) radionuclidic purity up to 99 + %. The recovered 225Ac had a similar identification to commercially available 225Ac originating from a 229Th/225Ac generator. Conclusion: This procedure, which involves the 226Ra(p,2n)225Ac reaction and the appropriate purification, has the potential to be a major alternative pathway for 225Ac production because it can be performed in any facility with a compact cyclotron to address the increasing demand for 225Ac. [ABSTRACT FROM AUTHOR]

Purpose: This review discusses the current state of prostate-specific membrane antigen (PSMA)-based alpha therapy of metastatic castration-resistant prostate cancer (mCRPC). With this in-depth discussion on the growing field of PSMA-based alpha therapy (PAT), we aimed to increase the interactions between basic scientists and physician–scientists in order to advance the field. Methods: To achieve this, we discuss the potential, current status, and opportunities for alpha therapy and strategies, attempted to date, and important questions that need to be addressed. The paper reviews important concepts, including whom to treat, how to treat, what to expect regarding treatment outcome, and toxicity, and areas requiring further investigations. Results: There is much excitement about the potential of this field. Much of the potential exists because these therapies utilize unique mechanisms of action, difficult to achieve with other conventional therapies. Conclusion: A better understanding of the strengths and limitations of PAT may help in creating an effective therapy for mCRPC and design a rational combinatorial approach to treatment by targeting different tumor pathways. [ABSTRACT FROM AUTHOR]

CE credit: For CE credit, you can access the test for this article, as well as additional JNMT CE tests, online at https://www.snmmilearningcenter.org Complete the test online no later than March 2025. Your online test will be scored immediately. You may make 3 attempts to pass the test and must answer 75% of the questions correctly to receive Continuing Education Hour (CEH) credit. Credit amounts can be found in the SNMMI Learning Center Activity. SNMMI members will have their CEH credit added to their VOICE transcript automatically; nonmembers will be able to print out a CE certificate upon successfully completing the test. The online test is free to SNMMI members; nonmembers must pay $15.00 by credit card when logging onto the website to take the test.α-emitting radionuclides provide an effective means of delivering large radiation doses to targeted treatment locations. 223RaCl2 is Food and Drug Administration-approved for treatment of metastatic castration-resistant prostate cancer, and 225Ac (225Ac-lintuzumab) radiolabeled antibodies have been shown to be beneficial for patients with acute myeloid leukemia. In recent years, there has been increasing use of α-emitters in theranostic agents with both small- and large-molecule constructs. The proper precautionary means for their use and surveying documentation of these isotopes in a clinical setting are an essential accompaniment to these treatments. Methods: Patient treatment data collected over a 3-y period, as well as regulatory requirements and safety practices, are described. Commonly used radiation instruments were evaluated for their ability to identify potential radioactive material spills and contamination events during a clinical administration of 225Ac. These instruments were placed at 0.32 cm from a 1.0-cm 225Ac disk source for measurement purposes. Radiation background values, efficiencies, and minimal detectable activities were measured and calculated for each type of detector. Results: The median external measured dose rate from 223RaCl2 patients (n = 611) was 2.5 μSv h-1 on contact and 0.2 μSv h-1 at 1 m immediately after administration. Similarly, 225Ac-lintuzumab (n = 19) patients had median external dose rates of 2.0 μSv h-1 on contact and 0.3 μSv h-1 at 1 m. For the measurement of 225Ac samples, a liquid scintillation counter was found to have the highest overall efficiency (97%), whereas a ZnS α-probe offered the lowest minimal detectable activity at 3 counts per minute. Conclusion: In this article, we report data from 630 patients who were undergoing treatment with the α-emitting isotopes 223Ra and 225Ac. Although α-emitters have the ability to deliver a higher internal radiation dose to the exposed tissues than can other unsealed radionuclides, they typically present minimal concerns about external dose rate. Additionally, α-radiation can be efficiently detected with appropriate radiation instrumentation, such as a liquid scintillation counter or ZnS probe, which should be prioritized when surveying for spills of α-emitters. [ABSTRACT FROM AUTHOR]

Objective . 225 Ac radiopharmaceuticals have tremendous potential for targeted alpha therapy, however, 225 Ac ( t 1/2 = 9.9 d) lacks direct gamma emissions for in vivo imaging. 226 Ac ( t 1/2 = 29.4 h) is a promising element-equivalent matched diagnostic radionuclide for preclinical evaluation of 225 Ac radiopharmaceuticals. 226 Ac has two gamma emissions (158 keV and 230 keV) suitable for SPECT imaging. This work is the first feasibility study for in vivo quantitative 226 Ac SPECT imaging and validation of activity estimation. Approach . 226 Ac was produced at TRIUMF (Vancouver, Canada) with its Isotope Separator and Accelerator (ISAC) facility. [ 226 Ac]Ac 3+ was radiolabelled with the bioconjugate crown-TATE developed for therapeutic targeting of neuroendocrine tumours. Mice with AR42J tumour xenografts were injected with either 2 MBq of [ 226 Ac]Ac-crown-TATE or 4 MBq of free [ 226 Ac]Ac 3+ activity and were scanned at 1, 2.5, 5, and 24 h post injection in a preclinical microSPECT/CT. Quantitative SPECT images were reconstructed from the 158 keV and 230 keV photopeaks with attenuation, background, and scatter corrections. Image-based 226 Ac activity measurements were assessed from volumes of interest within tumours and organs of interest. Imaging data was compared with ex vivo biodistribution measured via gamma counter. Main results . We present, to the best of our knowledge, the first ever in vivo quantitative SPECT images of 226 Ac activity distributions. Time-activity curves derived from SPECT images quantify the in vivo biodistribution of [ 226 Ac]Ac-crown-TATE and free [ 226 Ac]Ac 3+ activity. Image-based activity measurements in the tumours and organs of interest corresponded well with ex vivo Ac quantitative SPECT imaging for accurate measurement of actinium biodistribution in a preclinical model. This imaging method could facilitate more efficient development of novel actinium labelled compounds by providing accurate quantitative Significance . Here in, we established the feasibility of in vivo 226 Ac quantitative SPECT imaging for accurate measurement of actinium biodistribution in a preclinical model. This imaging method could facilitate more efficient development of novel actinium labelled compounds by providing accurate quantitative in vivo pharmacokinetic information essential for estimating toxicities, dosimetry, and therapeutic potency., (© 2024 Institute of Physics and Engineering in Medicine.)

Purpose: This pilot study investigates the efficacy and safety profile as well as predictive biomarkers of 225 Ac-PSMA-617-augmented 177 Lu-PSMA-617 radioligand therapy (RLT) in a cohort of high-risk patients with metastatic castration-resistant prostate cancer (mCRPC), enrolled in a prospective registry (NCT04833517)., Patients and Methods: A group of n = 33 high-risk mCRPC patients received 177 Lu-PSMA-617 RLT, augmented by 1 or more cycles of 225 Ac-PSMA-617. Response was assessed by prostate-specific antigen (PSA) serum value after 2 cycles of treatment. Overall survival (OS) and PSA-based progression-free survival were evaluated using Kaplan-Meier analysis. To assess the side effect profile, Common Terminology Criteria for Adverse Events were applied. In total, 12 potential pretherapeutic biomarkers were tested for association with OS., Results: The median decrease in serum PSA value was -49.1%, and 16/33 (48.5%) patients experienced a partial response after 2 cycles RLT. The median PSA-based progression-free survival and median OS was 7.2 and 14.8 months, respectively. Alkaline phosphatase ( P < 0.001), lactate dehydrogenase ( P = 0.035), Eastern European Oncology Group Performance Score ( P = 0.037), and the presence of visceral metastases ( P = 0.029) revealed significant association with OS in Kaplan-Meier analysis (log-rank test). Most of the recorded adverse events were rated as mild or moderate. Higher-grade adverse events were very limited with only 1 case (3.0%) of grade 3 anemia. Treatment-related mild xerostomia was recorded in 6/33 (18.2%) patients., Conclusions: 225 Ac-PSMA-617 augmentation in high-risk mCRPC undergoing 177 Lu-PSMA-617 RLT appears to be an effective treatment option with a favorable safety profile. The pretherapeutic values of alkaline phosphatase, lactate dehydrogenase, the Eastern European Oncology Group Performance Score, and the presence of visceral metastases may be appropriate biomarkers predicting survival outcome of this treatment regimen., Competing Interests: Conflicts of interest and sources of funding: none declared., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Osteosarcoma (OS) is a prevalent primary bone cancer affecting both humans and canines. This study describes initial insights into the interaction of the human monoclonal antibody IF3 to an insulin-like growth factor 2 receptor (IGF2R) radiolabeled with either alpha-emitting Actinium-225 ( 225 Ac) or beta-emitting Lutetium-177 ( 177 Lu) radionuclides with the OS cells and tumor microenvironment (TME) in experimental human and canine OS., Basic Procedures: SCID mice bearing canine Gracie or human OS-33 OS tumors were treated with 177 Lu- or 225 Ac-labeled IF3 antibody, sacrificed at 24, 72 or 168 h post-treatment and their tumors were analyzed by immunohistochemistry (IHC) for the presence of OS cells, various elements of TME as well as for the double DNA strand breaks with γH2AX and caspase 3 assays., Main Findings: IHC revealed a reduction in IGF2R-positive OS cells and OS stem cell populations post therapy with 225 Ac- and 177 Lu-labeled IF3 antibody. Notably, radiolabeled IF3 antibody effectively diminished pro-tumorigenic M2 macrophages, highlighting its therapeutic promise. The study also unveiled varied responses of natural killer (NK) cells and M1 macrophages, shedding light on the intricate TME interplay. Time-dependent increase in γ-H2AX staining in canine Gracie and human OS-33 tumors treated with [ 177 Lu]Lu-IF3 and [ 225 Ac]Ac-IF3 was observed at 24 and 72 h post-RIT., Principal Conclusions: These findings suggest that radiolabeled antibodies offer a hopeful avenue for personalized OS treatment, emphasizing the importance of understanding their impact on the TME and potential synergies with immunotherapy., Competing Interests: Declaration of competing interest I, Ekaterina Dadachova, serve as an associate editor of NMB. I declare that I do not have any conflict of interest by being a senior author on the submitted manuscript., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: Initially, prostate cancer responds to hormone therapy, but eventually resistance develops. Beta emitter-based prostate-specific membrane antigen (PSMA)-targeted radionuclide therapy is approved for the treatment of metastatic castration-resistant prostate cancer. Here we introduce a targeted alpha therapy (TAT) consisting of the PSMA antibody pelgifatamab covalently linked to a macropa chelator and labeled with actinium-225 and compare its efficacy and tolerability with other TATs., Experimental Design: The in vitro characteristics and in vivo biodistribution, antitumor efficacy, and tolerability of 225Ac-macropa-pelgifatamab (225Ac-pelgi) and other TATs were investigated in cell line- and patient-derived prostate cancer xenograft models. The antitumor efficacy of 225Ac-pelgi was also investigated in combination with the androgen receptor inhibitor darolutamide., Results: Actinium-225-labeling of 225Ac-pelgi was efficient already at room temperature. Potent in vitro cytotoxicity was seen in PSMA-expressing (LNCaP, MDA-PCa-2b, and C4-2) but not in PSMA-negative (PC-3 and DU-145) cell lines. High tumor accumulation was seen for both 225Ac-pelgi and 225Ac-DOTA-pelgi in the MDA-PCa-2b xenograft model. In the C4-2 xenograft model, 225Ac-pelgi showed enhanced antitumor efficacy with a T/Cvolume (treatment/control) ratio of 0.10 compared with 225Ac-DOTA-pelgi, 225Ac-DOTA-J591, and 227Th-HOPO-pelgifatamab (227Th-pelgi; all at 300 kBq/kg) with T/Cvolume ratios of 0.37, 0.39, and 0.33, respectively. 225Ac-pelgi was less myelosuppressive than 227Th-pelgi. 225Ac-pelgi showed dose-dependent treatment efficacy in the patient-derived KuCaP-1 model and strong combination potential with darolutamide in both cell line- (22Rv1) and patient-derived (ST1273) xenograft models., Conclusions: These results provide a strong rationale to investigate 225Ac-pelgi in patients with prostate cancer. A clinical phase I study has been initiated (NCT06052306)., (©2024 American Association for Cancer Research.)

Glioblastoma is the most common and malignant primary brain tumour, with a poor prognosis. Introduction of new treatment options is critically important. The study aimed to assess the appropriateness of escalation doses and toxicity of [225Ac]Ac-DOTA-SP therapy. Material and methods: A total of 21 patients (age of 43.0 ± 9.5 years), with histologically confirmed recurrent or conversion glioblastoma grade 4 following a standard therapy, have been included in the study. One to 2 intracavitary port-a-cath systems were stereotactically inserted. Patients were treated with escalation dose protocol with 10, 20 and 30 MBq per cycle totally 1–6 doses of [225Ac]Ac-DOTA-SP in 2-month intervals. Therapeutic response was monitored by clinical performance status and MRI imaging. Results: Treatment was well tolerated with mostly mild temporary adverse effects (oedema, epileptic seizures, aphasia, hemiparesis) mainly in the group of patients treated with 30 MBq of [225Ac]Ac-DOTA-SP. Only one patient treated with 30 MBq revealed thrombopenia grade 3. There was no other grade 3 and 4 toxicity related to [225Ac]Ac-DOTA-treatment in all groups. The median overall survival time from the primary diagnosis (OS-d) was 35.0 months and from the diagnosis of the recurrence/conversion (OS-r/c) was 13.2 months. From the start of treatment with [225Ac]Ac-DOTA-SP, the median PFS was 2.4 months, and the OS-t was 9.0 months. There were no statistically significant differences between the investigated dose escalation groups. Conclusions: Treatment of recurrent glioblastoma with [225Ac]Ac-DOTA-SP is safe and well tolerated up to 30 MBq per cycle. The escalation dose protocol showed good tolerability. Only mild temporary adverse effects were observed. No remarkable haematological, kidney and liver toxicity was seen. [ABSTRACT FROM AUTHOR]

The structural and bonding properties of Bi and Ac complexes with cyclen-based chelating ligands have been studied using relativistic DFT calculations in conjunction with TZ2P all-electron basis sets. Besides the parent cyclen ligand, the study has covered its extensions with pyridine-type (Lpy), carboxylate (DOTA, DOTPA), picolinate (MeDO2PA) and phosphonate (DOTMP) pendant arms. The effect of the cyclen ring size has been probed by increasing it from [12]aneN4 to [16]aneN4. Additional extensions in the DOTA complexes included the H2O ligand at the 9th coordination site as well as the p-SCN-Bn substituent (a popular linker to the targeting vector). The study focuses on the complex stability, the nature of bonding and the differences between Ac and Bi in the complexes. The metal–ligand interactions have been analysed by the Extended Transition State method combined with Natural Orbitals of Chemical Valence theory and Quantum Theory of Atoms in Molecules models. [ABSTRACT FROM AUTHOR]

In this work, the resin capacity factors of Ac, Am and Th on the DGA extraction chromatographic resin have been investigated between 0.5 and 2.0 M nitric acid without and with addition of elevated concentrations of the selective tetravalent complexant, 343HOPO. The resin capacity factors decreased with increasing 343HOPO concentration but remained high enough to support a selective removal of a tetravalent element. The Ac and Am capacity factors were also investigated under Th loading which yields generally reduced uptake on the resin. It was shown that loading effects could be fully scavenged by the addition of 343HOPO complexant. These results indicate that separation steps for Ac involving significant amounts of Th can be handled by selective tetravalent complexation with the DGA system. [ABSTRACT FROM AUTHOR]