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Key Points Antibodies with practical healthcare applications are being introduced into modern medicine at a rapid pace by academic laboratories and industry. Therapeutic applications of these biologics are becoming increasingly important for cancer, either by promoting the body's own defence against the tumour or as a carrier for immunotoxins, drugs or radiation. Radioimmunotherapy, which is the subject of this Review, exploits the immune protein as a carrier for radioactive isotopes, tracers or targeted therapeutics. The radioantibody is introduced into the blood or a body cavity such as the peritoneum, pleura or intrathecal space, and is carried to its natural target or antigen-binding site on the tumour cell by blood flow, diffusion or the bulk flow of fluid. Cancer cells naturally produce cancer-associated biological molecules, which are adaptive features of malignant change that are suitable as antigenic binding sites owing to their relatively high abundance in cancer cells in comparison to normal tissues. These cancer-associated antigens may be located in the membrane, cytoplasm or organelles, including the nucleus. Typical concentrations of target antigens are in the nanomolar to low micromolar range. Cancer-selective antibodies and related immunoproteins are particularly well suited for conjugation with radioisotopes, for the purpose of detection or targeted radiotherapy. As a rule of thumb, the concentration of antibody at the binding site should approximate but not exceed the concentration of antigen (that is, the nanomolar range), and this amount of carrier is enormous relative to the required concentrations of attached radioisotopes for detection or therapy. This is because radioisotopes are among the most energetic moieties known, and this energy can be used for imaging or radiotherapy when attached to antibodies, in the femto-molar to pico-molar range. The modern manufacture of tumour-selective antibodies bearing tumour-killing radioactive cargo has effectively harnessed the power of the atom to safely destroy cancer cells. This Review presents fundamental concepts of chemistry, physics and biology that are essential for the effective radioimmunotherapy of human cancer. The eradication of cancer remains a vexing problem despite recent advances in our understanding of the molecular basis of neoplasia. One therapeutic approach that has demonstrated potential involves the selective targeting of radionuclides to cancer-associated cell surface antigens using monoclonal antibodies. Such radioimmunotherapy (RIT) permits the delivery of a high dose of therapeutic radiation to cancer cells, while minimizing the exposure of normal cells. Although this approach has been investigated for several decades, the cumulative advances in cancer biology, antibody engineering and radiochemistry in the past decade have markedly enhanced the ability of RIT to produce durable remissions of multiple cancer types.

This review summarizes recent progress and developments as well as the most important pitfalls in targeted alpha-particle therapy, covering single alpha-particle emitters as well as in vivo alpha-particle generators. It discusses the production of radionuclides like 211At, 223Ra, 225Ac/213Bi, labelling and delivery employing various targeting vectors (small molecules, chelators for alpha-emitting nuclides and their biomolecular targets as well as nanocarriers), general radiopharmaceutical issues, preclinical studies, and clinical trials including the possibilities of therapy prognosis and follow-up imaging. Special attention is given to the nuclear recoil effect and its impacts on the possible use of alpha emitters for cancer treatment, proper dose estimation, and labelling chemistry. The most recent and important achievements in the development of alpha emitters carrying vectors for preclinical and clinical use are highlighted along with an outlook for future developments.

Targeted alpha particle therapy (TAT) has emerged as a promising strategy for the treatment of prostate cancer (PCa). Actinium-225 ( Ac), 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 Ac in PCa are PSMA-targeted TAT agents, notably [ Ac]Ac-PSMA-617, [ Ac]Ac-PSMA-I&T and [ Ac]Ac-J591. Ongoing investigations spotlight [ Ac]Ac-hu11B6, [ Ac]Ac-YS5, and [ Ac]Ac-SibuDAB, targeting hK2, CD46, and PSMA, respectively. Despite these efforts, hurdles in Ac 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 Th, Ra, At, Bi, Pb or Tb, providing viable alternatives for TAT.

Combining targeted alpha and beta therapy may address challenges such as toxicity, treatment resistance, and tumor heterogeneity. We evaluated the feasibility and therapeutic effectiveness of a DOTA-PRIT approach using a Lu/ Ac radioisotope cocktail, directly compared with monotherapies targeting GPA33 in human colorectal cancer (CRC) xenografts in mice. A three-step pretargeting regimen was employed: an anti-GPA33/anti-DOTA bispecific antibody (BsAb), a dendrimeric clearing agent, and radioligands labeled with Lu, Ac, alone or in combination. Serial biodistribution studies in GPA33(+) SW1222 xenografts evaluated how co-injection of Lu and Ac radioligands affected tumor uptake and biodistribution. iQID digital autoradiography was used to visualize isotope distribution in tumor and kidney samples. Mice bearing SW1222 and LS174T xenografts received mono- or combination-therapy regimens delivering 37-38 Gy to tumors. Dose-escalation studies, histopathology, and qPCR analysis of DNA-damage and apoptosis-related genes were also performed. Biodistribution and autoradiography confirmed that the Lu- and Ac-labeled ligand effectively bound to pretargeted GPA33(+) xenografts when co-administered. High therapeutic indices were maintained across treatment groups, with autoradiography showing general overlap of co-injected probes. Combination therapy demonstrated comparable efficacy to monotherapies. At 150 d post-treatment, no treatment group had reached median survival; 5/9 mice receiving the cocktail (62.9 MBq Lu + 18.5 kBq Ac) were alive, including two tumor-free. In comparison, 4/8 mice in the Lu group and 8/10 in the Ac group survived, with 3 and 5 tumor-free animals, respectively. Combination therapy was well tolerated, showing no significant adverse effects on body weight or blood cell counts compared to healthy controls. Combined administration was safe up to 62.9 MBq Lu + 37 kBq Ac, resulting in 10/10 histological cures. Our findings confirm the feasibility of a combined Lu and Ac DOTA-PRIT in mice with established SW1222 xenografts, demonstrating tolerability and effectiveness comparable to monotherapy at equivalent average absorbed tumor doses.

Alpha-particle radionuclide-antibody conjugates are being clinically evaluated against solid tumors even when they moderately express the targeted markers. At this limit of lower tumor-absorbed doses, to maintain efficacy, the few(er) intratumorally delivered alpha-particles need to traverse/hit as many different cancer cells as possible. We complement antibody-radioconjugate therapies with a separate nanocarrier delivering a fraction of the same total injected radioactivity to tumor regions geographically different than those affected by targeting antibodies; these carrier-cocktails collectively distribute the alpha-particle emitters better. Methods The efficacy of actinium-225 delivered by our carrier-cocktails was assessed in vitro and on mice with orthotopic MDA-MB-436 and/or MDA-MB-231 triple-negative breast cancers and/or an ectopic BxPC3 pancreatic cancer. Cells/tumors were chosen to express low-to-moderate levels of HER1, as model antibody-targeted marker. Results Independent of cell line, antibody-radioconjugates were most lethal on cell monolayers. On spheroids, with radii greater than alpha-particles’ range, carrier-cocktails improved killing efficacy ( p  < 0.0500). Treatment with carrier-cocktails decreased the MDA-MB-436 and MDA-MB-231 orthotopic tumor volumes by 73.7% and 72.1%, respectively, relative to treatment with antibody-radioconjugates alone, at same total injected radioactivity; these carrier-cocktails completely eliminated formation of spontaneous metastases vs. 50% and 25% elimination in mice treated with antibody-radioconjugates alone. In BxPC3 tumor-bearing mice, carrier-cocktails increased the median survival to 25–26 days (in male–female animals) vs. 20–21 days of mice treated with antibody-radioconjugates alone (vs. 17 days for non-treated animals). Survival with carrier-cocktail radiotherapy was further prolonged by pre-injecting low-dose, standard-of-care, gemcitabine ( p  = 0.0390). Conclusion Tumor-agnostic carrier-cocktails significantly enhance the therapeutic efficacy of existing alpha-particle radionuclide-antibody treatments.

The α-emitting radionuclide actinium-225 possesses nuclear properties that are highly promising for use in targeted α therapy (TAT), a therapeutic strategy that employs α particle emissions to destroy tumors. A key factor, however, that may hinder the clinical use of actinium-225 is the poor understanding of its coordination chemistry, which creates challenges for the development of suitable chelation strategies for this ion. In this article, we provide an overview of the known chemistry of actinium and a summary of the chelating agents that have been explored for use in actinium-225-based TAT. This overview provides a starting point for researchers in the field of TAT to gain an understanding of this valuable therapeutic radionuclide.

Purpose Although 221 Fr and 213 Bi have sufficient gamma emission probabilities, quantitative SPECT after [ 225 Ac]Ac-PSMA-I&T therapy remains challenging due to low therapeutic activities. Furthermore, 221 Fr and 213 Bi may underlie a different pharmacokinetics due to alpha recoil. We conducted a quantitative SPECT study and a urine analysis to investigate the pharmacokinetics of 221 Fr and 213 Bi and the impact on image-based lesion and kidney dosimetry. Methods Five patients (7.7 ± 0.2 MBq [ 225 Ac]Ac-PSMA-I&T) underwent an abdominal SPECT/CT (1 h) at 24 and 48 h (Siemens Symbia T2, high-energy collimator, 440 keV/218 keV (width 20%), 78 keV (width 50%)). Quantitative SPECT was reconstructed using MAP-EM with attenuation and transmission-dependent scatter corrections and resolution modelling. Time-activity curves for kidneys (CT-based) and lesions (80% isocontour 24 h) were fitted mono-exponentially. Urine samples collected along with each SPECT/CT were measured in a gamma counter until secular equilibrium was reached. Results Mean kidney and lesion effective half-lives were as follows: 213 Bi, 27 ± 6/38 ± 10 h; 221 Fr, 24 ± 6/38 ± 11 h; 78 keV, 23 ± 7/39 ± 13 h. The 213 Bi-to- 221 Fr kidney SUV ratio increased by an average of 9% from 24 to 48 h. Urine analysis revealed an increasing 213 Bi-to- 225 Ac ratio (24 h, 0.98 ± 0.15; 48 h, 1.08 ± 0.09). Mean kidney and lesion absorbed doses were 0.17 ± 0.06 and 0.36 ± 0.1 Sv RBE = 5 /MBq using 221 Fr and 213 Bi SPECT images, compared to 0.16 ± 0.05/0.18 ± 0.06 and 0.36 ± 0.1/0.38 ± 0.1 Sv RBE = 5 /MBq considering either the 221 Fr or 213 Bi SPECT. Conclusion SPECT/CT imaging and urine analysis showed minor differences of up to 10% in the daughter-specific pharmacokinetics. These variances had a minimal impact on the lesion and kidney dosimetry which remained within 8%.

Purpose This systematic review and meta-analysis evaluates xerostomia occurrence in prostate cancer (PC) patients undergoing [ 225 Ac]Ac-prostate-specific membrane antigen ([ 225 Ac]Ac-PSMA) therapy. Methods Following the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P) guidelines, comprehensive electronic searches were conducted across PubMed, Scopus, and Web of Science. The study included articles addressing xerostomia as a side effect of [ 225 Ac]Ac-PSMA therapy in clinical settings, encompassing both tandem and monotherapy strategies. Methodological quality was assessed using the National Institutes of Health (NIH) Assessment Tool. Stata software was employed to perform pooled xerostomia rates, heterogeneity analysis, meta-regression, and publication bias analysis. Results Twenty studies met inclusion criteria, comprising 2949 [ 225 Ac]Ac-PSMA cycles administered to 1207 PC patients. For [ 225 Ac]Ac-PSMA monotherapy, the pooled rate of any-grade xerostomia was 84% (95%CI: 69–94%). Grade 1–2 xerostomia had a pooled rate 83% (95%CI: 71–93%), while therapy discontinuation due to xerostomia was 5% (95%CI: 0–13%). Grade 3 xerostomia was evident in 13% (95%CI: 7–20%). [ 225 Ac]Ac/[ 177 Lu]Lu-PSMA tandem therapy resulted in lower pooled rate of 68% for grade 1–2 toxicity (95%CI: 17–100%). Indirect comparison revealed a two-fold decrease in xerostomia risk with tandem protocol compared to monotherapy. Significant heterogeneity was observed, primarily influenced by baseline median prostate-specific antigen values ( p  = 0.04). Publication bias was present in most xerostomia subgroups, with trim-and-fill analysis adjusting for effect size in specific categories. Conclusion Xerostomia is most pronounced in patients undergoing [ 225 Ac]Ac-PSMA monotherapy. Tandem approach with [ 177 Lu]Lu-PSMA could reduce xerostomia rates and improve compliance. Further large-scale, prospective studies are necessary for generalization and result consolidation.

Targeted alpha therapy (TAT) pairs the specificity of antigen targeting with the lethality of alpha particles to eradicate cancerous cells. Actinium-225 [ 225 Ac; t 1/2  = 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, 227 Ac [t 1/2  = 21.772(3) years]. We expect these results to direct renewed efforts for 225 Ac-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. Despite the progression of Actinium-225 (225Ac) radiopharmaceuticals, there is still a limited understanding of Ac coordination chemistry due to its radioactivity, poor availability, and lack of stable isotopes. Here, the authors demonstrate a platform to characterize the solution and solid-state behavior of the longest-lived Ac isotope, 227Ac.

In targeted alpha-particle therapy, actinium-225 (Ac-225) has emerged as a radionuclide of potential, driving extensive efforts to develop innovative radiopharmaceuticals. High-resolution imaging of alpha particles is required for precisely detecting alpha-emitting radionuclides in cellular environments and small organs. Here, we report real-time trajectory imaging of alpha particles emitted by Ac-225 and its daughter radionuclides, utilizing an alpha particle trajectory imaging system. This system incorporates a magnification unit, a cooled electron-multiplying charge-coupled device (EM-CCD) camera, and a Ce-doped Gd 3 Al 2 Ga 3 O 12 (GAGG) scintillator. Alpha particles were projected onto the GAGG scintillator, producing magnified images that were captured at 100 ms intervals. We successfully tracked particle trajectories with varying lengths and intensities for 4 different alpha particles emitted from Ac-225 and its daughter radionuclides with a spatial resolution of 1.0 μm. Notably, we achieved the imaging of sequentially emitted trajectories from Fr-221 and its decay product At-217, characterized by short decay intervals, along with the extended trajectories of high-energy alpha particles emitted by Po-213. These results demonstrate that high-resolution trajectory imaging, integrated with temporal and energy information, offers profound insights into the real-time behavior of Ac-225 and its daughter radionuclides within living cells or tissue sections, thereby driving advancements in targeted alpha-particle therapy.