[The lacrimal apparatus as an organ at risk during radionuclide therapy].

Within the framework of the article, the authors analyzed the available information about the damage to the lacrimal apparatus during radionuclide therapy. In focus of article lesions of the lacrimal production system, the main and accessory lacrimal glands, as well as lacrimal drainage are considered. It was found that damage to the lacrimal apparatus is characteristic of 131I therapy for thyroid cancer, as well as for radioligand therapy using anti-PSMA antibodies labeled with 177Lu and 225Ac. 177Lu-PSMA and 225Ac-PSMA may damage the lacrimal gland with the formation of a clinically pronounced "dry eye syndrome". The pathogenesis of such lesions is associated with the accumulation of a radioisotope in the tissues of the lacrimal apparatus, while during therapy with 131I, accumulation is realized due to the expression of the sodium-iodine symporter in the nasolacrimal duct, and during therapy with 177Lu-PSMA and 225Ac-PSMA, the radiobiological effect is realized in connection with the expression PSMA by lacrimal tissue. An analysis of the available sources showed that to date there are no results of systematic studies on the problem, there is a lack of knowledge regarding the individual risks of developing these complications, methods for their prevention that have proven effectiveness have not been developed, and the treatment methods used, having relatively low efficiency, are not specialized. The authors concluded that the strengthening of interdisciplinary interaction, as well as the organization verification methodology and correct studies, can contribute to solving problems related to the study of the complications under consideration.

Automated radiolabeling and handling of 177 Lu- and 225 Ac-PSMA-617 using a robotic pipettor.

While automated modules for F-18 and C-11 radiosyntheses are standardized with features such as multiple reactors, vacuum connection and semi-preparative HPLC, labeling and processing of compounds with radiometals such as Zr-89, Lu-177 and Ac-225 often do not require complex manipulations and are frequently performed manually by a radiochemist. These procedures typically involve transferring solutions to and from vials using pipettes followed by heating of the reaction mixture, and do not require all the features found in most commercial automated synthesis units marketed as F-18 or C-11 modules. Here we present an efficient automated method for performing radiosyntheses involving radiometals by adapting a commercially available robotic pipettor originally developed for high-throughput processing of biological samples. While a robotic pipettor is less costly than a radiosynthesis module, it holds many similar advantages over manual radiosynthesis such as minimization of operator error, lower operator exposure rates, and abbreviated synthesis times, among others. To demonstrate the feasibility of using the OpenTrons OT-2 robotic pipettor to perform automated radiosyntheses, we radiolabeled and formulated 177 Lu-PSMA-617 and 225 Ac-PSMA-617 on the system. The OT-2 was then used to help streamline the quality control process for both products, further minimizing manual handling by and exposure to the radiochemist.

Actinium-225-PSMA radioligand therapy of metastatic castration-resistant prostate cancer (WARMTH Act): a multicentre, retrospective study.

BACKGROUND: Actinium-225 (225Ac) prostate-specific membrane antigen (PSMA) radioligand therapy (RLT) is a novel therapy for metastatic castration-resistant prostate cancer (mCRPC). We aimed to report the safety and antitumour activity of 225Ac-PSMA RLT of mCRPC in a large cohort of patients treated at multiple centres across the world. METHODS: This retrospective study included patients treated at seven centres in Australia, India, Germany, and South Africa. We pooled data of consecutive patients of any age and Eastern Cooperative Oncology Group performance status with histopathologically confirmed adenocarcinoma of the prostate who were treated with one or more cycles of 8 MBq 225Ac-PSMA RLT administered intravenously for mCRPC. Previous lines of mCRPC treatment included taxane-based chemotherapy, androgen-receptor-axis inhibitors, lutetium-177 (177Lu) PSMA RLT, and radium-223 dichloride. The primary outcomes were overall survival and progression-free survival. FINDINGS: Between Jan 1, 2016, and May 31, 2023, 488 men with mCRPC received 1174 cycles of 225Ac-PSMA RLT (median two cycles, IQR 2-4). The mean age of the patients was 68·1 years (SD 8·8), and the median baseline prostate-specific antigen was 169·5 ng/mL (IQR 34·6-519·8). Previous lines of treatment were docetaxel in 324 (66%) patients, cabazitaxel in 103 (21%) patients, abiraterone in 191 (39%) patients, enzalutamide in 188 (39%) patients, 177Lu-PSMA RLT in 154 (32%) patients, and radium-223 dichloride in 18 (4%) patients. The median follow-up duration was 9·0 months (IQR 5·0-17·5). The median overall survival was 15·5 months (95% CI 13·4-18·3) and median progression-free survival was 7·9 months (6·8-8·9). In 347 (71%) of 488 patients, information regarding treatment-induced xerostomia was available, and 236 (68%) of the 347 patients reported xerostomia after the first cycle of 225Ac-PSMA RLT. All patients who received more than seven cycles of 225Ac-PSMA RLT reported xerostomia. Grade 3 or higher anaemia occurred in 64 (13%) of 488 patients, leukopenia in 19 (4%), thrombocytopenia in 32 (7%), and renal toxicity in 22 (5%). No serious adverse events or treatment-related deaths were recorded. INTERPRETATION: 225Ac-PSMA RLT shows a substantial antitumour effect in mCRPC and represents a viable therapy option in patients treated with previous lines of approved agents. Xerostomia is a common side-effect. Severe bone marrow and renal toxicity are less common adverse events. FUNDING: None.

CD46-Targeted Theranostics for PET and 225Ac-Radiopharmaceutical Therapy of Multiple Myeloma.

PURPOSE: Multiple 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 DESIGN: In 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. CONCLUSIONS: Our 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.

A review of recent advancements in Actinium-225 labeled compounds and biomolecules for therapeutic purposes.

In nuclear medicine, cancers that cannot be cured or can only be treated partially by traditional techniques like surgery or chemotherapy are killed by ionizing radiation as a form of therapeutic treatment. Actinium-225 is an alpha-emitting radionuclide that is highly encouraging as a therapeutic approach and more promising for targeted alpha therapy (TAT). Actinium-225 is the best candidate for tumor cells treatment and has physical characteristics such as high (LET) linear energy transfer (150 keV per µm), half-life (t1/2 = 9.92d), and short ranges (400-100 µm) which prevent the damage of normal healthy tissues. The introduction of various new radiopharmaceuticals and radioisotopes has significantly assisted the advancement of nuclear medicine. Ac-225 radiopharmaceuticals continuously demonstrate their potential as targeted alpha therapeutics. 225 Ac-labeled radiopharmaceuticals have confirmed their importance in medical and clinical areas by introducing [225 Ac]Ac-PSMA-617, [225 Ac]Ac-DOTATOC, [225 Ac]Ac-DOTA-substance-P, reported significantly improved response in patients with prostate cancer, neuroendocrine, and glioma, respectively. The development of these radiopharmaceuticals required a suitable buffer, incubation time, optimal pH, and reaction temperature. There is a growing need to standardize quality control (QC) testing techniques such as radiochemical purity (RCP). This review aims to summarize the development of the Ac-225 labeled compounds and biomolecules. The current state of their reported resulting clinical applications is also summarized as well.

Actinium-225 Targeted Agents: Where Are We Now?

α-particle targeted radionuclide therapy has shown promise for optimal cancer management, an exciting new era for brachytherapy. Alpha-emitting nuclides can have significant advantages over gamma- and beta-emitters due to their high linear energy transfer (LET). While their limited path length results in more specific tumor 0kill with less damage to surrounding normal tissues, their high LET can produce substantially more lethal double strand DNA breaks per radiation track than beta particles. Over the last decade, the physical and chemical attributes of Actinium-225 (225Ac) including its half-life, decay schemes, path length, and straightforward chelation ability has peaked interest for brachytherapy agent development. However, this has been met with challenges including source availability, accurate modeling for standardized dosimetry for brachytherapy treatment planning, and laboratory space allocation in the hospital setting for on-demand radiopharmaceuticals production. Current evidence suggests that a simple empirical approach based on 225Ac administered radioactivity may lead to inconsistent outcomes and toxicity. In this review article, we highlight the recent advances in 225Ac source production, dosimetry modeling, and current clinical studies.

The role of the DC component in human perception of AC-DC hybrid electric fields and a comparison with the AC component.

As part of the energy transition in Germany, high-voltage overhead power lines will be operated using hybrid systems that combine alternating and direct current (AC and DC). The degree to which humans perceive hybrid electric fields (EFs) is dependent on the proportion of both EF types. To investigate the impact of the DC component, a study assessed 49 participants with above-average EF detection ability under conditions with a low DC component of 1-4 kilovolts per meter (kV/m) and varying AC EFs between 1 and 14 kV/m. The detection thresholds of combined AC/DC EFs decreased with an increase in the DC component and ranged from 9.6 to 6.83 kV/m on average for the group. The results suggest that even minor variations in the DC component significantly affect human perception of hybrid EFs. These findings complement the results of an earlier study that investigated the AC component in hybrid EFs. Correlational analyses of both studies demonstrated the reliability of participants' performance. This study contributes to our understanding of EF-related effects on human perception and can aid in the planning of energy transmission near areas where humans work or live.

RYZ101 (Ac-225 DOTATATE) Opportunity beyond Gastroenteropancreatic Neuroendocrine Tumors: Preclinical Efficacy in Small-Cell Lung Cancer.

Overexpression of somatostatin receptors (SSTR), particularly SSTR2, is found in gastroenteropancreatic neuroendocrine tumors (GEP-NET), and subsets of other solid tumors such as small-cell lung cancer (SCLC). SCLC accounts for approximately 13% to 15% of lung cancer and lacks effective therapeutic options. IHC analysis indicates that up to 50% of SCLC tumors are SSTR2-positive, with a substantial subset showing high and homogenous expression. Peptide receptor radionuclide therapy with radiolabeled somatostatin analogue, Lu-177 DOTATATE, has been approved for GEP-NETs. Different strategies aimed at improving outcomes, such as the use of alpha-emitting radioisotopes, are currently being investigated. RYZ101 (Ac-225 DOTATATE) is comprised of the alpha-emitting radioisotope actinium-225, chemical chelator DOTA, and octreotate (TATE), a somatostatin analogue. In the cell-based competitive radioligand binding assay, RAYZ-10001-La (lanthanum surrogate for RYZ101) showed high binding affinity (Ki = 0.057 nmol/L) to human SSTR2 and >600-fold selectivity against other SSTR subtypes. RAYZ-10001-La exhibited efficient internalization to SSTR2-positive cells. In multiple SSTR2-expressing SCLC xenograft models, single-dose intravenous RYZ101 3 µCi (0.111 MBq) or 4 µCi (0.148 MBq) significantly inhibited tumor growth, with deeper responses, including sustained regression, observed in the models with higher SSTR2 levels. The antitumor effect was further enhanced when RYZ101 was combined with carboplatin and etoposide at clinically relevant doses. In summary, RYZ101 is a highly potent, alpha-emitting radiopharmaceutical agent, and preclinical data demonstrate the potential of RYZ101 for the treatment of patients with SSTR-positive cancers.

Prognostic value of neutrophil-to-lymphocyte ratio in patients with metastatic castration-resistant prostate cancer receiving prostate-specific membrane antigen targeted radionuclide therapy.

BACKGROUND: Neutrophil count:lymphocyte count ratio (NLR) may be a prognostic factor for men with advanced prostate cancer. We hypothesized that it is associated with prostate-specific antigen (PSA) response and survival in men treated with prostate-specific membrane antigen (PSMA)-targeted radionuclide therapy (TRT). METHODS: Data of 180 men with metastatic castration-resistant prostate cancer (mCRPC) who were treated in sequential prospective radionuclide clinical trials from 2002 to 2021 (utilizing 177Lu-J591, 90Y-J591, 177Lu-PSMA-617, or 225Ac-J591) were retrospectively analyzed. We used a logistic regression to determine the association between NLR and ≥50% PSA decline (PSA50) and a Cox proportional hazards model to investigate the association between NLR and overall survival (OS). RESULTS: A total of 94 subjects (52.2%) received 177Lu-J591, 51 (28.3%) 177Lu-PSMA-617, 28 (15.6%) 225Ac-J591, and 7 (3.9%) 90Y-J591. The median NLR of 3.75 was used as cut-off (low vs. high NLR; n = 90, respectively). On univariate analysis, NLR was not associated with PSA50 (HR 1.08; 95% confidence interval [CI] 0.99-1.17, p = 0.067). However, it was associated with worse OS (hazard ratio [HR] 1.06, 95% CI 1.02-1.09, p = 0.002), also after controlling for circulating tumor cell count and cancer and leukemia group B risk group (HR 1.05; 95% CI 1.003-1.11, p = 0.036). Men with high NLR were at a higher hazard of death from all causes (HR 1.43, 95% CI 1.05-1.94, p = 0.024). CONCLUSIONS: NLR provides prognostic information in the setting of patients with mCRPC receiving treatment with PSMA-TRT.

Efficacy and Safety of Actinium-225 Prostate-Specific Membrane Antigen Radioligand Therapy in Metastatic Prostate Cancer: A Systematic Review and Metanalysis.

BACKGROUND: Actinium-225 (Ac-225) labelled PSMA RLT has been tested recently in metastatic castration-resistant prostate cancer (mCRPC), with encouraging results. Ac-225, being an alpha emitter, is expected to have higher efficacy and fewer side effects compared to the beta-emitters such as Lutetium-177. We have performed a meta-analysis to assess the therapeutic responses, survival effects, and significant side effects of Ac-225 PSMA RLT in patients with mCRPC. METHODOLOGY: Systematic literature search was carried out from five electronic databases PubMed/MEDLINE, SCOPUS, EMBASE, Web of Science, and Cochrane Library until March 2021. Eight studies were found to be eligible for this metanalysis. RESULTS: Eight studies with 226 patients were analyzed in this metanalysis. 81% (95% CI 73-89) patients had a decline in PSA levels. 60% of the patients showed more than 50% PSA decline. Two studies assessed survival effects of radioligand naïve patients compared to patients who had received Lu-PSMA therapy previously and the pooled HR for radioligand naïve patients is 0.22. The most common toxicity reported was xerostomia in 167 patients out of 226 patients (73.9%, 95% CI 67.6-79.5%); however, most of them were confined to grade I and II levels. Other reported side effects include hematologic toxicity and nephrotoxicity. CONCLUSION: Ac-PSMA RLT is a safe and potentially effective treatment option for patients with mCRPC.

Treatment of Prostate Cancer with CD46-targeted 225Ac Alpha Particle Radioimmunotherapy.

PURPOSE: Radiopharmaceutical 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. RESULTS: Biodistribution 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.

Response to RL-225Ac in prostate cancer: Effect of prior treatment with RL-177Lu: A systematic review of the literature.

BACKGROUND: Targeted radionuclide therapy with Actinium-225-labeled prostate-specific membrane antigen agents (225Ac-PSMA) is currently being studied in clinical trials for patients with metastatic castration-resistant prostate cancer (mCRPC). Compared to ß-emitting therapeutic radionuclides, alpha-emitters (e.g., 225Ac) have a significantly higher linear energy transfer and significantly shorter range. As a result, alpha emitters could be expected to improve efficacy and reduce bystander toxicity. This systematic literature review was conducted to evaluate the impact of sequencing of 177Lu-PSMA and 225Ac-PSMA targeted radionuclide therapy (TRT) in mCRPC. METHODS: The present systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. The searches were made using relevant keywords in the PubMed, Scopus, and Web of Science databases, and articles up to August 22, 2022, were included. Publications were excluded if they were duplicate publications, wrong study or publication format, or discussing a topic out of scope. Data on efficacy, toxicity, and health-related quality of life were extracted from the individual articles. The I2 index was used to measure the extent of heterogeneity amongst studies. In the studies that reported subgroup outcomes according to the prior status on 177Lu-PSMA TRT, pooled estimates of the main outcomes were generated through descriptive analysis. Quality assessment was performed using the Newark-Ottawa-scale. RESULTS: The study included 12 articles; 1 series was performed prospectively. In total, data of 329 patients were analyzed. About 40.1% (n = 132) of the included men were pretreated with 177Lu-PSMA TRT. Seven studies, including data of 212 individuals, were eligible for quantitative analysis based on reporting outcomes of the subgroups according to their prior status on 177Lu-PSMA TRT. >25% PSA decline after 225Ac-PSMA TRT was lower in individuals who received prior 177Lu-PSMA TRT (pooled median 42.7%) compared to those who did not (pooled median 15.4%). The pooled medians of the reported median progression-free survival and overall survival for pretreated versus not pretreated individuals was 4.3 versus 14.3 months and 11.1 versus 9.2 months, respectively. However, the outcomes for each individual study were reported inconsistently (I2 = 99.9%). None of the included studies stratified the report of adverse events or changes in health-related quality of life for the subgroups. CONCLUSIONS: 225Ac-PSMA TRT is an experimental treatment for men with mCRPC. There is limited data available from high-quality trials but so far PSMA-targeted TRT has demonstrated a low morbidity profile. Our review revealed that there is a possible decrease in efficacy of targeted alpha-particle therapy if individuals previously were exposed to 177Lu-PSMA TRT. However, the level of evidence is low. The underlying mechanism by which 177Lu-PSMA TRT might trigger possible radioresistance as well as randomized controlled trials are required to establish the therapeutic efficacy and safety of 225-Ac-PSMA TRT in men refractory to 177Lu-PSMA TRT.

Gastro-Enteric-Pancreatic Neuroendocrine Tumor Treatment: Actinium-225-DOTATATE and Combined Therapies.

The role of lutetium-177-DOTATATE in advanced well-differentiated gastro-entero-pancreatic neuroendocrine tumors is well established. However, there is a scope for improving treatment outcomes. Actinium-225-DOTATATE is a form of targeted alpha therapy (TAT) that results in more efficient tumor cell killing owing to the substantially higher linear energy transfer of alpha particles. Systemic TAT is also safe given that the shorter path length of the alpha particles spares the surrounding healthy tissue and results in relatively fewer adverse events. Combination therapies with radiosensitizing and other chemotherapeutic agents have also gained popularity, especially in the setting of higher grade and fluorodeoxyglucose-avid tumors.

Estimating the Gibbs Hydration Energies of Actinium and Trans-Plutonium Actinides.

The use of actinides for medical, scientific and technological purposes has gained momentum in the recent years. This creates a need to understand their interactions with biomolecules, both at the interface and as they become complexed. Calculation of the Gibbs binding energies of the ions to biomolecules, i. e., the Gibbs energy change associated with a transfer of an ion from the water phase to its binding site, could help to understand the actinides' toxicities and to design agents that bind them with high affinities. To this end, there is a need to obtain accurate reference values for actinide hydration, that for most actinides are not available from experiment. In this study, a set of ionic radii is developed that enables future calculations of binding energies for Pu3+ and five actinides with renewed scientific and technological interest: Ac3+ , Am3+ , Cm3+ , Bk3+ and Cf3+ . Reference hydration energies were calculated using quantum chemistry and ion solvation theory and agree well for all ions except Ac3+ , where ion solvation theory seems to underestimate the magnitude of the Gibbs hydration energy. The set of radii and reference energies that are presented here provide means to calculate binding energies for actinides and biomolecules.

The evolution of PRRT for the treatment of neuroendocrine tumors; What comes next?

Lu-177 has been developed for the treatment of patients with peptide receptor radionuclide therapy (PRRT). A second generation pure no-carrier-added Lu-177 has a high specific activity and has waste disposal advantages over the first generation carrier-added Lu-177. PRRT has recently been developed for the treatment of neuroendocrine tumors (NETs). The majority of pancreatic and gastroenteric NETs (GEP-NETs) express the somatostatin receptors (SSTRs) 2 and 5. These receptors can be specifically targeted with a somatostatin peptide analogue (DOTATOC/DOTATATE) which can be chelated to a positron emission tomography (PET) emitting radioisotope such as Ga-68 for imaging or to a ß-emitting radioisotope Lu-177 for therapy. A key advantage of this approach is that the receptor expression can be demonstrated by PET imaging before the patient is treated. Clinical studies in G1 and G2 GEP-NETS have demonstrated that PRRT is extremely effective in terms of progression free survival (PFS), symptom control and quality of life, with a well-established safety profile. A beneficial effect on outcome survival awaits to be confirmed. The first commercially available product Lu-177-DOTATATE was approved following the NETTER-1 trial in G1 and G2 GE-NETS. Lu-177-DOTATATE 7,4 GBq every 8 weeks for 4 cycles, together with octreotide LAR 30 mg monthly, demonstrated a median PFS of 28,4 months compared to 8,5 months for octreotide LAR 60 mg monthly. A second pivotal study COMPETE is currently in progress, comparing no carrier-added (n.c.a.) Lu-177-DOTATOC to the m-TOR inhibitor Everolimus in both GE-NETs and PNETs. Two studies, NETTER-2 and COMPOSE are currently underway in patients with high grade G2 and G3 NETs. Novel SSTR antagonists are being developed as next generation targeting molecules for SSTR2-expressing tumors. Antagonists have a higher tumor binding to receptors than agonists, opening up the potential indications for SSTR2 targeting to tumors which have a relatively lower expression of SSTR2 compared to NET such as small cell lung cancer, hepatocellular carcinoma and breast cancer. In addition to Lu-177, radioisotopes with different radiation properties such as Tb-161 and the α-emitter Ac-225 are being developed which have the potential to improve treatment efficacy across the range of G1 to G3 NETs.

Preclinical Evaluation of 225Ac-Labeled Single-Domain Antibody for the Treatment of HER2pos Cancer.

Human epidermal growth factor receptor type 2 (HER2) is overexpressed in various cancers; thus, HER2-targeting single-domain antibodies (sdAb) could offer a useful platform for radioimmunotherapy. In this study, we optimized the labeling of an anti-HER2-sdAb with the α-particle-emitter 225Ac through a DOTA-derivative. The formed radioconjugate was tested for binding affinity, specificity and internalization properties, whereas cytotoxicity was evaluated by clonogenic and DNA double-strand-breaks assays. Biodistribution studies were performed in mice bearing subcutaneous HER2pos tumors to estimate absorbed doses delivered to organs and tissues. Therapeutic efficacy and potential toxicity were assessed in HER2pos intraperitoneal ovarian cancer model and in healthy C57Bl/6 mice. [225Ac]Ac-DOTA-2Rs15d exhibited specific cell uptake and cell-killing capacity in HER2pos cells (EC50 = 3.9 ± 1.1 kBq/mL). Uptake in HER2pos lesions peaked at 3 hours (9.64 ± 1.69% IA/g), with very low accumulation in other organs (<1% IA/g) except for kidneys (11.69 ± 1.10% IA/g). α-camera imaging presented homogeneous uptake of radioactivity in tumors, although heterogeneous in kidneys, with a higher signal density in cortex versus medulla. In mice with HER2pos disseminated tumors, repeated administration of [225Ac]Ac-DOTA-2Rs15d significantly prolonged survival (143 days) compared to control groups (56 and 61 days) and to the group treated with HER2-targeting mAb trastuzumab (100 days). Histopathologic evaluation revealed signs of kidney toxicity after repeated administration of [225Ac]Ac-DOTA-2Rs15d. [225Ac]Ac-DOTA-2Rs15d efficiently targeted HER2pos cells and was effective in treatment of intraperitoneal disseminated tumors, both alone and as an add-on combination with trastuzumab, albeit with substantial signs of inflammation in kidneys. This study warrants further development of [225Ac]Ac-DOTA-2Rs15d.

[Research and Development of 211At-MABG, 225Ac Production, and Anti-Podoplanin Antibody Therapy in Japan].

In Japan, research and development of"targeted radioisotope therapy: TRT"or"targeted α therapy: TAT"is focusing the 2 α nuclides, 225Ac, 211At. In this article, I would like to provide a brief summary of the following TAT agents, 211At-MABG and 225Ac anti-podoplanin antibody.

Protactinium and Actinium Monohydrides: A Theoretical Study on Their Spectroscopic and Thermodynamic Properties.

Spectroscopic and thermodynamics properties including bond dissociation energies (BDEs), adiabatic electron affinities (AEAs), and ionization energies (IEs) have been predicted for AcH and PaH using the Feller-Peterson-Dixon composite approach. Comparisons with previous studies on ThH and UH were performed to identify possible trends in the actinide series. Multireference CASPT2 calculations were used to predict the spin-orbit effects and obtain potential energy curves for the low-lying Ω states around the equilibrium distance as well as the vertical detachment energies (VDEs) from AcH- and PaH- to excited states of the neutral species. The calculated AEA for AnH (An = Ac, Th, Pa, U) showed that the AEA increases from AcH (0.425 eV) to ThH (0.820 eV) and decreases to PaH (0.781 eV) and to UH (0.457 eV), whereas the IE values are 5.887 eV (AcH), 6.181 eV (ThH), 6.204 eV (PaH), and 6.182 eV (UH). The ground state of AcH, AcH-, PaH, and PaH- are predicted to be1Σ+0,2Π3/2, 3H4, and 4I9/2, respectively. The BDEs for AcH and PaH are 276.4 and 237.2 kJ/mol, and those for AcH- and PaH- are 242.8 and 239.8 kJ/mol, respectively. The natural bond analysis shows a significant ionic character, An+H-, in the bonding of the neutral hydrides.

Challenges and opportunities in developing Actinium-225 radiopharmaceuticals.

Actinium-225 (225Ac) has emerged as a promising therapeutic radioisotope for targeted alpha therapy. It emits net four alpha particles during its decay to stable daughter bismuth-209, rightly called an in-vivo nano-generator. Compared to the worldwide demand of 225Ac, the amount produced via depleted thorium-229 sources is minimal, making it an expensive radionuclide. However, many research groups are working on optimizing the parameters for the production of 225Ac via different routes, including cyclotrons, reactors and high-energy linear accelerators. The present review article focuses on the various aspects associated with the development of 225Ac radiopharmaceuticals. It includes the challenges and opportunities associated with the production methods, labeling chemistry, in-vivo kinetics and dosimetry of 225Ac radiopharmaceuticals. A brief description is also given about the 225Ac radiopharmaceuticals at preclinical stages, clinical trials and used routinely.

Regulating alpha-emitting radioisotopes and specific considerations for actinium-225 containing actinium-227.

Although alpha-emitting radioisotopes have favorable characteristics for limiting external exposure to radiation workers, there are significant dose consequences associated with accidental internal uptake. Consequently, regulatory requirements and license restrictions are designed to limit such risks to users. This paper will review regulatory limits for decommissioning financial assurance and annual limits on intake for actinium-227, review US Nuclear Regulatory Commission guidance for alpha contamination monitoring, and discuss regulatory examples from the Wisconsin Department of Health Services.