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Frontiers in Medicine 2021Targeted alpha therapy (TAT) using alpha particle-emitting radionuclides is in the spotlight after the approval of RaCl for patients with metastatic castration-resistant... (Review)
Review
Targeted alpha therapy (TAT) using alpha particle-emitting radionuclides is in the spotlight after the approval of RaCl for patients with metastatic castration-resistant prostate cancer and the development of several alpha emitter-based radiopharmaceuticals. It is acknowledged that alpha particles are highly cytotoxic because they produce complex DNA lesions. Hence, the nucleus is considered their critical target, and many studies did not report any effect in other subcellular compartments. Moreover, their physical features, including their range in tissues (<100 μm) and their linear energy transfer (50-230 keV/μm), are well-characterized. Theoretically, TAT is indicated for very small-volume, disseminated tumors (e.g., micrometastases, circulating tumor cells). Moreover, due to their high cytotoxicity, alpha particles should be preferred to beta particles and X-rays to overcome radiation resistance. However, clinical studies showed that TAT might be efficient also in quite large tumors, and biological effects have been observed also away from irradiated cells. These distant effects are called bystander effects when occurring at short distance (<1 mm), and systemic effects when occurring at much longer distance. Systemic effects implicate the immune system. These findings showed that cells can die without receiving any radiation dose, and that a more complex and integrated view of radiobiology is required. This includes the notion that the direct, bystander and systemic responses cannot be dissociated because DNA damage is intimately linked to bystander effects and immune response. Here, we provide a brief overview of the paradigms that need to be revisited.
PubMed: 34386508
DOI: 10.3389/fmed.2021.692436 -
Seminars in Nuclear Medicine Mar 2020Prostate-specific membrane antigen (PSMA)-targeting radio-ligand therapy with beta-emitting Lutetium has already been investigated in several early phase dosimetry... (Review)
Review
Prostate-specific membrane antigen (PSMA)-targeting radio-ligand therapy with beta-emitting Lutetium has already been investigated in several early phase dosimetry studies, demonstrated promising results in phase-2, and recently the first phase-3 trial finished recruitment. In contrast, PSMA-targeting alpha-particle therapy (TAT) has only been evaluated in few preclinical experiments, preliminary dosimetry attempts and some retrospective observational studies, yet. First clinical experience with Ac-PSMA-617 demonstrates promising antitumor activity with a 63%-70% PSA-response rate, 10-15 months duration of response and complete remissions in approximately ten percent of patients, some of them with enduring relapse-free survival. Nevertheless, without comparative trials there is no prove whether, applied in identical clinical situations, Ac-PSMA-617 is really more efficiently than Lu-PSMA-617 or vice versa. However, there is some good rationale, that PSMA-TAT might have advantages in particular clinical indications. This includes patients with diffuse type red-marrow infiltration by reducing off-target radiation to surrounding cells; ablation of micrometastases after favorable response to other previous therapy or someday in early stage disease. Also treatment escalation of patients, either with poor response to Lu-PSMA or harboring adverse prognostic biomarkers, appears promising. In preclinical research, alpha-radiation demonstrated stronger induction of abscopal effects than beta-radiation; favoring its usage as a combination partner with immunotherapies. So, further evaluation of PSMA-TAT is definitely warranted. Recently, de-escalated treatment protocols and application of Ac/Lu-PSMA "cocktail"-regimens improved the tolerability of Ac-PSMA-617 TAT, reducing the risk for development dry-mouth syndrome. This opens new avenues for future application in earlier stage disease.
Topics: Actinium; Alpha Particles; Dipeptides; Heterocyclic Compounds, 1-Ring; Humans; Male; Neoplasm Staging; Prostate-Specific Antigen; Prostatic Neoplasms; Safety
PubMed: 32172798
DOI: 10.1053/j.semnuclmed.2020.02.004 -
Scientific Reports May 2023In search for critical elements, polymetallic nodules at the deep abyssal seafloor are targeted for mining operations. Nodules efficiently scavenge and retain several...
In search for critical elements, polymetallic nodules at the deep abyssal seafloor are targeted for mining operations. Nodules efficiently scavenge and retain several naturally occurring uranium-series radioisotopes, which predominantly emit alpha radiation during decay. Here, we present new data on the activity concentrations of thorium-230, radium-226, and protactinium-231, as well as on the release of radon-222 in and from nodules from the NE Pacific Ocean. In line with abundantly published data from historic studies, we demonstrate that the activity concentrations for several alpha emitters are often higher than 5 Bq g at the surface of the nodules. These observed values can exceed current exemption levels by up to a factor of 1000, and even entire nodules commonly exceed these limits. Exemption levels are in place for naturally occurring radioactive materials (NORM) such as ores and slags, to protect the public and to ensure occupational health and radiation safety. In this context, we discuss three ways of radiation exposure from nodules, including the inhalation or ingestion of nodule fines, the inhalation of radon gas in enclosed spaces and the potential concentration of some radioisotopes during nodule processing. Seen in this light, inappropriate handling of polymetallic nodules poses serious health risks.
Topics: Alpha Particles; Mining; Radioisotopes; Pacific Ocean; Uranium; Radiation Monitoring
PubMed: 37198245
DOI: 10.1038/s41598-023-33971-w -
Nanoscale May 2022Radiation detectors are widely used in physics, materials science, chemistry, and biology. Halide perovskites are known for their superior properties including tunable... (Review)
Review
Radiation detectors are widely used in physics, materials science, chemistry, and biology. Halide perovskites are known for their superior properties including tunable bandgaps and chemical compositions, high defect tolerance, solution-processable synthesis of films and crystals, and high carrier diffusion length. Recently, halide perovskites have attracted enormous interest as particle radiation detectors for both charged (α and β) and uncharged (neutrons) particles. Solid-state detectors based on single crystal perovskites can detect α particles and thermal neutrons with energy-resolved spectra. Halide perovskite scintillators are also able to detect β particles and fast neutrons. In this review, we briefly introduce the fundamentals of radiation detection and summarize the recent progress on halide perovskite detectors for particle radiation.
PubMed: 35470846
DOI: 10.1039/d2nr01292h -
The Quarterly Journal of Nuclear... Mar 2023The use of alpha emitting radiotherapeutics is increasing, with further growth expected due to a number of clinical trials currently running involving new alpha...
The use of alpha emitting radiotherapeutics is increasing, with further growth expected due to a number of clinical trials currently running involving new alpha emitters. However, literature concerning radiation safety aspects of alpha emitting radionuclides is limited and most of the available literature concerns Ra. In general, the occupational exposure from alpha emitting radionuclides is expected to be low, as are doses to the public from external exposure. However, care must be taken to avoid skin contamination, inhalation, and ingestion. Not all alpha emitting radionuclides are identical, they often have very different associated decay chains and emissions. The decay chains and the manufacturing process should be carefully examined to identify any long-lived progeny or impurities. These may have an impact on the radiation safety processes required to limit occupational exposure and for waste management. Doses to the public must also be assessed, either arising directly from exposure to patients treated with radiotherapeutics, or via waste streams. Risk assessments should be in place when starting a new service covering all aspects of the preparation and administration, as well as any foreseeable incidents such as skin contamination or patient death, and the appropriate steps to take in these instances. It is imperative that with the increase in the use of alpha emitting radiotherapeutics more literature is published on radiation safety aspects, especially for new alpha emitting radiotherapeutics which often have very different characteristics than the currently established ones.
Topics: Humans; Radiation Protection; Radioisotopes; Risk Assessment; Alpha Particles; Radiation Dosage
PubMed: 36633588
DOI: 10.23736/S1824-4785.22.03501-4 -
Journal of Medical Imaging and... Dec 2019The short range and high linear energy transfer of α-particles offer the potential for efficient tumor killing while sparing surrounding normal cells. Hematologic... (Review)
Review
INTRODUCTION
The short range and high linear energy transfer of α-particles offer the potential for efficient tumor killing while sparing surrounding normal cells. Hematologic malignancies are ideally suited to targeted α-therapy because of easy accessibility of malignant cells in blood and bone marrow and their radiosensitivity.
METHODS
A series of clinical trials were conducted to assess the safety and antileukemic effects of lintuzumab, an anti-CD33 antibody, labeled with the α-emitters bismuth-213 (Bi) and actinium-225 (Ac) in patients with acute myeloid leukemia (AML).
RESULTS
Initial studies showed that Bi-lintuzumab had antileukemic activity and could produce remissions after partial cytoreduction with cytarabine. A phase I trial demonstrated that a single infusion of Ac-lintuzumab could be given safely at doses up to 111 kBq/kg with antileukemic activity at all dose levels studied. A second phase I study showed that 28% of older patients with untreated AML had objective responses after receiving fractionated-dose Ac-lintuzumab and low-dose cytarabine. A phase II study of Ac-lintuzumab monotherapy in this population produced remissions in 69% of patients receiving two fractions of 74 kBq/kg and 22% of patients receiving two 55.5-kBq/kg fractions.
CONCLUSIONS
Studies with Bi-lintuzumab provided proof of principle for systemically administered α-particle therapy. Ac-lintuzumab was active against advanced AML and produced remissions in older patients with untreated AML in combination with low-dose cytarabine and as a single agent. These studies provide the rationale for development of Ac-lintuzumab in combination with a variety of agents in AML and in other hematologic malignancies such as myelodysplastic syndrome and multiple myeloma.
Topics: Actinium; Alpha Particles; Antibodies, Monoclonal, Humanized; Antimetabolites, Antineoplastic; Bismuth; Clinical Trials as Topic; Combined Modality Therapy; Cytarabine; Hematologic Neoplasms; Humans; Radioimmunotherapy; Radiotherapy
PubMed: 31253514
DOI: 10.1016/j.jmir.2019.05.008 -
International Journal of Molecular... Dec 2020Largely unnoticed, all life on earth is constantly exposed to low levels of ionizing radiation. Radon, an imperceptible natural occurring radioactive noble gas,... (Review)
Review
Largely unnoticed, all life on earth is constantly exposed to low levels of ionizing radiation. Radon, an imperceptible natural occurring radioactive noble gas, contributes as the largest single fraction to radiation exposure from natural sources. For that reason, radon represents a major issue for radiation protection. Nevertheless, radon is also applied for the therapy of inflammatory and degenerative diseases in galleries and spas to many thousand patients a year. In either case, chronic environmental exposure or therapy, the effect of radon on the organism exposed is still under investigation at all levels of interaction. This includes the physical stage of diffusion and energy deposition by radioactive decay of radon and its progeny and the biological stage of initiating and propagating a physiologic response or inducing cancer after chronic exposure. The purpose of this manuscript is to comprehensively review the current knowledge of radon and its progeny on physical background, associated cancer risk and potential therapeutic effects.
Topics: Air Pollution, Indoor; Animals; Clinical Trials as Topic; Environmental Exposure; Humans; Neoplasms; Radiation Exposure; Radiation Monitoring; Radon; Risk Assessment; Risk Factors
PubMed: 33396815
DOI: 10.3390/ijms22010316 -
PET Clinics Jul 2024Novel prostate-specific membrane antigen (PSMA) ligands labeled with α-emitting radionuclides are sparking a growing interest in prostate cancer treatment. These... (Review)
Review
Novel prostate-specific membrane antigen (PSMA) ligands labeled with α-emitting radionuclides are sparking a growing interest in prostate cancer treatment. These targeted alpha therapies (TATs) have attractive physical properties that deem them effective in progressive metastatic castrate-resistant prostate cancer (mCRPC). Among the PSMA TAT radiopharmaceuticals, [225Ac]Ac-PSMA has been used extensively on a compassionate basis and is currently undergoing phase I trials. Notably, TAT has the potential to improve quality of life and has favorable antitumor activity and outcomes in multiple scenarios other than in mCRPC. In addition, resistance mechanisms to TAT may be amenable to combination therapies.
Topics: Humans; Radiopharmaceuticals; Male; Glutamate Carboxypeptidase II; Antigens, Surface; Prostatic Neoplasms, Castration-Resistant; Prostatic Neoplasms; Alpha Particles; Actinium
PubMed: 38658230
DOI: 10.1016/j.cpet.2024.03.003 -
Frontiers in Cell and Developmental... 2022Exposure to environmental ionizing radiation is prevalent, with greatest lifetime doses typically from high Linear Energy Transfer (high-LET) alpha particles the... (Review)
Review
Exposure to environmental ionizing radiation is prevalent, with greatest lifetime doses typically from high Linear Energy Transfer (high-LET) alpha particles the radioactive decay of radon gas in indoor air. Particle radiation is highly genotoxic, inducing DNA damage including oxidative base lesions and DNA double strand breaks. Due to the ionization density of high-LET radiation, the consequent damage is highly clustered wherein ≥2 distinct DNA lesions occur within 1-2 helical turns of one another. These multiply-damaged sites are difficult for eukaryotic cells to resolve either quickly or accurately, resulting in the persistence of DNA damage and/or the accumulation of mutations at a greater rate per absorbed dose, relative to lower LET radiation types. The proximity of the same and different types of DNA lesions to one another is challenging for DNA repair processes, with diverse pathways often confounding or interplaying with one another in complex ways. In this context, understanding the state of the higher order chromatin compaction and arrangements is essential, as it influences the density of damage produced by high-LET radiation and regulates the recruitment and activity of DNA repair factors. This review will summarize the latest research exploring the processes by which clustered DNA damage sites are induced, detected, and repaired in the context of chromatin.
PubMed: 35912116
DOI: 10.3389/fcell.2022.910440 -
Seminars in Nuclear Medicine Mar 2020The short range and high linear energy transfer of α-particles offer the potential for efficient tumor killing while sparing normal bystander cells. Hematologic... (Review)
Review
The short range and high linear energy transfer of α-particles offer the potential for efficient tumor killing while sparing normal bystander cells. Hematologic malignancies are ideally suited to targeted α-particle therapy (TAT) due to easy accessibility of malignant cells in blood, bone marrow, lymph nodes, and spleen as well as their radiosensitivity. Most clinical trials using α-particle therapy for hematologic malignancies have focused on acute myeloid leukemia (AML); however, preclinical studies have shown activity against other diseases such as non-Hodgkin's lymphoma and multiple myeloma. To date, the short-lived radionuclide bismuth-213 (Bi) and its parent actinium-225 (Ac) have been used clinically, but trials with astatinie-211 (At) have recently begun, and thorium-227 (Th) has shown promising preclinical results. Lintuzumab is a humanized monoclonal antibody that targets the cell surface antigen CD33, which is expressed on the vast majority of AML cells. Initial studies showed that Bi-labeled lintuzumab had antileukemic activity and could produce remissions after partial cytoreduction with cytarabine. An initial phase I trial demonstrated that a single infusion of Ac-lintuzumab could be given safely at doses upto 111 kBq/kg with antileukemic activity across all dose levels. A second phase I study showed that fractionated-dose Ac-lintuzumab could be safely combined with low-dose cytarabine and produced objective responses in 28% of older patients with untreated AML. In a phase II study, treatment with Ac-lintuzumab monotherapy for a similar patient population resulted in remission in 69% of patients receiving two fractions of 74 kBq/kg and 22% of patients receiving two 55.5-kBq/kg fractions. Additionally, TAT may be useful in intensifying antileukemic therapy prior to hematopoietic cell transplantation, and pretargeting strategies offer the possibility for improved tumor-to-normal organ dose ratios.
Topics: Alpha Particles; Clinical Trials as Topic; Hematologic Neoplasms; Humans; Molecular Targeted Therapy; Safety
PubMed: 32172800
DOI: 10.1053/j.semnuclmed.2019.09.002