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Cancer Biotherapy & Radiopharmaceuticals Aug 2020α-Emitting radionuclides have been approved for cancer treatment since 2013, with increasing degrees of success. Despite this clinical utility, little is known... (Review)
Review
α-Emitting radionuclides have been approved for cancer treatment since 2013, with increasing degrees of success. Despite this clinical utility, little is known regarding the mechanisms of action of α particles in this setting, and accurate assessments of the dosimetry underpinning their effectiveness are lacking. However, targeted alpha therapy (TAT) is gaining more attention as new targets, synthetic chemistry approaches, and α particle emitters are identified, constructed, developed, and realized. From a radiobiological perspective, α particles are more effective at killing cells compared to low linear energy transfer radiation. Also, from these direct effects, it is now evident from preclinical and clinical data that α emitters are capable of both producing effects in nonirradiated bystander cells and stimulating the immune system, extending the biological effects of TAT beyond the range of α particles. The short range of α particles makes them a potent tool to irradiate single-cell lesions or treat solid tumors by minimizing unwanted irradiation of normal tissue surrounding the cancer cells, assuming a high specificity of the radiopharmaceutical and good stability of its chemical bonds. Clinical approval of RaCl in 2013 was a major milestone in the widespread application of TAT as a safe and effective strategy for cancer treatment. In addition, Ac-prostate specific membrane antigen treatment benefit in metastatic castrate-resistant prostate cancer patients, refractory to standard therapies, is another game-changing piece in the short history of TAT clinical application. Clinical applications of TAT are growing with different radionuclides and combination therapies, and in different clinical settings. Despite the remarkable advances in TAT dosimetry and imaging, it has not yet been used to its full potential. Labeled Th and Ac appear to be promising candidates and could represent the next generation of agents able to extend patient survival in several clinical scenarios.
Topics: Alpha Particles; Drug Approval; Drug Development; Humans; Molecular Targeted Therapy; Neoplasms; Radiation Oncology; Radioisotopes; Radiopharmaceuticals
PubMed: 32552031
DOI: 10.1089/cbr.2020.3576 -
European Journal of Nuclear Medicine... Dec 2021The approval of RaCl for cancer therapy in 2013 has heralded a resurgence of interest in the development of α-particle emitting radiopharmaceuticals. In the last...
The approval of RaCl for cancer therapy in 2013 has heralded a resurgence of interest in the development of α-particle emitting radiopharmaceuticals. In the last decade, over a dozen α-emitting radiopharmaceuticals have entered clinical trials, spawned by strong preclinical studies. In this article, we explore the potential role of α-particle therapy in cancer treatment. We begin by providing a background for the basic principles of therapy with α-emitters, and we explore recent breakthroughs in therapy with α-emitting radionuclides, including conjugates with small molecules and antibodies. Finally, we discuss some outstanding challenges to the clinical adoption of α-therapies and potential strategies to address them.
Topics: Alpha Particles; Humans; Neoplasms; Radioisotopes; Radiopharmaceuticals
PubMed: 34175980
DOI: 10.1007/s00259-021-05431-y -
Nuclear Medicine and Biology Jan 2021Targeted alpha therapy (TAT) is an area of research with rapidly increasing importance as the emitted alpha particle has a significant effect on inducing cytotoxic... (Review)
Review
Targeted alpha therapy (TAT) is an area of research with rapidly increasing importance as the emitted alpha particle has a significant effect on inducing cytotoxic effects on tumor cells while mitigating dose to normal tissues. Two significant isotopes of interest within the area of TAT are thorium-227 and actinium-225 due to their nuclear characteristics. Both isotopes have physical half-lives suitable for coordination with larger biomolecules, and additionally actinium-225 has potential to serve as an in vivo generator. In this review, the authors will discuss the production, purification, labeling reactions, and biological studies of actinium-225 and thorium-227 complexes and clinical studies.
Topics: Alpha Particles; Animals; Humans; Isotope Labeling; Radiochemistry
PubMed: 33558017
DOI: 10.1016/j.nucmedbio.2020.08.004 -
Scientific Reports Jun 2023Ionizing radiation is known to be DNA damaging and mutagenic, however less is known about which mutational footprints result from exposures of human cells to different...
Ionizing radiation is known to be DNA damaging and mutagenic, however less is known about which mutational footprints result from exposures of human cells to different types of radiation. We were interested in the mutagenic effects of particle radiation exposures on genomes of various human cell types, in order to gauge the genotoxic risks of galactic cosmic radiation, and of certain types of tumor radiotherapy. To this end, we exposed cultured cell lines from the human blood, breast and lung to fractionated proton and alpha particle (helium nuclei) beams at doses sufficient to considerably affect cell viability. Whole-genome sequencing revealed that mutation rates were not overall markedly increased upon proton and alpha exposures. However, there were modest changes in mutation spectra and distributions, such as the increases in clustered mutations and of certain types of indels and structural variants. The spectrum of mutagenic effects of particle beams may be cell-type and/or genetic background specific. Overall, the mutational effects of repeated exposures to proton and alpha radiation on human cells in culture appear subtle, however further work is warranted to understand effects of long-term exposures on various human tissues.
Topics: Humans; Protons; Alpha Particles; Cosmic Radiation; Radiation, Ionizing; Mutation; Mutagens
PubMed: 37328655
DOI: 10.1038/s41598-023-36845-3 -
Current Radiopharmaceuticals 2018Radiopharmaceutical therapy is a cancer treatment modality by which radiation is delivered directly to targeted tumor cells or to their microenvironment. This makes it... (Review)
Review
BACKGROUND
Radiopharmaceutical therapy is a cancer treatment modality by which radiation is delivered directly to targeted tumor cells or to their microenvironment. This makes it possible to deliver highly potent alpha-particle radiation. The short-range and highly potent nature of alpha-particles require a dosimetry methodology that considers microscale distributions of the alpha-emitting agent. The high energy deposition density along an alpha-particle track causes a spectrum of DNA lesions. The majority of these are irreparable DNA double-stranded breaks. Accordingly the biologic effects of alpha- particles are largely impervious to the adaptive and resistance mechanism that renders other therapeutics ineffectual.
OBJECTIVES
In this review, the radiobiology and dosimetry of alpha-particle emitting radionuclides as related to their use in radiopharmaceutical therapy, are presented.
CONCLUSION
Alpha-particle emitter radiopharmaceutical therapy is distinguished from other treatment modalities. Its safe clinical use requires an understanding of its unique dosimetry and radiobiology.
Topics: Alpha Particles; DNA Breaks, Double-Stranded; Humans; Neoplasms; Radiobiology; Radiochemistry; Radioimmunotherapy; Radioisotopes; Radiometry; Radiopharmaceuticals; Relative Biological Effectiveness
PubMed: 29697036
DOI: 10.2174/1874471011666180426130058 -
Cancer Biotherapy & Radiopharmaceuticals Aug 2020Targeted alpha therapy (TAT) can deliver high localized burden of radiation selectively to cancer cells as well as the tumor microenvironment, while minimizing toxicity... (Review)
Review
Targeted alpha therapy (TAT) can deliver high localized burden of radiation selectively to cancer cells as well as the tumor microenvironment, while minimizing toxicity to normal surrounding cell. Radium-223 (Ra), the first-in-class α-emitter approved for bone metastatic castration-resistant prostate cancer has shown the ability to prolong patient survival. Targeted Thorium-227 (Th) conjugates represent a new class of therapeutic radiopharmaceuticals for TAT. They are comprised of the α-emitter Th complexed to a chelator conjugated to a tumor-targeting monoclonal antibody. In this review, the authors will focus out interest on this therapeutic agent. In recent studies Th-labeled radioimmunoconjugates showed a relevant stability both in serum and vivo conditions with a significant antigen-dependent inhibition of cell growth. Unlike Ra, the parent radionuclide Th can form highly stable chelator complexes and is therefore amenable to targeted radioimmunotherapy. The authors discuss the future potential role of Th TAT in the treatment of several solid as well as hematologic malignancies.
Topics: Alpha Particles; Antibodies, Monoclonal; Biomarkers, Tumor; DNA Breaks, Double-Stranded; Drug Stability; Humans; Immunoconjugates; Molecular Targeted Therapy; Neoplasms; Radiopharmaceuticals; Thorium; Tumor Microenvironment
PubMed: 31967907
DOI: 10.1089/cbr.2019.3105 -
Journal of Medical Imaging and... Dec 2019Radiolabeled antibodies allow for selective targeting of the cancer cells within a tumor. Both beta- and alpha-emitting radioisotopes can be linked to the antibodies for... (Review)
Review
Radiolabeled antibodies allow for selective targeting of the cancer cells within a tumor. Both beta- and alpha-emitting radioisotopes can be linked to the antibodies for delivery of radiation to the cells. The choice of the radionuclide would depend on the biological characteristics of the antibody including its biodistribution and biological half-life. Alpha-emitting isotopes deliver high energy to target sites within short range and therefore less radiation to adjacent normal tissues. Whole antibodies have long biological clearance times that may be limiting due to radiation levels to blood and marrow. Novel strategies, such as development of smaller antibody fragments such as minibodies and diabodies, which have faster biological clearance, engineered bispecific antibodies, and multistep targeting that uses pretargeting and bioorthogonal click chemistry methods, appear promising. Several novel targets are being investigated in early-phase studies. This review provides a brief summary and current status of radioimmunotargeted agents in oncology.
Topics: Alpha Particles; Humans; Neoplasms; Radioimmunotherapy; Radiometry; Radiotherapy; Theranostic Nanomedicine
PubMed: 31451417
DOI: 10.1016/j.jmir.2019.07.006 -
Seminars in Nuclear Medicine Jul 2018Promising therapies are being developed or are in early-stage clinical trials that employ the use of alpha- and beta-emitting radionuclides to cure hematologic... (Review)
Review
Promising therapies are being developed or are in early-stage clinical trials that employ the use of alpha- and beta-emitting radionuclides to cure hematologic malignancies. However, these targeted radionuclide therapies have not yet met their expected potential for cancer treatment. A primary reason is lack of biodistribution, dosimetry, and dose-response information at cellular levels, which are directly related to optimal targeting, achieving a requisite therapeutic dose, and assessing the safety profile in normal organs and tissues. The current set of imaging tools, such as film autoradiography, scintigraphy, and SPECT/CT, available to researchers and clinicians do not allow the effective assessment of radiation absorbed dose distributions at cellular levels because resolutions are poor, measurement and analytical times are long, and the spatial resolutions are low-generally resulting in poor signal-to-noise ratios. Recently, new radiation digital autoradiography imaging tools have been developed that promise to address these challenges. They include scintillation-, gaseous-, and semiconductor-based radiation-detection technologies that localize the emission location of charged particles on an event-by-event basis at resolutions up to 20 µm FWHM for alpha and beta emitters. These imaging systems allow radionuclide activity concentrations to be quantified to unprecedented levels (mBq/µg) and provide real-time imaging and simultaneous imaging capabilities of both high- and low-activity samples without dynamic range limitations that plague traditional autoradiography. Additionally, large-area imagers are available (>20 × 20 cm) to accommodate high-throughput imaging studies. This article reviews the various detector classes and their associated performance trade-offs to provide researchers with an overview of the current technologies available for selecting an optimal detector configuration to meet imaging requirement needs.
Topics: Alpha Particles; Autoradiography; Beta Particles; Diagnostic Imaging
PubMed: 29852946
DOI: 10.1053/j.semnuclmed.2018.02.008 -
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 -
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