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Scientific Reports Jul 2023There is agreement that high-LET radiation has a high Relative Biological Effectiveness (RBE) when delivered as a single treatment, but how it interacts with radiations...
There is agreement that high-LET radiation has a high Relative Biological Effectiveness (RBE) when delivered as a single treatment, but how it interacts with radiations of different qualities, such as X-rays, is less clear. We sought to clarify these effects by quantifying and modelling responses to X-ray and alpha particle combinations. Cells were exposed to X-rays, alpha particles, or combinations, with different doses and temporal separations. DNA damage was assessed by 53BP1 immunofluorescence, and radiosensitivity assessed using the clonogenic assay. Mechanistic models were then applied to understand trends in repair and survival. 53BP1 foci yields were significantly reduced in alpha particle exposures compared to X-rays, but these foci were slow to repair. Although alpha particles alone showed no inter-track interactions, substantial interactions were seen between X-rays and alpha particles. Mechanistic modelling suggested that sublethal damage (SLD) repair was independent of radiation quality, but that alpha particles generated substantially more sublethal damage than a similar dose of X-rays, [Formula: see text]. This high RBE may lead to unexpected synergies for combinations of different radiation qualities which must be taken into account in treatment design, and the rapid repair of this damage may impact on mechanistic modelling of radiation responses to high LETs.
Topics: Radiation, Ionizing; Alpha Particles; Biological Assay; DNA Damage; Radiation Tolerance
PubMed: 37433844
DOI: 10.1038/s41598-023-38295-3 -
Current Radiopharmaceuticals 2018
Topics: Actinium; Alpha Particles; Animals; Bismuth; Humans; Neoplasms; Radiochemistry; Radioisotopes; Radionuclide Generators; Radiopharmaceuticals
PubMed: 30378473
DOI: 10.2174/187447101103180911115600 -
International Journal of Radiation... Feb 2020We present an α-irradiation setup for the irradiation of primary human cell cultures under controlled conditions using Am α-particles. To irradiate samples with...
We present an α-irradiation setup for the irradiation of primary human cell cultures under controlled conditions using Am α-particles. To irradiate samples with α-particles in a valid manner, a reliable dosimetry is a great challenge because of the short α-range and the complex energy spectrum. Therefore, the distance between α-source and sample must be minimal. In the present setup, this is achieved by cells growing on a 2 μm thick biaxially-oriented polyethylene terephthalate (boPET) foil which is only 2.7 mm apart from the source. A precise and reproducible exposure time is realized through a mechanical shutter. The fluence, energy spectra and the corresponding linear energy transfer are determined by the source geometry and the material traversed. They were measured and calculated, yielding a dose rate of 8.2 ± 2.4 Gy/min. To improve cell growth on boPET foils, they were treated with air plasma. This treatment increased the polarity and thus the ability of cells attaching to the surface of the foil. Several tests including cell growth, staining for a marker of DNA double-strand breaks and a colony-forming assay were performed and confirm our dosimetry. With our setup, it is possible to irradiate cell cultures under defined conditions with α-particles. The plasma-treated foil is suitable for primary human cell cultures as shown in cell experiments, confirming also the expected number of particle traversals.
Topics: Alpha Particles; Americium; Animals; CHO Cells; Cell Line; Collagen; Cricetinae; Cricetulus; Dose-Response Relationship, Radiation; Histones; Humans; Keratinocytes; Linear Energy Transfer; Oxygen; Polyethylene Terephthalates; Primary Cell Culture; Radiometry; Reproducibility of Results
PubMed: 31682776
DOI: 10.1080/09553002.2020.1683641 -
Molecular Imaging and Biology Dec 2023Critical advances in radionuclide therapy have led to encouraging new options for cancer treatment through the pairing of clinically useful radiation-emitting... (Review)
Review
Critical advances in radionuclide therapy have led to encouraging new options for cancer treatment through the pairing of clinically useful radiation-emitting radionuclides and innovative pharmaceutical discovery. Of the various subatomic particles used in therapeutic radiopharmaceuticals, alpha (α) particles show great promise owing to their relatively large size, delivered energy, finite pathlength, and resulting ionization density. This review discusses the therapeutic benefits of α-emitting radiopharmaceuticals and their pairing with appropriate diagnostics, resulting in innovative "theranostic" platforms. Herein, the current landscape of α particle-emitting radionuclides is described with an emphasis on their use in theranostic development for cancer treatment. Commonly studied radionuclides are introduced and recent efforts towards their production for research and clinical use are described. The growing popularity of these radionuclides is explained through summarizing the biological effects of α radiation on cancer cells, which include DNA damage, activation of discrete cell death programs, and downstream immune responses. Examples of efficient α-theranostic design are described with an emphasis on strategies that lead to cellular internalization and the targeting of proteins involved in therapeutic resistance. Historical barriers to the clinical deployment of α-theranostic radiopharmaceuticals are also discussed. Recent progress towards addressing these challenges is presented along with examples of incorporating α-particle therapy in pharmaceutical platforms that can be easily converted into diagnostic counterparts.
Topics: Radiopharmaceuticals; Alpha Particles; Radioisotopes; Pharmaceutical Preparations; Neoplasms
PubMed: 37845582
DOI: 10.1007/s11307-023-01857-y -
Seminars in Nuclear Medicine Mar 2020As a treatment modality that is fundamentally different from other therapies against cancer, radiopharmaceutical therapy with alpha-particle emitters has drawn the... (Review)
Review
As a treatment modality that is fundamentally different from other therapies against cancer, radiopharmaceutical therapy with alpha-particle emitters has drawn the attention of the therapy community and also the biopharmaceutical industry. Alpha-particles cause a preponderance of complex DNA double-strand breaks (DSBs). This provides an opportunity to either enhance cell kill by using DNA DSB repair inhibitors or identify patients who are likely to be high responders to alpha-emitter RPT. The short-range and high potency of alpha-particles requires special dosimetry considerations. These are reviewed in light of recent updates to the phantoms and associated dosimetric quantities used for dosimetry calculations. A formalism for obtaining the necessary microscale pharmacokinetic information from patient nuclear medicine imaging is presented. Alpha-emitter based radiopharmaceutical therapy is an exciting cancer therapy modality that is being revisited. Further development of imaging and dosimetric methods specific to alpha-particle emitters, coupled with standardization of the methods and rigorous evidence that dosimetry applied to alphaRPT improves patient care are needed moving forward.
Topics: Alpha Particles; Humans; Radiobiology; Radiometry; Radiopharmaceuticals
PubMed: 32172797
DOI: 10.1053/j.semnuclmed.2019.11.002 -
Annals of Oncology : Official Journal... Nov 2019Amongst therapeutic radiopharmaceuticals, targeted alpha therapy (TαT) can deliver potent and local radiation selectively to cancer cells as well as the tumor... (Review)
Review
Amongst therapeutic radiopharmaceuticals, targeted alpha therapy (TαT) can deliver potent and local radiation selectively to cancer cells as well as the tumor microenvironment and thereby control cancer while minimizing toxicity. In this review, we discuss the history, progress, and future potential of TαT in the treatment of prostate cancer, including dosimetry-individualized treatment planning, combinations with small-molecule therapies, and conjugation to molecules directed against antigens expressed by prostate cancer cells, such as prostate-specific membrane antigen (PSMA) or components of the tumor microenvironment. A clinical proof of concept that TαT is efficacious in treating bone-metastatic castration-resistant prostate cancer has been demonstrated by radium-223 via improved overall survival and long-term safety/tolerability in the phase III ALSYMPCA trial. Dosimetry calculation and pharmacokinetic measurements of TαT provide the potential for optimization and individualized treatment planning for a precision medicine-based cancer management paradigm. The ability to combine TαTs with other agents, including chemotherapy, androgen receptor-targeting agents, DNA repair inhibitors, and immuno-oncology agents, is under investigation. Currently, TαTs that specifically target prostate cancer cells expressing PSMA represents a promising therapeutic approach. Both PSMA-targeted actinium-225 and thorium-227 conjugates are under investigation. The described clinical benefit, safety and tolerability of radium-223 and the recent progress in TαT trial development suggest that TαT occupies an important new role in prostate cancer treatment. Ongoing studies with newer dosimetry methods, PSMA targeting, and novel approaches to combination therapies should expand the utility of TαT in prostate cancer treatment.
Topics: Actinium; Alpha Particles; Clinical Trials, Phase III as Topic; Dipeptides; Heterocyclic Compounds, 1-Ring; Humans; Male; Precision Medicine; Progression-Free Survival; Prostate-Specific Antigen; Prostatic Neoplasms; Radioimmunotherapy; Radiopharmaceuticals; Radiotherapy Planning, Computer-Assisted; Tumor Microenvironment
PubMed: 31418764
DOI: 10.1093/annonc/mdz270 -
Journal of Nuclear Medicine : Official... Oct 2022Ra is a bone-seeking, α-particle-emitting radionuclide approved for the treatment of patients with metastatic prostate cancer and is currently being tested in a variety...
Ra is a bone-seeking, α-particle-emitting radionuclide approved for the treatment of patients with metastatic prostate cancer and is currently being tested in a variety of clinical trials for primary and metastatic cancers to bone. Clinical evaluation of Ra hematologic safety showed a significantly increased rate of neutropenia and thrombocytopenia in patients, hinting at myelosuppression as a side effect. In this study, we investigated the consequences of Ra treatment on bone marrow biology by combining flow cytometry, single-cell RNA sequencing, three-dimensional multiphoton microscopy and bone marrow transplantation analyses. Ra accumulated in bones and induced zonal radiation damage confined to the bone interface, followed by replacement of the impaired areas with adipocyte infiltration, as monitored by 3-dimensional multiphoton microscopy ex vivo. Flow cytometry and single-cell transcriptomic analyses on bone marrow hematopoietic populations revealed transient, nonspecific Ra-mediated cytotoxicity on resident populations, including stem, progenitor, and mature leukocytes. This toxicity was paralleled by a significant decrease in white blood cells and platelets in peripheral blood-an effect that was overcome within 40 d after treatment. Ra exposure did not impair full hematopoietic reconstitution, suggesting that bone marrow function is not permanently hampered. Our results provide a comprehensive explanation of Ra reversible effects on bone marrow cells and exclude long-term myelotoxicity, supporting safety for patients.
Topics: Alpha Particles; Bone Marrow; Bone and Bones; Flow Cytometry; Humans; Male; Radioisotopes
PubMed: 35177425
DOI: 10.2967/jnumed.121.263310 -
Molecules (Basel, Switzerland) Apr 2021Bone metastasis remains a major cause of death in cancer patients, and current therapies for bone metastatic disease are mainly palliative. Bone metastases arise after... (Review)
Review
Bone metastasis remains a major cause of death in cancer patients, and current therapies for bone metastatic disease are mainly palliative. Bone metastases arise after cancer cells have colonized the bone and co-opted the normal bone remodeling process. In addition to bone-targeted therapies (e.g., bisphosphonate and denosumab), hormone therapy, chemotherapy, external beam radiation therapy, and surgical intervention, attempts have been made to use systemic radiotherapy as a means of delivering cytocidal radiation to every bone metastatic lesion. Initially, several bone-seeking beta-minus-particle-emitting radiopharmaceuticals were incorporated into the treatment for bone metastases, but they failed to extend the overall survival in patients. However, recent clinical trials indicate that radium-223 dichloride (RaCl), an alpha-particle-emitting radiopharmaceutical, improves the overall survival of prostate cancer patients with bone metastases. This success has renewed interest in targeted alpha-particle therapy development for visceral and bone metastasis. This review will discuss (i) the biology of bone metastasis, especially focusing on the vicious cycle of bone metastasis, (ii) how bone remodeling has been exploited to administer systemic radiotherapies, and (iii) targeted radiotherapy development and progress in the development of targeted alpha-particle therapy for the treatment of prostate cancer bone metastasis.
Topics: Alpha Particles; Bone Neoplasms; Humans; Ligands; Male; Prostate-Specific Antigen; Prostatic Neoplasms; Radiopharmaceuticals
PubMed: 33918705
DOI: 10.3390/molecules26082162 -
Molecules (Basel, Switzerland) Nov 2019Targeted alpha-particle therapy (TAT) aims to selectively deliver radionuclides emitting α-particles (cytotoxic payload) to tumors by chelation to monoclonal... (Review)
Review
Targeted alpha-particle therapy (TAT) aims to selectively deliver radionuclides emitting α-particles (cytotoxic payload) to tumors by chelation to monoclonal antibodies, peptides or small molecules that recognize tumor-associated antigens or cell-surface receptors. Because of the high linear energy transfer (LET) and short range of alpha (α) particles in tissue, cancer cells can be significantly damaged while causing minimal toxicity to surrounding healthy cells. Recent clinical studies have demonstrated the remarkable efficacy of TAT in the treatment of metastatic, castration-resistant prostate cancer. In this comprehensive review, we discuss the current consensus regarding the properties of the α-particle-emitting radionuclides that are potentially relevant for use in the clinic; the TAT-mediated mechanisms responsible for cell death; the different classes of targeting moieties and radiometal chelators available for TAT development; current approaches to calculating radiation dosimetry for TATs; and lead optimization via medicinal chemistry to improve the TAT radiopharmaceutical properties. We have also summarized the use of TATs in pre-clinical and clinical studies to date.
Topics: Alpha Particles; Animals; Antibodies, Monoclonal; Humans; Neoplasms; Radioisotopes; Radiometry; Radiopharmaceuticals
PubMed: 31779154
DOI: 10.3390/molecules24234314 -
Journal of Medical Imaging and... Dec 2019This talk briefly reviews the earlier work in the field and highlights the contributions of colleagues whose clear vision paved the road for success of TAT. The talk... (Review)
Review
This talk briefly reviews the earlier work in the field and highlights the contributions of colleagues whose clear vision paved the road for success of TAT. The talk primarily will focus on the development of the radioisotopes for application in TAT. The challenges regarding release of daughter radioisotopes will be briefly discussed, and a summary of the alternative approaches for production of Ac will be presented.
Topics: Actinium; Alpha Particles; Humans; Neoplasms; Radioisotopes; Radiotherapy
PubMed: 31420270
DOI: 10.1016/j.jmir.2019.07.002