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PloS One 2023DNA double strand breaks (DSBs) are a deleterious form of DNA damage. Densely ionising alpha radiation predominantly induces complex DSBs and sparsely ionising gamma...
DNA double strand breaks (DSBs) are a deleterious form of DNA damage. Densely ionising alpha radiation predominantly induces complex DSBs and sparsely ionising gamma radiation-simple DSBs. We have shown that alphas and gammas, when applied simultaneously, interact in producing a higher DNA damage response (DDR) than predicted by additivity. The mechanisms of the interaction remain obscure. The present study aimed at testing whether the sequence of exposure to alphas and gammas has an impact on the DDR, visualised by live NBS1-GFP (green fluorescent protein) focus dynamics in U2OS cells. Focus formation, decay, intensity and mobility were analysed up to 5 h post exposure. Focus frequencies directly after sequential alpha → gamma and gamma → alpha exposure were similar to gamma alone, but gamma → alpha foci quickly declined below the expected values. Focus intensities and areas following alpha alone and alpha → gamma were larger than after gamma alone and gamma → alpha. Focus movement was most strongly attenuated by alpha → gamma. Overall, sequential alpha → gamma exposure induced the strongest change in characteristics and dynamics of NBS1-GFP foci. Possible explanation is that activation of the DDR is stronger when alpha-induced DNA damage precedes gamma-induced DNA damage.
Topics: Alpha Particles; Gamma Rays; Records; DNA Breaks, Double-Stranded; DNA Damage; Green Fluorescent Proteins
PubMed: 37307266
DOI: 10.1371/journal.pone.0286902 -
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 -
Applied Radiation and Isotopes :... Nov 2009An alpha-particle irradiator that can facilitate investigations of alpha-radiation effects on human cells in radiation protection, carcinogenesis and radioimmunotherapy...
An alpha-particle irradiator that can facilitate investigations of alpha-radiation effects on human cells in radiation protection, carcinogenesis and radioimmunotherapy was constructed. The irradiator was based on a 1.3 GBq (238)Pu source, housed in a stainless steel tube flushed with helium. Radiation provided by (238)Pu consists mainly of alpha-particles with energy of 5.5 MeV. The alpha-particle fluence and energy spectra were measured with a silicon semiconductor detector. Monte Carlo simulations were used to estimate the mean number of alpha-particles and the mean absorbed alpha-particle dose to cells for various irradiation times and distances between cells and source. There was a linear dependence between exposure time and alpha-particle fluence for exposure times above 1s. The alpha-particle activity concentration varied with a factor 2.7 over the source area, while the variation in energy peak position was <4%. At the cell nucleus position and with a distance of 45 mm between the source and the mylar dish surface, the alpha-fluence was 4.6 x 10(4)counts/(mm(2)s), the average incident alpha-particle energy was 2.5 MeV and the average linear energy transfer was 167 keV/microm. The average dose rate to the cells, with 5 microm diameter nucleus, was 1.2 Gy/s. The (238)Pu alpha-particle irradiator is feasible for irradiation of cells and it can be used for studies of both direct effects and bystander effects of alpha-radiation.
Topics: Alpha Particles; Cell Culture Techniques; Computer-Aided Design; Equipment Design; Equipment Failure Analysis; Plutonium; Radiation Dosage; Radiation Equipment and Supplies; Radiometry
PubMed: 19716308
DOI: 10.1016/j.apradiso.2009.08.003 -
Targeted Oncology Apr 2018Alpha-emitters are radionuclides that decay through the emission of high linear energy transfer α-particles and possess favorable pharmacologic profiles for cancer... (Review)
Review
Alpha-emitters are radionuclides that decay through the emission of high linear energy transfer α-particles and possess favorable pharmacologic profiles for cancer treatment. When coupled with monoclonal antibodies, peptides, small molecules, or nanoparticles, the excellent cytotoxic capability of α-particle emissions has generated a strong interest in exploring targeted α-therapy in the pre-clinical setting and more recently in clinical trials in oncology. Multiple obstacles have been overcome by researchers and clinicians to accelerate the development of targeted α-therapies, especially with the recent improvement in isotope production and purification, but also with the development of innovative strategies for optimized targeting. Numerous studies have demonstrated the in vitro and in vivo efficacy of the targeted α-therapy. Radium-223 (Ra) dichloride (Xofigo®) is the first α-emitter to have received FDA approval for the treatment of prostate cancer with metastatic bone lesions. There is a significant increase in the number of clinical trials in oncology using several radionuclides such as Actinium-225 (Ac), Bismuth-213 (Bi), Lead-212 (Pb), Astatine (At) or Radium-223 (Ra) assessing their safety and preliminary activity. This review will cover their therapeutic application as well as summarize the investigations that provide the foundation for further clinical development.
Topics: Alpha Particles; Humans; Neoplasms
PubMed: 29423595
DOI: 10.1007/s11523-018-0550-9 -
Journal of Medical Imaging and... Dec 2019This review briefly describes recent promising developments of alpha emitter labelled compounds for targeted alpha therapy of bladder cancer, brain tumours,... (Review)
Review
This review briefly describes recent promising developments of alpha emitter labelled compounds for targeted alpha therapy of bladder cancer, brain tumours, neuroendocrine tumours, and prostate cancer.
Topics: Actinium; Alpha Particles; Bismuth; History, 20th Century; History, 21st Century; Humans; Neoplasms; Radioimmunotherapy; Radioisotopes; Radiotherapy
PubMed: 31405818
DOI: 10.1016/j.jmir.2019.06.046 -
Expert Opinion on Biological Therapy Aug 2016The combination of a targeted biomolecule that specifically defines the target and a radionuclide that delivers a cytotoxic payload offers a specific way to destroy... (Review)
Review
INTRODUCTION
The combination of a targeted biomolecule that specifically defines the target and a radionuclide that delivers a cytotoxic payload offers a specific way to destroy cancer cells. Targeted radionuclide therapy (TRNT) aims to deliver cytotoxic radiation to cancer cells and causes minimal toxicity to surrounding healthy tissues. Recent advances using α-particle radiation emphasizes their potential to generate radiation in a highly localized and toxic manner because of their high level of ionization and short range in tissue.
AREAS COVERED
We review the importance of targeted alpha therapy (TAT) and focus on nanobodies as potential beneficial vehicles. In recent years, nanobodies have been evaluated intensively as unique antigen-specific vehicles for molecular imaging and TRNT.
EXPERT OPINION
We expect that the efficient targeting capacity and fast clearance of nanobodies offer a high potential for TAT. More particularly, we argue that the nanobodies' pharmacokinetic properties match perfectly with the interesting decay properties of the short-lived α-particle emitting radionuclides Astatine-211 and Bismuth-213 and offer an interesting treatment option particularly for micrometastatic cancer and residual disease.
Topics: Alpha Particles; Animals; Astatine; Humans; Neoplasms; Pharmaceutical Vehicles; Radioisotopes; Single-Domain Antibodies
PubMed: 27145158
DOI: 10.1080/14712598.2016.1185412 -
Dalton Transactions (Cambridge, England... Nov 2007Monoclonal antibodies have become a viable strategy for the delivery of therapeutic, particle emitting radionuclides specifically to tumor cells to either augment... (Review)
Review
Monoclonal antibodies have become a viable strategy for the delivery of therapeutic, particle emitting radionuclides specifically to tumor cells to either augment anti-tumor action of the native antibodies or to solely take advantage of their action as targeting vectors. Proper and rational selection of radionuclide and antibody combinations is critical to making radioimmunotherapy (RIT) a standard therapeutic modality due to the fundamental and significant differences in the emission of either alpha- and beta-particles. The alpha-particle has a short path length (50-80 microm) that is characterized by high linear energy transfer (100 keV microm(-1)). Actively targeted alpha-therapy potentially offers a more specific tumor cell killing action with less collateral damage to the surrounding normal tissues than beta-emitters. These properties make targeted alpha-therapy an appropriate therapy to eliminate minimal residual or micrometastatic disease. RIT using alpha-emitters such as (213)Bi, (211)At, (225)Ac, and others has demonstrated significant activity in both in vitro and in vivo model systems. Limited numbers of clinical trials have progressed to demonstrate safety, feasibility, and therapeutic activity of targeted alpha-therapy, despite having to traverse complex obstacles. Further advances may require more potent isotopes, additional sources and more efficient means of isotope production. Refinements in chelation and/or radiolabeling chemistry combined with rational improvements of isotope delivery, targeting vectors, molecular targets, and identification of appropriate clinical applications remain as active areas of research. Ultimately, randomized trials comparing targeted alpha-therapy combined with integration into existing standards of care treatment regimens will determine the clinical utility of this modality.
Topics: Alpha Particles; Antibodies, Monoclonal; Humans; Neoplasms; Radioimmunotherapy
PubMed: 17992276
DOI: 10.1039/b704726f -
Microscopy Research and Technique Jan 2017Our aim was to study the influence of low doses (0.2-4 μGy) of α radiation on the stability of human erythrocytes isolated from healthy and diabetic erythrocytes....
Our aim was to study the influence of low doses (0.2-4 μGy) of α radiation on the stability of human erythrocytes isolated from healthy and diabetic erythrocytes. Absorption spectroscopy was used to measure the level of red blood cell (RBC) hemolysis, along with Mössbauer spectroscopy, which is a highly specific method suited to monitoring various hemoglobin forms. States of hemoglobin are sensitive to a homeostatic imbalance in red blood cells. Changes in the membrane skeleton organization of irradiated erythrocytes isolated from healthy donors were studied using atomic force microscopy (AFM). Hemolysis, in healthy red blood cells, showed characteristic discontinuities, depending on the α particle flux and the exposure time to the low doses applied. This phenomenon was not observed in severe diabetic cases, which could be a result of modified protein-lipid-sugar complexes and the attenuation/absence of some antioxidative enzymatic processes in their RBC membranes. Similar effects were also observed for red blood cells treated with low doses of neutron and γ-radiation. AFM measurements demonstrated a reorganization of the RBC membrane skeleton network depending on the time of RBC exposure to α radiation. This suggests that the changes in the activity of the acute defense processes against free radicals which are activated within the erythrocyte membrane irradiated with α-particles could additionally be up- or down regulated by modifications to the membrane-skeleton network. However, even the highest dose of α radiation applied in these studies did not cause any significant changes in the ability of hemoglobin to transport oxygen. Microsc. Res. Tech. 80:131-143, 2017. © 2016 Wiley Periodicals, Inc.
Topics: Alpha Particles; Cells, Cultured; Dose-Response Relationship, Radiation; Erythrocyte Membrane; Erythrocytes; Gamma Rays; Hemoglobins; Hemolysis; Homeostasis; Humans; Microscopy, Atomic Force
PubMed: 27859863
DOI: 10.1002/jemt.22803 -
Medical Physics Apr 2024Diffusing alpha-emitters Radiation Therapy ("Alpha DaRT") is a new technique that enables the use of alpha particles for the treatment of solid tumors. Alpha DaRT...
BACKGROUND
Diffusing alpha-emitters Radiation Therapy ("Alpha DaRT") is a new technique that enables the use of alpha particles for the treatment of solid tumors. Alpha DaRT employs interstitial sources carrying a few Ci of Ra below their surface, designed to release a chain of short-lived atoms (progeny of Ra) which emit alpha particles, along with beta, Auger, and conversion electrons, x- and gamma rays. These atoms diffuse around the source and create-primarily through their alpha decays-a lethal high-dose region measuring a few millimeters in diameter.
PURPOSE
While previous studies focused on the dose from the alpha emissions alone, this work addresses the electron and photon dose contributed by the diffusing atoms and by the atoms remaining on the source surface, for both a single Alpha DaRT source and multi-source lattices. This allows to evaluate the low-LET contribution to the tumor dose and tumor cell survival, and demonstrate the sparing of surrounding healthy tissue.
METHODS
The low-LET dose is calculated using the EGSnrc and FLUKA Monte Carlo (MC) codes. We compare the results of a simple line-source approximation with no diffusion to those of a full simulation, which implements a realistic source geometry and the spread of diffusing atoms. We consider two opposite scenarios: one with low diffusion and high Pb leakage, and the other with high diffusion and low leakage. The low-LET dose in source lattices is calculated by superposition of single-source contributions. Its effect on cell survival is estimated with the linear quadratic model in the limit of low dose rate.
RESULTS
For sources carrying 3 Ci/cm Ra arranged in a hexagonal lattice with 4 mm spacing, the minimal low-LET dose between sources is Gy for the two test cases and is dominated by the beta contribution. The low-LET dose drops below 5 Gy mm away from the outermost source in the lattice with an effective maximal dose rate of Gy/h. The accuracy of the line-source/no-diffusion approximation is for the total low-LET dose over clinically relevant distances (2-4 mm). The low-LET dose reduces tumor cell survival by a factor of .
CONCLUSIONS
The low-LET dose in Alpha DaRT can be modeled by conventional MC techniques with appropriate leakage corrections to the source activity. For 3 Ci/cm Ra sources, the contribution of the low-LET dose can reduce cell survival inside the tumor by up to two orders of magnitude. The low-LET dose to surrounding healthy tissue is negligible. Increasing source activities by a factor of 5 can bring the low-LET dose itself to therapeutic levels, in addition to the high-LET dose contributed by alpha particles, leading to a "self-boosted" Alpha DaRT configuration, and potentially allowing to increase the lattice spacing.
Topics: Humans; Neoplasms; Brachytherapy; Dose-Response Relationship, Radiation; Alpha Particles; Monte Carlo Method
PubMed: 38096442
DOI: 10.1002/mp.16885 -
Applied Radiation and Isotopes :... Jan 1999Radionuclides are used in nuclear medicine in a variety of diagnostic and therapeutic procedures. A knowledge of the radiation dose received by different organs in the... (Review)
Review
Radionuclides are used in nuclear medicine in a variety of diagnostic and therapeutic procedures. A knowledge of the radiation dose received by different organs in the body is essential to an evaluation of the risks and benefits of any procedure. In this paper, current methods for internal dosimetry are reviewed, as they are applied in nuclear medicine. Particularly, the Medical Internal Radiation Dose (MIRD) system for dosimetry is explained, and many of its published resources discussed. Available models representing individuals of different age and gender, including those representing the pregnant woman are described; current trends in establishing models for individual patients are also evaluated. The proper design of kinetic studies for establishing radiation doses for radiopharmaceuticals is discussed. An overview of how to use information obtained in a dosimetry study, including that of the effective dose equivalent (ICRP 30) and effective dose (ICRP 60), is given. Current trends and issues in internal dosimetry, including the calculation of patient-specific doses and in the use of small scale and microdosimetry techniques, are also reviewed.
Topics: Alpha Particles; Diagnostic Techniques, Radioisotope; Female; Humans; Male; Phantoms, Imaging; Pregnancy; Radiation Dosage; Radioisotopes; Radiometry; Technology, Radiologic; Tomography, Emission-Computed, Single-Photon
PubMed: 10028629
DOI: 10.1016/s0969-8043(98)00023-2