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Nuclear Medicine and Biology 2021In oncology, the holy grail of radiotherapy is specific radiation dose deposition in tumours with minimal healthy tissue toxicity. If used appropriately, injectable,... (Review)
Review
In oncology, the holy grail of radiotherapy is specific radiation dose deposition in tumours with minimal healthy tissue toxicity. If used appropriately, injectable, systemic radionuclide therapies could meet these criteria, even for treatment of micrometastases and single circulating tumour cells. The clinical use of α and β particle-emitting molecular radionuclide therapies is rising, however clinical translation of Auger electron-emitting radionuclides is hampered by uncertainty around their exact subcellular localisation, which in turn affects the accuracy of dosimetry. This review aims to discuss and compare the advantages and disadvantages of various subcellular localisation methods available to localise radiopharmaceuticals and radionuclides for in vitro investigations.
Topics: Alpha Particles; Radiation Dosage; Radiopharmaceuticals
PubMed: 33964707
DOI: 10.1016/j.nucmedbio.2021.03.010 -
Entropy (Basel, Switzerland) Feb 2023Classical statistical mechanics has long relied on assumptions such as the equipartition theorem to understand the behavior of the complicated systems of many particles....
Classical statistical mechanics has long relied on assumptions such as the equipartition theorem to understand the behavior of the complicated systems of many particles. The successes of this approach are well known, but there are also many well-known issues with classical theories. For some of these, the introduction of quantum mechanics is necessary, e.g., the ultraviolet catastrophe. However, more recently, the validity of assumptions such as the equipartition of energy in classical systems was called into question. For instance, a detailed analysis of a simplified model for blackbody radiation was apparently able to deduce the Stefan-Boltzmann law using purely classical statistical mechanics. This novel approach involved a careful analysis of a "metastable" state which greatly delays the approach to equilibrium. In this paper, we perform a broad analysis of such a metastable state in the classical Fermi-Pasta-Ulam-Tsingou (FPUT) models. We treat both the α-FPUT and β-FPUT models, exploring both quantitative and qualitative behavior. After introducing the models, we validate our methodology by reproducing the well-known FPUT recurrences in both models and confirming earlier results on how the strength of the recurrences depends on a single system parameter. We establish that the metastable state in the FPUT models can be defined by using a single degree-of-freedom measure-the spectral entropy (η)-and show that this measure has the power to quantify the distance from equipartition. For the α-FPUT model, a comparison to the integrable Toda lattice allows us to define rather clearly the lifetime of the metastable state for the standard initial conditions. We next devise a method to measure the lifetime of the metastable state tm in the α-FPUT model that reduces the sensitivity to the exact initial conditions. Our procedure involves averaging over random initial phases in the plane of initial conditions, the P1-Q1 plane. Applying this procedure gives us a power-law scaling for tm, with the important result that the power laws for different system sizes collapse down to the same exponent as Eα2→0. We examine the energy spectrum E(k) over time in the α-FPUT model and again compare the results to those of the Toda model. This analysis tentatively supports a method for an irreversible energy dissipation process suggested by Onorato et al.: four-wave and six-wave resonances as described by the "wave turbulence" theory. We next apply a similar approach to the β-FPUT model. Here, we explore in particular the different behavior for the two different signs of β. Finally, we describe a procedure for calculating tm in the β-FPUT model, a very different task than for the α-FPUT model, because the β-FPUT model is not a truncation of an integrable nonlinear model.
PubMed: 36832666
DOI: 10.3390/e25020300 -
Journal of Radiation Research Mar 2021During prostate cancer treatment with 223Ra. 219Rn (actinon) occurs and may be exhaled by the patient. Nurses and other hospital employees may inhale this radionuclide...
During prostate cancer treatment with 223Ra. 219Rn (actinon) occurs and may be exhaled by the patient. Nurses and other hospital employees may inhale this radionuclide and its decay products. The alpha-emitting decay products of actinon deposited within a body will irradiate tissues and organs. Therefore. it is necessary to evaluate organ doses of actinon progeny. The purpose of this study is to set up a dosimetric method to assess dose coefficients for actinon progeny. The effective dose coefficients were calculated separately for three modes. The unattached mode which concerned the activity median thermodynamic diameter (AMTD) of 1 nm. and the nucleation and accumulation modes which are represented by activity median aerodynamic diameters (AMAD) of 60 and 500 nm respectively. The recent biokinetic models of actinon progeny developed in the Occupational Intakes of Radionuclides (OIR) publications series of the International Commission of Radiological Protection (ICRP) were implemented on BIOKMOD (Biokinetic Modeling) to calculate the number of nuclear transformations per activity intake of actinon progeny. The organ equivalent and effective dose coefficients were determined using the dosimetric approach of the ICRP. The inhalation dose coefficients of actinon progeny are dominated by the contribution of lung dose. The calculated dose coefficients of 211Pb and 211Bi are 5.78 × 10-8 and 4.84 × 10-9 Sv.Bq-1 for unattached particles (AMTD = 1 nm). and 1.4 × 10-8 and 3.55 × 10-9 Sv.Bq-1 for attached particles (AMAD = 60 nm). and 7.37 × 10-9 and 1.91 × 10-9 Sv.Bq-1 for attached particles (AMAD = 500 nm). These values are much closer to those of the recently published ICRP 137.
Topics: Administration, Inhalation; Aerosols; Humans; Models, Biological; Particle Size; Radiation Dosage; Radiometry; Radon; Respiratory System
PubMed: 33512484
DOI: 10.1093/jrr/rraa140 -
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 -
Antioxidants (Basel, Switzerland) Feb 2023Protein particles have been reported as the potential carriers for the co-encapsulation of bioactive components. In this study, lysozyme, a basic protein, was used to...
Protein particles have been reported as the potential carriers for the co-encapsulation of bioactive components. In this study, lysozyme, a basic protein, was used to simultaneously encapsulate folic acid and -tocopherol at pH 4.0. The encapsulation efficiency and loading capacity of folic acid or -tocopherol increased with its respective concentration. Folic acid had no influence on the encapsulation of -tocopherol. However, the encapsulation of folic acid was improved by -tocopherol below 40 μg/mL but reduced by -tocopherol at higher concentrations. The encapsulation by lysozyme shielded folic acid, -tocopherol, or both partially from the attack of 2,2'-azino-bis-3-ethylbenzthiazoline-6-sulphonic acid (ABTS) radical cation. No masking effect of lysozyme encapsulation on -tocopherol was found in DPPH antioxidant activity assay. Furthermore, the DNA coating was used to improve the dispersion of lysozyme with folic acid and -tocopherol. The lysozyme/DNA particles with folic acid and -tocopherol showed a homogenous size distribution of 180-220 nm with ζ-potential values between -33 and -36 mV. The release and bioaccessibility of folic acid in lysozyme/DNA with -tocopherol were similar to that of folic acid alone, while the release of -tocopherol was delayed and its bioaccessibility was improved by encapsulation in lysozyme/DNA with folic acid. The data gathered here would provide guidance for the use of lysozyme-based co-encapsulating carriers in the development of functional foods.
PubMed: 36978812
DOI: 10.3390/antiox12030564 -
Genes Jan 2023Boron neutron capture therapy (BNCT) is an approach to the radiotherapy of solid tumors that was first outlined in the 1930s but has attracted considerable attention... (Review)
Review
Boron neutron capture therapy (BNCT) is an approach to the radiotherapy of solid tumors that was first outlined in the 1930s but has attracted considerable attention recently with the advent of a new generation of neutron sources. In BNCT, tumor cells accumulate B atoms that react with epithermal neutrons, producing energetic α particles and Li atoms that damage the cell's genome. The damage inflicted by BNCT appears not to be easily repairable and is thus lethal for the cell; however, the molecular events underlying the action of BNCT remain largely unaddressed. In this review, the chemistry of DNA damage during BNCT is outlined, the major mechanisms of DNA break sensing and repair are summarized, and the specifics of the repair of BNCT-induced DNA lesions are discussed.
Topics: Humans; Boron Neutron Capture Therapy; DNA Damage; Brain Neoplasms; Biological Phenomena
PubMed: 36672868
DOI: 10.3390/genes14010127 -
Frontiers in Oncology 2022Boron neutron capture therapy (BNCT) is a re-emerging therapy with the ability to selectively kill tumor cells. After the boron delivery agents enter the tumor tissue... (Review)
Review
Boron neutron capture therapy (BNCT) is a re-emerging therapy with the ability to selectively kill tumor cells. After the boron delivery agents enter the tumor tissue and enrich the tumor cells, the thermal neutrons trigger the fission of the boron atoms, leading to the release of boron atoms and then leading to the release of the α particles (He) and recoil lithium particles (Li), along with the production of large amounts of energy in the narrow region. With the advantages of targeted therapy and low toxicity, BNCT has become a unique method in the field of radiotherapy. Since the beginning of the last century, BNCT has been emerging worldwide and gradually developed into a technology for the treatment of glioblastoma multiforme, head and neck cancer, malignant melanoma, and other cancers. At present, how to develop and innovate more efficient boron delivery agents and establish a more accurate boron-dose measurement system have become the problem faced by the development of BNCT. We discuss the use of boron delivery agents over the past several decades and the corresponding clinical trials and preclinical outcomes. Furthermore, the discussion brings recommendations on the future of boron delivery agents and this therapy.
PubMed: 35433432
DOI: 10.3389/fonc.2022.788770 -
Journal of Nuclear Medicine : Official... May 2023Targeted radionuclide therapy (TRT) using targeting moieties labeled with α-particle-emitting radionuclides (α-TRT) is an intensely investigated treatment approach as...
Targeted α-Therapy Using Ac Radiolabeled Single-Domain Antibodies Induces Antigen-Specific Immune Responses and Instills Immunomodulation Both Systemically and at the Tumor Microenvironment.
Targeted radionuclide therapy (TRT) using targeting moieties labeled with α-particle-emitting radionuclides (α-TRT) is an intensely investigated treatment approach as the short range of α-particles allows effective treatment of local lesions and micrometastases. However, profound assessment of the immunomodulatory effect of α-TRT is lacking in literature. Using flow cytometry of tumors, splenocyte restimulation, and multiplex analysis of blood serum, we studied immunologic responses ensuing from TRT with an antihuman CD20 single-domain antibody radiolabeled with Ac in a human CD20 and ovalbumin expressing B16-melanoma model. Tumor growth was delayed with α-TRT and increased blood levels of various cytokines such as interferon-γ, C-C motif chemokine ligand 5, granulocyte-macrophage colony-stimulating factor, and monocyte chemoattractant protein-1. Peripheral antitumoral T-cell responses were detected on α-TRT. At the tumor site, α-TRT modulated the cold tumor microenvironment (TME) to a more hospitable and hot habitat for antitumoral immune cells, characterized by a decrease in protumoral alternatively activated macrophages and an increase in antitumoral macrophages and dendritic cells. We also showed that α-TRT increased the percentage of programmed death-ligand 1 (PD-L1)-positive (PD-L1) immune cells in the TME. To circumvent this immunosuppressive countermeasure we applied immune checkpoint blockade of the programmed cell death protein 1-PD-L1 axis. Combination of α-TRT with PD-L1 blockade potentiated the therapeutic effect, however, the combination aggravated adverse events. A long-term toxicity study revealed severe kidney damage ensuing from α-TRT. These data suggest that α-TRT alters the TME and induces systemic antitumoral immune responses, which explains why immune checkpoint blockade enhances the therapeutic effect of α-TRT. However, further optimization is warranted to avoid adverse events.
Topics: Animals; Humans; Single-Domain Antibodies; B7-H1 Antigen; Tumor Microenvironment; Immune Checkpoint Inhibitors; Immunomodulation; Melanoma, Experimental; Immunity; Cell Line, Tumor
PubMed: 37055223
DOI: 10.2967/jnumed.122.264752 -
Medicina (Kaunas, Lithuania) Apr 2024Radioactivity is a process in which the nuclei of unstable atoms spontaneously decay, producing other nuclei and releasing energy in the form of ionizing radiation in... (Review)
Review
Radioactivity is a process in which the nuclei of unstable atoms spontaneously decay, producing other nuclei and releasing energy in the form of ionizing radiation in the form of alpha (α) and beta (β) particles as well as the emission of gamma (γ) electromagnetic waves. People may be exposed to radiation in various forms, as casualties of nuclear accidents, workers in power plants, or while working and using different radiation sources in medicine and health care. Acute radiation syndrome (ARS) occurs in subjects exposed to a very high dose of radiation in a very short period of time. Each form of radiation has a unique pathophysiological effect. Unfortunately, higher organisms-human beings-in the course of evolution have not acquired receptors for the direct "capture" of radiation energy, which is transferred at the level of DNA, cells, tissues, and organs. Radiation in biological systems depends on the amount of absorbed energy and its spatial distribution, particularly depending on the linear energy transfer (LET). Photon radiation with low LET leads to homogeneous energy deposition in the entire tissue volume. On the other hand, radiation with a high LET produces a fast Bragg peak, which generates a low input dose, whereby the penetration depth into the tissue increases with the radiation energy. The consequences are mutations, apoptosis, the development of cancer, and cell death. The most sensitive cells are those that divide intensively-bone marrow cells, digestive tract cells, reproductive cells, and skin cells. The health care system and the public should raise awareness of the consequences of ionizing radiation. Therefore, our aim is to identify the consequences of ARS taking into account radiation damage to the respiratory system, nervous system, hematopoietic system, gastrointestinal tract, and skin.
Topics: Humans; Radiation, Ionizing; Acute Radiation Syndrome; Human Body; Linear Energy Transfer
PubMed: 38674299
DOI: 10.3390/medicina60040653 -
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