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The Quarterly Journal of Nuclear... Sep 2020This review provides a general overview of the current achievements and challenges in translational dosimetry for targeted alpha therapy (TAT). The concept of targeted... (Review)
Review
This review provides a general overview of the current achievements and challenges in translational dosimetry for targeted alpha therapy (TAT). The concept of targeted radionuclide therapy (TRNT) is described with an overview of its clinical applicability and the added value of TAT is discussed. For TAT, we focused on actinium-225 (225Ac) as an example for alpha particle emitting radionuclides and their features, such as limited range within tissue and high linear energy transfer, which make alpha particle emissions more effective in targeted killing of tumour cells compared to beta radiation. Starting with the state-of-the-art dosimetry for TRNT and TAT, we then describe the challenges that still need to be met in order to move to a personalized dosimetry approach for TAT. Specifically for 225Ac, we discuss the recoiled daughter effect which may provoke significant damage to healthy tissue or organs and should be considered. Next, a broad overview is given of the pre-clinical research on 225Ac-TAT with an extensive description of tools which are only available in a pre-clinical setting and their added value. In addition, we review the preclinical biodistribution and dosimetry studies that have been performed on TAT-agents and more specifically of 225Ac and its multiple progeny, and describe their potential role to better characterize the pharmacokinetic (PK) profile of TAT-agents and to optimize the use of theranostic approaches for dosimetry. Finally, we discuss the support pre-clinical studies may provide in understanding dose-effect relationships, linking radiation dose quantities to biological endpoints and even moving away from macro- to microdosimetry. As such, the translation of pre-clinical findings may provide valuable information and new approaches for improved clinical dosimetry, thus paving the way to personalized TAT.
Topics: Actinium; Alpha Particles; Animals; Humans; Radiometry; Translational Research, Biomedical
PubMed: 32441067
DOI: 10.23736/S1824-4785.20.03266-5 -
Current Radiopharmaceuticals Jul 2011Alpha-particle emitting radionuclides are attractive for targeted cancer therapies due to their physicochemical properties. Their high linear energy transfer (LET) and... (Review)
Review
Alpha-particle emitting radionuclides are attractive for targeted cancer therapies due to their physicochemical properties. Their high linear energy transfer (LET) and short particle range makes them particularly toxic at a microscopic level, which is ideal for treating disseminated micrometastases. However, their cytotoxic properties also place special demands on the pharmacokinetics of the tumor specific carrier vector, where high tumor-to-normal-tissue ratios are a prerequisite. Tumor specific antibodies are perhaps the most common vector for targeted therapy, but due to pharmacokinetics considerations antibodies will generally not meet the standard for α-particle radioimmunotherapy. However, the tumor specificity of monoclonal antibodies may be used in pretargeting techniques, strategies used to increase the selectivity of the radioactivity. The basic concept of pretargeting relies on a separate administration of a modified antibody and a radioactive ligand. The modified antibody is first injected and allowed to localize on the tumor. Then, the radiolabeled ligand is injected, which is a small molecule that rapidly localizes the modified antibody on tumor cells while non-localized ligand rapidly clears from the circulation, preferably through renal filtration. Several pretargeting strategies have been developed, in particular the avidin-biotin system and bispecific antibodies. Approaches under evaluation are the use of complementary DNA, morpholinos, and the use of infinite antigen binding. Preclinical and clinical studies of pretargeting have shown that favorable distribution of the radioactivity can be achieved, which may increase dose to the tumor as compared with the dose from directly labeled antibodies, and most important decrease the dose to normal tissues. This survey describes different pretargeting strategies, and includes a review of pretargeting with α emitting radionuclides.
Topics: Alpha Particles; Humans; Neoplasms; Radioimmunotherapy; Radioisotopes; Radiopharmaceuticals
PubMed: 22201711
DOI: 10.2174/1874471011104030248 -
Proceedings of the National Academy of... Sep 2002Low doses of alpha radiation in basements have been causally implicated in lung cancer. Previous studies have concentrated on high dose effects, for which no significant...
Low doses of alpha radiation in basements have been causally implicated in lung cancer. Previous studies have concentrated on high dose effects, for which no significant repair was found. In the present study, the methodology for measuring mutation by quantitating mitotic breaks and gaps was found to be applicable to G2-phase Chinese hamster ovary cells irradiated with 10-50 cGy of alpha radiation. The mutation yield in such cells closely resembles that of gamma irradiation. Caffeine, which inhibits repair, produces the same straight line increase of alpha and gamma mutation yields plotted against the dose. In the absence of caffeine, the repair of alpha radiation lesions is almost twice as great as for gamma radiation. Mitotic index changes substantiate these interpretations. It is proposed that the higher ion density associated with alpha radiation may result in fewer lesions being missed by the repair processes. The quantitation of chromosomal lesions for G2 cells exposed to low doses of alpha radiation, gamma radiation, or chemical mutagens in the presence and absence of caffeine is a rapid and reproducible methodology. Protection from mutational disease in a fashion similar to the use of sanitation for infectious disease appears practical.
Topics: Alpha Particles; Animals; CHO Cells; Chromosome Aberrations; Cricetinae; DNA Repair; G2 Phase; Gamma Rays; Humans; Lung Neoplasms; Mitotic Index; Mutagenesis; Neoplasms, Radiation-Induced; Radiation Dosage; Radiation Tolerance
PubMed: 12198179
DOI: 10.1073/pnas.152433699 -
Lancet (London, England) Mar 1990
Topics: Alpha Particles; Animals; Chromosomes, Human, Pair 2; Hematopoietic Stem Cells; Humans; Leukemia, Radiation-Induced; Mice
PubMed: 1969027
DOI: 10.1016/0140-6736(90)90439-c -
Nature Jun 1992
Topics: Alpha Particles; Hematopoietic Stem Cells; Humans; Leukemia, Radiation-Induced
PubMed: 1594042
DOI: 10.1038/357369b0 -
Nature Jun 1992
Topics: Alpha Particles; Animals; Hematopoietic Stem Cells; Leukemia, Radiation-Induced; Male; Mice
PubMed: 1594043
DOI: 10.1038/357370a0 -
Journal of Environmental Radioactivity Nov 2015Human activity has led to an increasing amount of radionuclides in the environment and subsequently to an increased risk of exposure of the biosphere to ionising...
Human activity has led to an increasing amount of radionuclides in the environment and subsequently to an increased risk of exposure of the biosphere to ionising radiation. Due to their high linear energy transfer, α-emitters form a threat to biota when absorbed or integrated in living tissue. Among these, (241)Am is of major concern due to high affinity for organic matter and high specific activity. This study examines the dose-dependent biological effects of α-radiation delivered by (241)Am at the morphological, physiological and molecular level in 14-day old seedlings of Arabidopsis thaliana after hydroponic exposure for 4 or 7 days. Our results show that (241)Am has high transfer to the roots but low translocation to the shoots. In the roots, we observed a transcriptional response of reactive oxygen species scavenging and DNA repair pathways. At the physiological and morphological level this resulted in a response which evolved from redox balance control and stable biomass at low dose rates to growth reduction, reduced transfer and redox balance decline at higher dose rates. This situation was also reflected in the shoots where, despite the absence of a transcriptional response, the control of photosynthesis performance and redox balance declined with increasing dose rate. The data further suggest that the effects in both organs were initiated in the roots, where the highest dose rates occurred, ultimately affecting photosynthesis performance and carbon assimilation. Though further detailed study of nutrient balance and (241)Am localisation is necessary, it is clear that radionuclide uptake and distribution is a major parameter in the global exposure effects on plant performance and health.
Topics: Alpha Particles; Americium; Antioxidants; Arabidopsis; DNA Damage; DNA Repair; Dose-Response Relationship, Radiation; Oxidative Stress; Photosynthesis; Plant Roots; Plant Shoots; Transcription, Genetic
PubMed: 26204519
DOI: 10.1016/j.jenvrad.2015.07.007 -
Advanced Drug Delivery Reviews Sep 2008Alpha particle-emitting isotopes have been proposed as novel cytotoxic agents for augmenting targeted therapy. Properties of alpha particle radiation such as their... (Review)
Review
Alpha particle-emitting isotopes have been proposed as novel cytotoxic agents for augmenting targeted therapy. Properties of alpha particle radiation such as their limited range in tissue of a few cell diameters and their high linear energy transfer leading to dense radiation damage along each alpha track are promising in the treatment of cancer, especially when single cells or clusters of tumor cells are targeted. Actinium-225 (225 Ac) is an alpha particle-emitting radionuclide that generates 4 net alpha particle isotopes in a short decay chain to stable 209 Bi, and as such can be described as an alpha particle nanogenerator. This article reviews the literature pertaining to the research, development, and utilization of targeted 225 Ac to potently and specifically affect cancer.
Topics: Actinium; Alpha Particles; Animals; Clinical Trials as Topic; Humans; Radiometry; Radionuclide Generators; Tissue Distribution
PubMed: 18514364
DOI: 10.1016/j.addr.2008.04.009 -
Neuroendocrinology 2019Neuroendocrine tumours (NETs) are being seen increasingly frequently, but to date only complete surgical resection is curative. However, among the various therapeutic... (Review)
Review
Neuroendocrine tumours (NETs) are being seen increasingly frequently, but to date only complete surgical resection is curative. However, among the various therapeutic options, peptide receptor radionuclide therapy, linking a radioactive moiety to an octreotide derivative, has been shown to be highly efficacious and a well-tolerated therapy, improving progression-free survival and probably overall survival. Nevertheless, the current radionuclides in use are beta particle emitters with non-optimal radiobiological properties. A new generation of alpha particle-emitting radionuclides is being developed, with advantages in terms of very high energy and a short path length, which should theoretically show higher efficacy. We survey the current developments in this field, emphasising the exciting potential of this novel form of therapy for NETs.
Topics: Alpha Particles; Animals; Humans; Neuroendocrine Tumors; Radioisotopes; Receptors, Peptide
PubMed: 30352433
DOI: 10.1159/000494760 -
Physica Medica : PM : An International... May 2024Diffusing alpha-emitters radiation therapy (DaRT) is a brachytherapy technique using α-particles to treat solid tumours. The high linear energy transfer (LET) and short...
PURPOSE
Diffusing alpha-emitters radiation therapy (DaRT) is a brachytherapy technique using α-particles to treat solid tumours. The high linear energy transfer (LET) and short range of α-particles make them good candidates for the targeted treatment of cancer. Treatment planning of DaRT requires a good understanding of the dose from α-particles and the other particles released in the Ra decay chain.
METHODS
The Geant4 Monte Carlo toolkit has been used to simulate a DaRT seed to better understand the dose contribution from all particles and simulate the DNA damage due to this treatment.
RESULTS
Close to the seed α-particles deliver the majority of dose, however at radial distances greater than 4 mm, the contribution of β-particles is greater. The RBE has been estimated as a function of number of double strand breaks (DSBs) and complex DSBs. A maximum seed spacing of 5.5 mm and 6.5 mm was found to deliver at least 20 Gy RBE weighted dose between the seeds for RBE and RBE respectively.
CONCLUSIONS
The DNA damage changes with radial distance from the seed and has been found to become less complex with distance, which is potentially easier for the cell to repair. Close to the seed α-particles contribute the majority of dose, however the contribution from other particles cannot be neglected and may influence the choice of seed spacing.
Topics: Alpha Particles; Monte Carlo Method; DNA Damage; Radiotherapy Dosage; Radiation Dosage; Relative Biological Effectiveness; Diffusion; Brachytherapy; Humans; Linear Energy Transfer; Radiotherapy Planning, Computer-Assisted; DNA Breaks, Double-Stranded
PubMed: 38701625
DOI: 10.1016/j.ejmp.2024.103367