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Radiation Research Dec 2021The mechanism underlying the carcinogenic potential of α radiation is not fully understood, considering that cell inactivation (e.g., mitotic cell death) as a main...
The mechanism underlying the carcinogenic potential of α radiation is not fully understood, considering that cell inactivation (e.g., mitotic cell death) as a main consequence of exposure efficiently counteracts the spreading of heritable DNA damage. The aim of this study is to improve our understanding of the effectiveness of α particles in inducing different types of chromosomal aberrations, to determine the respective values of the relative biological effectiveness (RBE) and to interpret the results with respect to exposure risk. Human peripheral blood lymphocytes (PBLs) from a single donor were exposed ex vivo to doses of 0-6 Gy X rays or 0-2 Gy α particles. Cells were harvested at two different times after irradiation to account for the mitotic delay of heavily damaged cells, which is known to occur after exposure to high-LET radiation (including α particles). Analysis of the kinetics of cells reaching first or second (and higher) mitosis after irradiation and aberration data obtained by the multiplex fluorescence in situ hybridization (mFISH) technique are used to determine of the cytogenetic risk, i.e., the probability for transmissible aberrations in surviving lymphocytes. The analysis shows that the cytogenetic risk after α exposure is lower than after X rays. This indicates that the actually observed higher carcinogenic effect of α radiation is likely to stem from small scale mutations that are induced effectively by high-LET radiation but cannot be resolved by mFISH analysis.
Topics: Alpha Particles; Chromosome Aberrations; Dose-Response Relationship, Radiation; Humans; In Situ Hybridization, Fluorescence; In Vitro Techniques; Lymphocytes; Relative Biological Effectiveness; Risk Factors
PubMed: 34411274
DOI: 10.1667/RADE-21-00116.1 -
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 2019Alpha emitters have always promised to deliver potential benefit in cancer therapy. Using the example of radium-223 (Xofigo) and the paradigm of ionising radiation, this...
Alpha emitters have always promised to deliver potential benefit in cancer therapy. Using the example of radium-223 (Xofigo) and the paradigm of ionising radiation, this review looks at targeted alpha therapy from the perspective of a radiation oncologist.
Topics: Alpha Particles; Humans; Male; Prostatic Neoplasms; Radiation Oncology; Radioisotopes; Radium
PubMed: 31427257
DOI: 10.1016/j.jmir.2019.06.044 -
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 -
Oncology (Williston Park, N.Y.) Apr 2012Approximately 85% to 90% of men with castration-resistant prostate cancer (CRPC) have radiological evidence of bone metastases. To date, however, therapies to manage... (Review)
Review
Approximately 85% to 90% of men with castration-resistant prostate cancer (CRPC) have radiological evidence of bone metastases. To date, however, therapies to manage bone metastases have been primarily palliative. Among CRPC patients with bone metastases, there is a significant unmet need for active antitumor treatment options that are highly efficacious and have a favorable safety profile. This article will present current information about alpha-pharmaceuticals, a new class of targeted cancer therapy for the treatment of patients with CRPC and bone metastases. It will review preclinical and clinical studies of the experimental radiopharmaceutical radium-223 chloride (Alpharadin), a first-in-class, highly targeted and well-tolerated alpha-pharmaceutical under development to improve survival in patients with bone metastases from advanced prostate cancer. Alpharadin kills cancer cells via alpha radiation from the decay of radium-223, a calcium mimetic that naturally self-targets to bone metastases. The mechanism of action of Alpharadin and specifics of administration, radiation protection, and patient management will be discussed.
Topics: Alpha Particles; Bone Neoplasms; Clinical Trials as Topic; Humans; Male; Prostatic Neoplasms; Radiation Protection; Radiopharmaceuticals; Radium
PubMed: 22655525
DOI: No ID Found -
Anti-cancer Agents in Medicinal... 2022One of the most rapidly growing options in the management of cancer therapy is Targeted Alpha Therapy (TAT) through which lethal α-emitting radionuclides conjugated to... (Review)
Review
One of the most rapidly growing options in the management of cancer therapy is Targeted Alpha Therapy (TAT) through which lethal α-emitting radionuclides conjugated to tumor-targeting vectors selectively deliver high amount of radiation to cancer cells.Ac, Bi, At, Bi, and 223Ra have been investigated by plenty of clinical trials and preclinical researches for the treatment of smaller tumor burdens, micro-metastatic disease, and post-surgery residual disease. In order to send maximum radiation to tumor cells while minimizing toxicity in normal cells, a high affinity of targeting vectors to cancer tissue is essential. Besides that, the stable and specific complex between chelating agent and α-emitters was found as a crucial parameter. The present review was planned to highlight recent achievements about TAT-based targeting vectors and chelating agents and provide further insight for future researches.
Topics: Actinium; Alpha Particles; Chelating Agents; Humans; Neoplasms; Radioimmunotherapy; Radium
PubMed: 34315393
DOI: 10.2174/1871520621666210727120308 -
Current Radiopharmaceuticals Oct 2011Alpha particle-emitting isotopes are being investigated in radioimmunotherapeutic applications because of their unparalleled cytotoxicity when targeted to cancer and... (Review)
Review
Alpha particle-emitting isotopes are being investigated in radioimmunotherapeutic applications because of their unparalleled cytotoxicity when targeted to cancer and their relative lack of toxicity towards untargeted normal tissue. Actinium- 225 has been developed into potent targeting drug constructs and is in clinical use against acute myelogenous leukemia. The key properties of the alpha particles generated by 225Ac are the following: i) limited range in tissue of a few cell diameters; ii) high linear energy transfer leading to dense radiation damage along each alpha track; iii) a 10 day halflife; and iv) four net alpha particles emitted per decay. Targeting 225Ac-drug constructs have potential in the treatment of cancer.
Topics: Actinium; Alpha Particles; Animals; Antibodies, Monoclonal; Clinical Trials as Topic; Humans; Liposomes; Models, Animal; Neoplasms; Radioimmunotherapy; Radiopharmaceuticals; Radiotherapy Dosage
PubMed: 22202153
DOI: 10.2174/1874471011104040306 -
Proceedings of the National Academy of... Mar 1983Synergistic interactions of indoor radon progeny with the cigarette smoking process have been evaluated experimentally. Smoking enhances the air concentration of...
Synergistic interactions of indoor radon progeny with the cigarette smoking process have been evaluated experimentally. Smoking enhances the air concentration of submicron particles and attached radon decay products. Fractionation in burning cigarettes gives rise to the association of radon progeny with large particles in mainstream cigarette smoke, which are selectively deposited in "hot spots" at bronchial bifurcations. Because smoke tars are resistant to dissolution in lung fluid, attached radon progeny undergo substantial radioactive decay at bifurcations before clearance. Radon progeny inhaled during normal breathing between cigarettes make an even larger contribution to the alpha-radiation dose at bifurcations. Progressive chemical and radiation damage to the epithelium at bifurcations gives rise to prolonged retention of insoluble 210Pb-enriched smoke particles produced by tobacco trichome combustion. The high incidence of lung cancer in cigarette smokers is attributed to the cumulative alpha-radiation dose at bifurcations from indoor radon and thoron progeny--218Po, 214Po, 212Po, and 212Bi--plus that from 210Po in 210Pb-enriched smoke particles. It is estimated that a carcinogenic alpha-radiation dose of 80-100 rads (1 rad = 0.01 J/kg = 0.01 Gy) is delivered to approximately equal to 10(7) cells (approximately equal to 10(6) cells at individual bifurcations) of most smokers who die of lung cancer.
Topics: Aerosols; Alpha Particles; Bronchi; Cocarcinogenesis; Humans; Lung; Lung Neoplasms; Radon; Tissue Distribution; Tobacco Use Disorder
PubMed: 6572389
DOI: 10.1073/pnas.80.5.1285 -
Tumour Biology : the Journal of the... Jun 2012The effectiveness of targeted α-therapy (TAT) can be explained by the properties of α-particles. Alpha particles are helium nuclei and are ~8,000 times larger than... (Review)
Review
The effectiveness of targeted α-therapy (TAT) can be explained by the properties of α-particles. Alpha particles are helium nuclei and are ~8,000 times larger than β(-)-particles (electrons). When emitted from radionuclides that decay via an α-decay pathway, they release enormous amounts of energy over a very short distance. Typically, the range of α-particles in tissue is 50-100 μm and they have high linear energy transfer (LET) with a mean energy deposition of 100 keV/μm, providing a more specific tumor cell killing ability without damage to the surrounding normal tissues than β(-)-emitters. Due to these properties, the majority of pre-clinical and clinical trials have demonstrated that α-emitters such as (225)Ac, (211)At, (212)Bi, (213)Bi, (212)Pb, (223)Ra, and (227)Th are ideal for the treatment of smaller tumor burdens, micrometastatic disease, and disseminated disease. Even though these α-emitters have favorable properties, the development of TAT has been limited by high costs, unresolved chemistry, and limited availability of the radionuclides. To overcome these limitations, more potent isotopes, additional sources, and more efficient isotope production methods should be addressed. Furthermore, better chelation and labeling methods with the improvements of isotope delivery, targeting vehicles, molecular targets, and identification of appropriate clinical applications are still required.
Topics: Alpha Particles; Animals; Clinical Trials as Topic; Drug Evaluation, Preclinical; Humans; Neoplasms; Radioimmunotherapy; Radioisotopes
PubMed: 22143940
DOI: 10.1007/s13277-011-0286-y -
Physics in Medicine and Biology Apr 2022. A systematic review of dosimetry in Targeted Alpha Therapy (TAT) has been performed, identifying the common issues.. The systematic review was performed in accordance... (Review)
Review
. A systematic review of dosimetry in Targeted Alpha Therapy (TAT) has been performed, identifying the common issues.. The systematic review was performed in accordance with the PRISMA guidelines, and the literature was searched using the Scopus and PubMed databases.. From the systematic review, three key points should be considered when performing dosimetry in TAT. (1) Biodistribution/Biokinetics: the accuracy of the biodistribution data is a limit to accurate dosimetry in TAT. The biodistribution of alpha-emitting radionuclides throughout the body is difficult to image directly, with surrogate radionuclide imaging, blood/faecal sampling, and animal studies able to provide information. (2) Daughter radionuclides: the decay energy of the alpha-emissions is sufficient to break the bond to the targeting vector, resulting in a release of free daughter radionuclides in the body. Accounting for daughter radionuclide migration is essential. (3) Small-scale dosimetry and microdosimetry: due to the short path length and heterogeneous distribution of alpha-emitters at the target site, small-scale/microdosimetry are important to account for the non-uniform dose distribution in a target region, organ or cell and for assessing the biological effect of alpha-particle radiation.. TAT is a form of cancer treatment capable of delivering a highly localised dose to the tumour environment while sparing the surrounding healthy tissue. Dosimetry is an important part of treatment planning and follow up. Being able to accurately predict the radiation dose to the target region and healthy organs could guide the optimal prescribed activity. Detailed dosimetry models accounting for the three points mentioned above will help give confidence in and guide the clinical application of alpha-emitting radionuclides in targeted cancer therapy.
Topics: Alpha Particles; Animals; Monte Carlo Method; Neoplasms; Radioisotopes; Radiometry; Tissue Distribution
PubMed: 35316802
DOI: 10.1088/1361-6560/ac5fe0