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Radiation and Environmental Biophysics Mar 2020At the tissue level, energy deposition in cells is determined by the microdistribution of alpha-emitting radionuclides in relation to sensitive target cells.... (Review)
Review
At the tissue level, energy deposition in cells is determined by the microdistribution of alpha-emitting radionuclides in relation to sensitive target cells. Furthermore, the highly localized energy deposition of alpha particle tracks and the limited range of alpha particles in tissue produce a highly inhomogeneous energy deposition in traversed cell nuclei. Thus, energy deposition in cell nuclei in a given tissue is characterized by the probability of alpha particle hits and, in the case of a hit, by the energy deposited there. In classical microdosimetry, the randomness of energy deposition in cellular sites is described by a stochastic quantity, the specific energy, which approximates the macroscopic dose for a sufficiently large number of energy deposition events. Typical examples of the alpha-emitting radionuclides in internal microdosimetry are radon progeny and plutonium in the lungs, plutonium and americium in bones, and radium in targeted radionuclide therapy. Several microdosimetric approaches have been proposed to relate specific energy distributions to radiobiological effects, such as hit-related concepts, LET and track length-based models, effect-specific interpretations of specific energy distributions, such as the dual radiation action theory or the hit-size effectiveness function, and finally track structure models. Since microdosimetry characterizes only the initial step of energy deposition, microdosimetric concepts are most successful in exposure situations where biological effects are dominated by energy deposition, but not by subsequently operating biological mechanisms. Indeed, the simulation of the combined action of physical and biological factors may eventually require the application of track structure models at the nanometer scale.
Topics: Alpha Particles; Animals; Bone and Bones; Humans; Lung; Radioisotopes; Radiometry
PubMed: 31863162
DOI: 10.1007/s00411-019-00826-w -
Cancer Biotherapy & Radiopharmaceuticals Aug 2020The rates of cancer incidence and mortality are increasing day by day. Although several conventional methods including surgery, chemotherapy, and radiotherapy (RT) exist... (Review)
Review
The rates of cancer incidence and mortality are increasing day by day. Although several conventional methods including surgery, chemotherapy, and radiotherapy (RT) exist for cancer treatment, they are insufficient in the eradication of all tumor tissues and have some side-effects such as narrow therapeutic index and serious side-effects to healthy tissues. Moreover, it may probably recur in time due to the survival and spreading of cancerous cells or any possible metastases. Targeted radionuclide therapy is a promising alternative. α particles are ideal for localized cell killing because of their high linear energy transfer and short ranges. However, upon emission of α particles, the daughter nuclides induce a recoil energy to lead decoupling from any chemical bond that may accumulate in normal tissues. Targeted α therapy can also be performed by targeted delivery systems apart from mAb, mAb fragments, peptides, and small molecules for selective tumor therapy. Targeted drug delivery systems have been developed to overcome the limitations of α therapy. Moreover, drug delivery systems are one of the most searched applications in cancer imaging and/or treatment due to their targeting ability to tumor or biocompatibility properties. The aim of this article is to summarize tumor therapy applications, targeted α RT approach, and to review the role of drug delivery systems in the delivery of α particles for cancer therapy and some instances of targeted α-emitting drug delivery systems from the literature.
Topics: Alpha Particles; Animals; Disease Models, Animal; Drug Carriers; Humans; Nanoparticles; Neoplasms; Radiation Oncology; Radiopharmaceuticals; Theranostic Nanomedicine
PubMed: 32302510
DOI: 10.1089/cbr.2019.3213 -
Scientific Reports Jun 2023Ionizing radiation is known to be DNA damaging and mutagenic, however less is known about which mutational footprints result from exposures of human cells to different...
Ionizing radiation is known to be DNA damaging and mutagenic, however less is known about which mutational footprints result from exposures of human cells to different types of radiation. We were interested in the mutagenic effects of particle radiation exposures on genomes of various human cell types, in order to gauge the genotoxic risks of galactic cosmic radiation, and of certain types of tumor radiotherapy. To this end, we exposed cultured cell lines from the human blood, breast and lung to fractionated proton and alpha particle (helium nuclei) beams at doses sufficient to considerably affect cell viability. Whole-genome sequencing revealed that mutation rates were not overall markedly increased upon proton and alpha exposures. However, there were modest changes in mutation spectra and distributions, such as the increases in clustered mutations and of certain types of indels and structural variants. The spectrum of mutagenic effects of particle beams may be cell-type and/or genetic background specific. Overall, the mutational effects of repeated exposures to proton and alpha radiation on human cells in culture appear subtle, however further work is warranted to understand effects of long-term exposures on various human tissues.
Topics: Humans; Protons; Alpha Particles; Cosmic Radiation; Radiation, Ionizing; Mutation; Mutagens
PubMed: 37328655
DOI: 10.1038/s41598-023-36845-3 -
Cancer Biotherapy & Radiopharmaceuticals Aug 2020α-Emitting radionuclides have been approved for cancer treatment since 2013, with increasing degrees of success. Despite this clinical utility, little is known... (Review)
Review
α-Emitting radionuclides have been approved for cancer treatment since 2013, with increasing degrees of success. Despite this clinical utility, little is known regarding the mechanisms of action of α particles in this setting, and accurate assessments of the dosimetry underpinning their effectiveness are lacking. However, targeted alpha therapy (TAT) is gaining more attention as new targets, synthetic chemistry approaches, and α particle emitters are identified, constructed, developed, and realized. From a radiobiological perspective, α particles are more effective at killing cells compared to low linear energy transfer radiation. Also, from these direct effects, it is now evident from preclinical and clinical data that α emitters are capable of both producing effects in nonirradiated bystander cells and stimulating the immune system, extending the biological effects of TAT beyond the range of α particles. The short range of α particles makes them a potent tool to irradiate single-cell lesions or treat solid tumors by minimizing unwanted irradiation of normal tissue surrounding the cancer cells, assuming a high specificity of the radiopharmaceutical and good stability of its chemical bonds. Clinical approval of RaCl in 2013 was a major milestone in the widespread application of TAT as a safe and effective strategy for cancer treatment. In addition, Ac-prostate specific membrane antigen treatment benefit in metastatic castrate-resistant prostate cancer patients, refractory to standard therapies, is another game-changing piece in the short history of TAT clinical application. Clinical applications of TAT are growing with different radionuclides and combination therapies, and in different clinical settings. Despite the remarkable advances in TAT dosimetry and imaging, it has not yet been used to its full potential. Labeled Th and Ac appear to be promising candidates and could represent the next generation of agents able to extend patient survival in several clinical scenarios.
Topics: Alpha Particles; Drug Approval; Drug Development; Humans; Molecular Targeted Therapy; Neoplasms; Radiation Oncology; Radioisotopes; Radiopharmaceuticals
PubMed: 32552031
DOI: 10.1089/cbr.2020.3576 -
Pharmaceutics Jan 2022Over the last decade, targeted alpha therapy has demonstrated its high effectiveness in treating various oncological diseases. Lead-212, with a convenient half-life of... (Review)
Review
Over the last decade, targeted alpha therapy has demonstrated its high effectiveness in treating various oncological diseases. Lead-212, with a convenient half-life of 10.64 h, and daughter alpha-emitter short-lived Bi ( = 1 h), provides the possibility for the synthesis and purification of complex radiopharmaceuticals with minimum loss of radioactivity during preparation. As a benefit for clinical implementation, it can be milked from a radionuclide generator in different ways. The main approaches applied for these purposes are considered and described in this review, including chromatographic, solution, and other techniques to isolate Pb from its parent radionuclide. Furthermore, molecules used for lead's binding and radiochemical features of preparation and stability of compounds labeled with Pb are discussed. The results of preclinical studies with an estimation of therapeutic and tolerant doses as well as recently initiated clinical trials of targeted radiopharmaceuticals are presented.
PubMed: 35057083
DOI: 10.3390/pharmaceutics14010189 -
European Journal of Nuclear Medicine... Dec 2021The approval of RaCl for cancer therapy in 2013 has heralded a resurgence of interest in the development of α-particle emitting radiopharmaceuticals. In the last...
The approval of RaCl for cancer therapy in 2013 has heralded a resurgence of interest in the development of α-particle emitting radiopharmaceuticals. In the last decade, over a dozen α-emitting radiopharmaceuticals have entered clinical trials, spawned by strong preclinical studies. In this article, we explore the potential role of α-particle therapy in cancer treatment. We begin by providing a background for the basic principles of therapy with α-emitters, and we explore recent breakthroughs in therapy with α-emitting radionuclides, including conjugates with small molecules and antibodies. Finally, we discuss some outstanding challenges to the clinical adoption of α-therapies and potential strategies to address them.
Topics: Alpha Particles; Humans; Neoplasms; Radioisotopes; Radiopharmaceuticals
PubMed: 34175980
DOI: 10.1007/s00259-021-05431-y -
Practical Radiation Oncology 2022Prostate cancer is a significant cause of morbidity and mortality among men worldwide. Although most patients present with localized or regional disease and experience... (Review)
Review
Prostate cancer is a significant cause of morbidity and mortality among men worldwide. Although most patients present with localized or regional disease and experience excellent outcomes with treatment, approximately 10% to 20% of patients develop castrate-resistant prostate cancer (CRPC) within 5 years of diagnosis. Bone metastases, which can cause pain and adversely affect quality of life, are common among this population. Radium-223 has a relatively short half-life and decays via α-decay. Its daughter products, α-particles, have a short path length in tissue and exhibit high linear energy transfer. Together, these properties allow radium-223 to achieve relatively high cell kill in its target tissue while sparing the surrounding normal tissues. Administered in the clinic as radium-223 dichloride (Xofigo), radium-223 acts as a calcium mimetic in the human body, forming complexes with hydroxyapatite. In areas of high bone turnover, such as the osteoblastic bone metastases that are common in patients with CRPC, radium-223 is preferentially incorporated into the bone matrix, where it can exert an antitumor effect. In May 2013, the U.S. Food and Drug Administration approved Xofigo for use in patients with CRPC who have symptomatic bone metastases and no visceral metastases. In this topic discussion, we review the mechanism of action and clinical efficacy of radium-223 in patients with metastatic CRPC. We also discuss its administration and handling, distribution and elimination, and associated toxicities.
Topics: Antineoplastic Agents; Bone Neoplasms; Humans; Male; Prostatic Neoplasms, Castration-Resistant; Quality of Life; Radium
PubMed: 35717046
DOI: 10.1016/j.prro.2022.03.004 -
Nuclear Medicine and Biology Jan 2021Targeted alpha therapy (TAT) is an area of research with rapidly increasing importance as the emitted alpha particle has a significant effect on inducing cytotoxic... (Review)
Review
Targeted alpha therapy (TAT) is an area of research with rapidly increasing importance as the emitted alpha particle has a significant effect on inducing cytotoxic effects on tumor cells while mitigating dose to normal tissues. Two significant isotopes of interest within the area of TAT are thorium-227 and actinium-225 due to their nuclear characteristics. Both isotopes have physical half-lives suitable for coordination with larger biomolecules, and additionally actinium-225 has potential to serve as an in vivo generator. In this review, the authors will discuss the production, purification, labeling reactions, and biological studies of actinium-225 and thorium-227 complexes and clinical studies.
Topics: Alpha Particles; Animals; Humans; Isotope Labeling; Radiochemistry
PubMed: 33558017
DOI: 10.1016/j.nucmedbio.2020.08.004 -
Cancer Biotherapy & Radiopharmaceuticals Aug 2020Targeted alpha therapy (TAT) can deliver high localized burden of radiation selectively to cancer cells as well as the tumor microenvironment, while minimizing toxicity... (Review)
Review
Targeted alpha therapy (TAT) can deliver high localized burden of radiation selectively to cancer cells as well as the tumor microenvironment, while minimizing toxicity to normal surrounding cell. Radium-223 (Ra), the first-in-class α-emitter approved for bone metastatic castration-resistant prostate cancer has shown the ability to prolong patient survival. Targeted Thorium-227 (Th) conjugates represent a new class of therapeutic radiopharmaceuticals for TAT. They are comprised of the α-emitter Th complexed to a chelator conjugated to a tumor-targeting monoclonal antibody. In this review, the authors will focus out interest on this therapeutic agent. In recent studies Th-labeled radioimmunoconjugates showed a relevant stability both in serum and vivo conditions with a significant antigen-dependent inhibition of cell growth. Unlike Ra, the parent radionuclide Th can form highly stable chelator complexes and is therefore amenable to targeted radioimmunotherapy. The authors discuss the future potential role of Th TAT in the treatment of several solid as well as hematologic malignancies.
Topics: Alpha Particles; Antibodies, Monoclonal; Biomarkers, Tumor; DNA Breaks, Double-Stranded; Drug Stability; Humans; Immunoconjugates; Molecular Targeted Therapy; Neoplasms; Radiopharmaceuticals; Thorium; Tumor Microenvironment
PubMed: 31967907
DOI: 10.1089/cbr.2019.3105 -
Journal of Medical Imaging and... Dec 2019Radiolabeled antibodies allow for selective targeting of the cancer cells within a tumor. Both beta- and alpha-emitting radioisotopes can be linked to the antibodies for... (Review)
Review
Radiolabeled antibodies allow for selective targeting of the cancer cells within a tumor. Both beta- and alpha-emitting radioisotopes can be linked to the antibodies for delivery of radiation to the cells. The choice of the radionuclide would depend on the biological characteristics of the antibody including its biodistribution and biological half-life. Alpha-emitting isotopes deliver high energy to target sites within short range and therefore less radiation to adjacent normal tissues. Whole antibodies have long biological clearance times that may be limiting due to radiation levels to blood and marrow. Novel strategies, such as development of smaller antibody fragments such as minibodies and diabodies, which have faster biological clearance, engineered bispecific antibodies, and multistep targeting that uses pretargeting and bioorthogonal click chemistry methods, appear promising. Several novel targets are being investigated in early-phase studies. This review provides a brief summary and current status of radioimmunotargeted agents in oncology.
Topics: Alpha Particles; Humans; Neoplasms; Radioimmunotherapy; Radiometry; Radiotherapy; Theranostic Nanomedicine
PubMed: 31451417
DOI: 10.1016/j.jmir.2019.07.006