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Current Radiopharmaceuticals 2024The low range of alpha particles provides an opportunity to better target cancer cells theoretically leading to the introduction of interesting alpha emitter... (Review)
Review
The low range of alpha particles provides an opportunity to better target cancer cells theoretically leading to the introduction of interesting alpha emitter radiopharmaceuticals including Ac, Pb, etc. The combination of high energy and short range of alpha emitters differentiates targeted radiotherapy from other methods and reduces unwanted cytotoxicity of the cells around the tumoral tissue. Among interesting alpha emitters candidates for targeted therapy, At, one of the radioisotopes with the best optimal decay properties, shows great promise for targeted radiotherapy in some animal prostate cancer xenograft studies and bone micro tumors with significant effects compared to other beta and alpha emitters and also demonstrates interesting properties for clinical applications. However, production and application of this alpha emitter in the development of actinium-based radiopharmaceuticals is hampered by many obstacles. This mini-review demonstrates At production methods, chemical separation, radiolabeling procedures, At-radiopharmaceuticals and their clinical trials, transport, logistics, and costs and future trends in the field for ultimate clinical applications. This review showed that there are limited clinical trials on Ac-based radiopharmaceuticals, which is due to the low accessibility of this radioisotope and other limitations. However, the development programs of major industries indicate the development of Ac-based radiopharmaceuticals in the future.
Topics: Radiopharmaceuticals; Humans; Astatine; Alpha Particles; Animals; Neoplasms
PubMed: 37937552
DOI: 10.2174/0118744710262325231025075638 -
Frontiers in Medicine 2022[Ra]RaCl and [Ra]RaCl are bone seekers, emitting high LET, and short range (< 100 μm) alpha-particles. Both radionuclides show similar decay properties; the total alpha... (Review)
Review
[Ra]RaCl and [Ra]RaCl are bone seekers, emitting high LET, and short range (< 100 μm) alpha-particles. Both radionuclides show similar decay properties; the total alpha energies are comparable (Ra: ≈28 MeV, Ra: ≈26 MeV). [Ra]RaCl has been used from the mid-1940s until 1990 for treating different bone and joint diseases with activities of up to approximately 50 MBq [Ra]RaCl. In 2013 [Ra]RaCl obtained marketing authorization by the FDA and by the European Union for the treatment of metastatic prostate cancer with an activity to administer of 0.055 MBq per kg body weight for six cycles. For intravenous injections in humans a model calculation using the biokinetic model of ICRP67 shows a ratio of organ absorbed dose coefficients (Ra:Ra) between 0.37 (liver) and 0.97 except for the kidneys (2.27) and blood (1.57). For the red marrow as primary organ-at-risk, the ratio is 0.57. The differences are mainly caused be the differing half-lives of the decay products of both radium isotopes. Both radionuclides show comparable DNA damage patterns in peripheral blood mononuclear cells after internal irradiation. Data on the long-term radiation-associated side effects are only available for treatment with [Ra]RaCl. Two epidemiological studies followed two patient groups treated with [Ra]RaCl for more than 25 years. One of them was the "Spiess study", a cohort of 899 juvenile patients who received several injections of [Ra]RaCl with a mean specific activity of 0.66 MBq/kg. Another patient group of ankylosing spondylitis patients was treated with 10 repeated intravenous injections of [Ra]RaCl, 1 MBq each, 1 week apart. In total 1,471 of these patients were followed-up in the "Wick study". In both studies, an increased cancer mortality by leukemia and solid cancers was observed. Similar considerations on long-term effects likely apply to [Ra]RaCl as well since the biokinetics are similar and the absorbed doses in the same range. However, this increased risk will most likely not be observed due to the much shorter life expectancy of prostate cancer patients treated with [Ra]RaCl.
PubMed: 36687439
DOI: 10.3389/fmed.2022.1057373 -
Frontiers in Pharmacology 2019Glioblastoma is the most common malignant adult brain tumor and has a very poor patient prognosis. The mean survival for highly proliferative glioblastoma is only 10 to... (Review)
Review
Glioblastoma is the most common malignant adult brain tumor and has a very poor patient prognosis. The mean survival for highly proliferative glioblastoma is only 10 to 14 months despite an aggressive current therapeutic approach known as Stupp's protocol, which consists of debulking surgery followed by radiotherapy and chemotherapy. Despite several clinical trials using anti-angiogenic targeted therapies, glioblastoma medical care remains without major progress in the last decade. Recent progress in nuclear medicine, has been mainly driven by advances in biotechnologies such as radioimmunotherapy, radiopeptide therapy, and radionanoparticles, and these bring a new promising arsenal for glioblastoma therapy. For therapeutic purposes, nuclear medicine practitioners classically use β particle emitters like I, Y, Re, or Lu. In the glioblastoma field, these radioisotopes are coupled with nanoparticles, monoclonal antibodies, or peptides. These radiopharmaceutical compounds have resulted in a stabilization and/or improvement of the neurological status with only transient side effects. In nuclear medicine, the glioblastoma-localized and targeted internal radiotherapy proof-of-concept stage has been successfully demonstrated using β emitting isotopes. Similarly, α particle emitters like Bi, At, or Ac appear to be an innovative and interesting alternative. Indeed, α particles deliver a high proportion of their energy inside or at close proximity to the targeted cells (within a few micrometers from the emission point versus several millimeters for β particles). This physical property is based on particle-matter interaction differences and results in α particles being highly efficient in killing tumor cells with minimal irradiation of healthy tissues and permits targeting of isolated tumor cells. The first clinical trials confirmed this idea and showed good therapeutic efficacy and less side effects, thus opening a new and promising era for glioblastoma medical care using α therapy. The objective of this literature review is focused on the developing field of nuclear medicine and aims to describe the various parameters such as targets, vectors, isotopes, or injection route (systemic and local) in relation to the clinical and preclinical results in glioblastoma pathology.
PubMed: 31354487
DOI: 10.3389/fphar.2019.00772 -
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 -
Journal of Nuclear Medicine : Official... Nov 2021Encouraging results from targeted α-therapy have received significant attention from academia and industry. However, the limited availability of suitable radionuclides...
Encouraging results from targeted α-therapy have received significant attention from academia and industry. However, the limited availability of suitable radionuclides has hampered widespread translation and application. In the present review, we discuss the most promising candidates for clinical application and the state of the art of their production and supply. In this review, along with 2 forthcoming reviews on chelation and clinical application of α-emitting radionuclides, will provide a comprehensive assessment of the field.
Topics: Alpha Particles; Radioimmunotherapy
PubMed: 34301779
DOI: 10.2967/jnumed.120.261016 -
Journal of Labelled Compounds &... Sep 2019Targeted alpha therapy (TAT) is a promising approach for the treatment of cancer. The use of alpha emitters for cancer therapy has two distinct advantages over... (Review)
Review
Targeted alpha therapy (TAT) is a promising approach for the treatment of cancer. The use of alpha emitters for cancer therapy has two distinct advantages over conventional therapies. The short range of alpha radiation in human tissue (less than 0.1 mm), corresponding to only a few cell diameters, allows selective killing of targeted cancer cells while sparing surrounding healthy tissue. At the same time, the high energy (several MeV) of alpha radiation and its associated high linear energy transfer leads to highly effective cell kill. Consequently, alpha radiation can destroy cells which otherwise exhibit resistance to treatment with beta or gamma irradiation or chemotherapeutic drugs, and can thus offer a therapeutic option for tumors resistant to conventional therapies. Recent results demonstrating the remarkable therapeutic efficacy of alpha emitters to treat various cancers have underlined the clinical potential of TAT. This paper describes the recent clinical experience with Bi and Ac. In view of the enormous benefit of targeted cancer treatment with alpha emitters, their production will have to be considerably increased beyond current supply capabilities. Alternative production methods based on the irradiation of uranium, thorium, or radium targets at reactors or accelerator facilities have the potential to meet future demand.
Topics: Actinium; Alpha Particles; Bismuth; Humans; Radiochemistry; Radioisotopes; Radiotherapy
PubMed: 31369165
DOI: 10.1002/jlcr.3792 -
Medical Physics Mar 2023Diffusing alpha-emitters Radiation Therapy ("DaRT") is a new method, presently in clinical trials, which allows treating solid tumors by alpha particles. DaRT relies on...
BACKGROUND
Diffusing alpha-emitters Radiation Therapy ("DaRT") is a new method, presently in clinical trials, which allows treating solid tumors by alpha particles. DaRT relies on interstitial seeds carrying μCi-level Ra activity below their surface, which release a chain of short-lived alpha emitters that spread throughout the tumor volume primarily by diffusion. Alpha dose calculations in DaRT are based on describing the transport of alpha emitting atoms, requiring new modeling techniques.
PURPOSE
A previous study introduced a simplified framework, the "Diffusion-Leakage (DL) model", for DaRT alpha dose calculations, and employed it to a point source, as a basic building block of arbitrary configurations of line sources. The aim of this work, which is divided into two parts, is to extend the model to realistic seed geometries (in Part I), and to employ single-seed calculations to study the properties of DaRT seed lattices (Part II). Such calculations can serve as a pragmatic guide for treatment planning in future clinical trials.
METHODS
We derive a closed-form asymptotic solution for an infinitely long cylindrical source, and extend it to an approximate time-dependent expression that assumes a uniform temporal profile at all radial distances from the source. We then develop a finite-element one-dimensional numerical scheme for a complete time-dependent solution of this geometry and validate it against the closed-form expressions. Finally, we discuss a two-dimensional axisymmetric scheme for a complete time-dependent solution for a seed of finite diameter and length. Different solutions are compared over the relevant parameter space, providing guidelines on their usability and limitations.
RESULTS
We show that approximating the seed as a finite line source comprised of point-like segments significantly underestimates the correct alpha dose, as predicted by the full two-dimensional calculation. The time-dependent one-dimensional solution is shown to coincide to sub-percent-level with the two-dimensional calculation in the seed midplane, and maintains an accuracy of a few percent up to ∼2 mm from the seed edge.
CONCLUSIONS
For actual treatment plans, the full two-dimensional solution should be used to generate dose lookup tables, similarly to the TG-43 format employed in conventional brachytherapy. Given the accuracy of the one-dimensional solution up to ∼2 mm from the seed edge it can be used for efficient parametric studies of DaRT seed lattices.
Topics: Humans; Brachytherapy; Neoplasms; Alpha Particles; Radiotherapy Dosage; Monte Carlo Method
PubMed: 36464914
DOI: 10.1002/mp.16145 -
Current Oncology (Toronto, Ont.) Oct 2022Boron neutron capture therapy (BNCT) is a binary modality that is used to treat a variety of malignancies, using neutrons to irradiate boron-10 (B) nuclei that have... (Review)
Review
Boron neutron capture therapy (BNCT) is a binary modality that is used to treat a variety of malignancies, using neutrons to irradiate boron-10 (B) nuclei that have entered tumor cells to produce highly linear energy transfer (LET) alpha particles and recoil Li nuclei (B [n, α] Li). Therefore, the most important part in BNCT is to selectively deliver a large number of B to tumor cells and only a small amount to normal tissue. So far, BNCT has been used in more than 2000 cases worldwide, and the efficacy of BNCT in the treatment of head and neck cancer, malignant meningioma, melanoma and hepatocellular carcinoma has been confirmed. We collected and collated clinical studies of second-generation boron delivery agents. The combination of different drugs, the mode of administration, and the combination of multiple treatments have an important impact on patient survival. We summarized the critical issues that must be addressed, with the hope that the next generation of boron delivery agents will overcome these challenges.
Topics: Humans; Boron Neutron Capture Therapy; Boron; Brain Neoplasms; Melanoma; Head and Neck Neoplasms
PubMed: 36290899
DOI: 10.3390/curroncol29100622 -
Cancers Feb 2020Pancreatic ductal adenocarcinoma (PDAC) has long been associated with low survival rates. A lack of accurate diagnostic tests and limited treatment options contribute to... (Review)
Review
Pancreatic ductal adenocarcinoma (PDAC) has long been associated with low survival rates. A lack of accurate diagnostic tests and limited treatment options contribute to the poor prognosis of PDAC. Radioimmunotherapy using α- or β-emitting radionuclides has been identified as a potential treatment for PDAC. By harnessing the cytotoxicity of α or β particles, radioimmunotherapy may overcome the anatomic and physiological factors which traditionally make PDAC resistant to most conventional treatments. Appropriate selection of target receptors and the development of selective and cytotoxic radioimmunoconjugates are needed to achieve the desired results of radioimmunotherapy. The aim of this review is to examine the growing preclinical and clinical trial evidence regarding the application of α and β radioimmunotherapy for the treatment of PDAC. A systematic search of MEDLINE and Scopus databases was performed to identify 34 relevant studies conducted on α or β radioimmunotherapy of PDAC. Preclinical results demonstrated α and β radioimmunotherapy provided effective tumour control. Clinical studies were limited to investigating β radioimmunotherapy only. Phase I and II trials observed disease control rates of 11.2%-57.9%, with synergistic effects noted for combination therapies. Further developments and optimisation of treatment regimens are needed to improve the clinical relevance of α and β radioimmunotherapy in PDAC.
PubMed: 32092952
DOI: 10.3390/cancers12020481 -
Theranostics 2024Targeted alpha particle therapy (TAT) has emerged as a promising strategy for the treatment of prostate cancer (PCa). Actinium-225 (Ac), a potent alpha-emitting... (Review)
Review
Targeted alpha particle therapy (TAT) has emerged as a promising strategy for the treatment of prostate cancer (PCa). Actinium-225 (Ac), a potent alpha-emitting radionuclide, may be incorporated into targeting vectors, causing robust and in some cases sustained antitumor responses. The development of radiolabeling techniques involving EDTA, DOTA, DOTPA, and Macropa chelators has laid the groundwork for advancements in this field. At the forefront of clinical trials with Ac in PCa are PSMA-targeted TAT agents, notably [Ac]Ac-PSMA-617, [Ac]Ac-PSMA-I&T and [Ac]Ac-J591. Ongoing investigations spotlight [Ac]Ac-hu11B6, [Ac]Ac-YS5, and [Ac]Ac-SibuDAB, targeting hK2, CD46, and PSMA, respectively. Despite these efforts, hurdles in Ac production, daughter redistribution, and a lack of suitable imaging techniques hinder the development of TAT. To address these challenges and additional advantages, researchers are exploring alpha-emitting isotopes including Th, Ra, At, Bi, Pb or Tb, providing viable alternatives for TAT.
Topics: Humans; Male; Actinium; Prostatic Neoplasms; Alpha Particles; Radiopharmaceuticals; Animals
PubMed: 38773983
DOI: 10.7150/thno.96403