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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 -
Journal of Nuclear Medicine : Official... Jun 2018With a short particle range and high linear energy transfer, α-emitting radionuclides demonstrate high cell-killing efficiencies. Even with the existence of numerous... (Review)
Review
With a short particle range and high linear energy transfer, α-emitting radionuclides demonstrate high cell-killing efficiencies. Even with the existence of numerous radionuclides that decay by α-particle emission, only a few of these can reasonably be exploited for therapeutic purposes. Factors including radioisotope availability and physical characteristics (e.g., half-life) can limit their widespread dissemination. The first part of this review will explore the diversity, basic radiochemistry, restrictions, and hurdles of α-emitters.
Topics: Alpha Particles; Humans; Isotope Labeling; Radiochemistry
PubMed: 29545378
DOI: 10.2967/jnumed.116.186338 -
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 -
Seminars in Nuclear Medicine Mar 2020In 2018 bladder cancer (urothelial carcinoma) was ranked twelfth concerning worldwide diagnosis of malignancies. At the time point of diagnosis of bladder cancer,... (Review)
Review
In 2018 bladder cancer (urothelial carcinoma) was ranked twelfth concerning worldwide diagnosis of malignancies. At the time point of diagnosis of bladder cancer, approximately 75% of patients present with a nonmuscle-invasive disease (NMIBC), while the remaining 25% show invasion of tumor cells in the muscle layer of the bladder wall (MIBC). Among NMIBC tumors, flat, high-grade carcinoma in situ (CIS) is a therapeutic challenge. CIS shows a tendency to invade the muscle tissue of the bladder wall and thus become a MIBC. Standard therapy of NMIBC (including CIS) is done via intravesical instillation of BCG (bacillus Calmette Guerin) inducing a local immune reaction that finally promotes elimination of bladder cancer cells. However, BCG treatment of NMIBC proves to be ineffective in approximately 40% of patients. Therefore, new therapeutic approaches for the treatment of bladder cancer are urgently needed. Among promising new treatment options that are currently being investigated are the use of immune checkpoint inhibitors, and targeted approaches attacking (among others) long noncoding RNAs, micro RNAs, cancer stem cells, PARP1, and receptor signaling pathways. Moreover, the use of antibody-drug-conjugates (ADCs) is investigated also in bladder cancer therapy. Another approach that has been successfully established in preclinical studies uses the cytotoxic power of the alpha-emitter Bi-213 coupled to an antibody targeting EGFR. Overexpression of EGFR has been demonstrated in the majority of patients suffering from CIS. Feasibility, safety, toxicity and therapeutic efficacy of intravesical instillation of Bi-213-anti-EGFR have been evaluated in a pilot study. Since the results of the pilot study proved to be promising, a further optimization of alpha-emitter immunotherapy in bladder cancer seems mandatory.
Topics: Alpha Particles; Humans; Immunotherapy; Molecular Targeted Therapy; Urinary Bladder Neoplasms
PubMed: 32172801
DOI: 10.1053/j.semnuclmed.2020.02.006 -
International Journal of Molecular... Dec 2017The skeleton is the target tissue for many types of tumors, and, recently, the survival of patients with prostate cancer metastasis has been increased using α-emitting... (Review)
Review
The skeleton is the target tissue for many types of tumors, and, recently, the survival of patients with prostate cancer metastasis has been increased using α-emitting drugs known as targeted α therapies. The use of α-radiopharmaceuticals in medicine was hypothesized at the beginning of the nineteenth century after the observation that α-radionuclides were associated with high cell-killing energy and low tissue penetration in healthy tissues. In the prostate cancer (PC) scenario, current research suggests that this class of radiopharmaceuticals has limited toxicity, and that the mechanism of action does not overlap with pre-existing drugs, allowing us to extend therapeutic armaments and address medical oncology towards personalized and precision medicine. Ongoing studies may extend these benefits also to bone metastases deriving from other neoplasms. The aim of this review is to summarize the current research on targeted α therapies and try to identify the right patient to be treated in the right time in order to integrate in these medications in the every-day clinical practice.
Topics: Alpha Particles; Bone Neoplasms; Brachytherapy; Dose-Response Relationship, Radiation; Humans; Male; Practice Guidelines as Topic; Prostatic Neoplasms; Radioisotopes; Radium; Randomized Controlled Trials as Topic
PubMed: 29283383
DOI: 10.3390/ijms19010074 -
Nuclear Medicine and Biology 2022Lanthanum radiometals are well positioned to serve as theranostic PET radiometals for targeted radionuclide therapy. The positron emitters La and La show promise to... (Review)
Review
Lanthanum radiometals are well positioned to serve as theranostic PET radiometals for targeted radionuclide therapy. The positron emitters La and La show promise to serve as unique PET imaging agents for Ac targeted alpha-particle therapy, the Ce/La pair has PET imaging potential with both Ac and Th, and La has potential in targeted Auger-Meitner electron therapy. With easily accessible cyclotron production routes, effective and efficient chemical separations, and robust chelation chemistry, these radionuclides are well poised for additional preclinical and clinical PET and targeted radionuclide therapy studies. This review summarizes recent advances in radiolanthanum production and preclinical applications that demonstrate the strong potential of these radionuclides in PET and targeted radionuclide therapy.
Topics: Alpha Particles; Cyclotrons; Positron-Emission Tomography; Precision Medicine; Radioisotopes
PubMed: 35487834
DOI: 10.1016/j.nucmedbio.2022.04.005 -
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 -
Current Radiopharmaceuticals 2018
Topics: Actinium; Alpha Particles; Animals; Bismuth; Humans; Neoplasms; Radiochemistry; Radioisotopes; Radionuclide Generators; Radiopharmaceuticals
PubMed: 30378473
DOI: 10.2174/187447101103180911115600 -
International Journal of Radiation... Feb 2020We present an α-irradiation setup for the irradiation of primary human cell cultures under controlled conditions using Am α-particles. To irradiate samples with...
We present an α-irradiation setup for the irradiation of primary human cell cultures under controlled conditions using Am α-particles. To irradiate samples with α-particles in a valid manner, a reliable dosimetry is a great challenge because of the short α-range and the complex energy spectrum. Therefore, the distance between α-source and sample must be minimal. In the present setup, this is achieved by cells growing on a 2 μm thick biaxially-oriented polyethylene terephthalate (boPET) foil which is only 2.7 mm apart from the source. A precise and reproducible exposure time is realized through a mechanical shutter. The fluence, energy spectra and the corresponding linear energy transfer are determined by the source geometry and the material traversed. They were measured and calculated, yielding a dose rate of 8.2 ± 2.4 Gy/min. To improve cell growth on boPET foils, they were treated with air plasma. This treatment increased the polarity and thus the ability of cells attaching to the surface of the foil. Several tests including cell growth, staining for a marker of DNA double-strand breaks and a colony-forming assay were performed and confirm our dosimetry. With our setup, it is possible to irradiate cell cultures under defined conditions with α-particles. The plasma-treated foil is suitable for primary human cell cultures as shown in cell experiments, confirming also the expected number of particle traversals.
Topics: Alpha Particles; Americium; Animals; CHO Cells; Cell Line; Collagen; Cricetinae; Cricetulus; Dose-Response Relationship, Radiation; Histones; Humans; Keratinocytes; Linear Energy Transfer; Oxygen; Polyethylene Terephthalates; Primary Cell Culture; Radiometry; Reproducibility of Results
PubMed: 31682776
DOI: 10.1080/09553002.2020.1683641 -
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