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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 -
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 -
The Enzymes 2022Boron Neutron Capture Therapy (BNCT) is a tumor cell selective high LET (linear energy transfer) particle beam therapy. The patient is administrated a boron (B) compound... (Review)
Review
Boron Neutron Capture Therapy (BNCT) is a tumor cell selective high LET (linear energy transfer) particle beam therapy. The patient is administrated a boron (B) compound via intravenous injection or infusion, and when B is sufficiently accumulated in the tumor, neutron beams containing epithermal neutrons as the main component are irradiated. Epithermal neutrons lose energy in the body and become thermal neutrons. The captured B undergoes a (n, α) reaction with thermal neutrons, and the resulting α particles and Li nuclei have short ranges of 9-10μm and 4-5μm, respectively, and do not reach the surrounding cells in normal tissues. Therefore, these high LET-heavy charged particles can selectively kill cancer cells. The cell-killing effect of these heavy charged particles is thought to be triggered by DNA damage. It is known that DNA damage caused by heavy charged particles is more serious and difficult to repair than DNA damage caused by Low LET radiation such as X-rays and γ-rays. This review focuses on DNA damage, e.g., DNA strand breaks and DNA damage repair caused by BNCT and describes the resulting biological response.
Topics: Humans; Boron Neutron Capture Therapy; DNA Damage; Neutrons; DNA Repair
PubMed: 36336409
DOI: 10.1016/bs.enz.2022.08.005 -
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 -
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 -
Genes Jan 2023Boron neutron capture therapy (BNCT) is an approach to the radiotherapy of solid tumors that was first outlined in the 1930s but has attracted considerable attention... (Review)
Review
Boron neutron capture therapy (BNCT) is an approach to the radiotherapy of solid tumors that was first outlined in the 1930s but has attracted considerable attention recently with the advent of a new generation of neutron sources. In BNCT, tumor cells accumulate B atoms that react with epithermal neutrons, producing energetic α particles and Li atoms that damage the cell's genome. The damage inflicted by BNCT appears not to be easily repairable and is thus lethal for the cell; however, the molecular events underlying the action of BNCT remain largely unaddressed. In this review, the chemistry of DNA damage during BNCT is outlined, the major mechanisms of DNA break sensing and repair are summarized, and the specifics of the repair of BNCT-induced DNA lesions are discussed.
Topics: Humans; Boron Neutron Capture Therapy; DNA Damage; Brain Neoplasms; Biological Phenomena
PubMed: 36672868
DOI: 10.3390/genes14010127 -
Frontiers in Oncology 2022Boron neutron capture therapy (BNCT) is a re-emerging therapy with the ability to selectively kill tumor cells. After the boron delivery agents enter the tumor tissue... (Review)
Review
Boron neutron capture therapy (BNCT) is a re-emerging therapy with the ability to selectively kill tumor cells. After the boron delivery agents enter the tumor tissue and enrich the tumor cells, the thermal neutrons trigger the fission of the boron atoms, leading to the release of boron atoms and then leading to the release of the α particles (He) and recoil lithium particles (Li), along with the production of large amounts of energy in the narrow region. With the advantages of targeted therapy and low toxicity, BNCT has become a unique method in the field of radiotherapy. Since the beginning of the last century, BNCT has been emerging worldwide and gradually developed into a technology for the treatment of glioblastoma multiforme, head and neck cancer, malignant melanoma, and other cancers. At present, how to develop and innovate more efficient boron delivery agents and establish a more accurate boron-dose measurement system have become the problem faced by the development of BNCT. We discuss the use of boron delivery agents over the past several decades and the corresponding clinical trials and preclinical outcomes. Furthermore, the discussion brings recommendations on the future of boron delivery agents and this therapy.
PubMed: 35433432
DOI: 10.3389/fonc.2022.788770 -
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 -
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 -
Seminars in Nuclear Medicine Mar 2020As a treatment modality that is fundamentally different from other therapies against cancer, radiopharmaceutical therapy with alpha-particle emitters has drawn the... (Review)
Review
As a treatment modality that is fundamentally different from other therapies against cancer, radiopharmaceutical therapy with alpha-particle emitters has drawn the attention of the therapy community and also the biopharmaceutical industry. Alpha-particles cause a preponderance of complex DNA double-strand breaks (DSBs). This provides an opportunity to either enhance cell kill by using DNA DSB repair inhibitors or identify patients who are likely to be high responders to alpha-emitter RPT. The short-range and high potency of alpha-particles requires special dosimetry considerations. These are reviewed in light of recent updates to the phantoms and associated dosimetric quantities used for dosimetry calculations. A formalism for obtaining the necessary microscale pharmacokinetic information from patient nuclear medicine imaging is presented. Alpha-emitter based radiopharmaceutical therapy is an exciting cancer therapy modality that is being revisited. Further development of imaging and dosimetric methods specific to alpha-particle emitters, coupled with standardization of the methods and rigorous evidence that dosimetry applied to alphaRPT improves patient care are needed moving forward.
Topics: Alpha Particles; Humans; Radiobiology; Radiometry; Radiopharmaceuticals
PubMed: 32172797
DOI: 10.1053/j.semnuclmed.2019.11.002