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Journal of Medical Imaging and... Dec 2019Despite ongoing efforts with new chemotherapeutics, small-molecule inhibitors and biologics, patients with distant metastases continue to have a grim prognosis.... (Review)
Review
Despite ongoing efforts with new chemotherapeutics, small-molecule inhibitors and biologics, patients with distant metastases continue to have a grim prognosis. Radiopharmaceutical therapy (RPT) with alpha-particle-emitting radionuclides has shown efficacy against widespread disease. Alpha-particle emitters are particularly effective because their short range and high energy deposit density lead to complex and largely irreparable DNA double-strand breaks. The high potency against tumors can also lead to high toxicity. Unlike most systemic treatment of cancer, the biodistribution of RPT agents may be imaged in humans using nuclear medicine imaging modalities. In this context, dosimetry provides a precision medicine approach to implementing RPT with alpha-emitters.
Topics: Alpha Particles; Humans; Neoplasms; Radiation Injuries; Radiometry; Radiopharmaceuticals; Radiotherapy; Radiotherapy Dosage
PubMed: 31537496
DOI: 10.1016/j.jmir.2019.07.007 -
Seminars in Nuclear Medicine Mar 2020Neuroendocrine tumors (NET) are a heterogeneous group of neoplasms, arising from cells of the endocrine system, with various clinical behaviors. Although these neoplasms... (Review)
Review
Neuroendocrine tumors (NET) are a heterogeneous group of neoplasms, arising from cells of the endocrine system, with various clinical behaviors. Although these neoplasms are considered rare, a significant increase in the incidence and detectability of NET has been noted in many epidemiological studies in recent years. Among the various therapeutic options, peptide receptor radionuclide therapy (PRRT), using somatostatine has been shown to be highly effective and a well-tolerated therapy, improving survival parameters. The current use of radionuclides for PRRT is β-emitters. Due to hypoxia cancer tissue could be resistant for β-emitters. Quite long penetration range had a significant impact on side effects. α-particles with higher energy and shorter penetration range in comparison to β-particles, have distinct advantages for use in targeted therapy. The clinical experience with somatostatine based targeted α therapy (TAT) in NET showed very promising results even in patienicts refractory to treatment with β-emitters. This article summarizes current developments in preclinical and clinical investigation on TAT in NET.
Topics: Alpha Particles; Animals; Clinical Trials as Topic; Humans; Molecular Targeted Therapy; Neuroendocrine Tumors; Treatment Outcome
PubMed: 32172802
DOI: 10.1053/j.semnuclmed.2019.11.003 -
Cells May 2020Compact chromatin is linked to a poor tumour prognosis and resistance to radiotherapy from photons. We investigated DNA damage induction and repair in the context of...
Compact chromatin is linked to a poor tumour prognosis and resistance to radiotherapy from photons. We investigated DNA damage induction and repair in the context of chromatin structure for densely ionising alpha radiation as well as its therapeutic potential. Chromatin opening by histone deacetylase inhibitor trichostatin A (TSA) pretreatment reduced clonogenic survival and increased γH2AX foci in MDA-MB-231 cells, indicative of increased damage induction by free radicals using gamma radiation. In contrast, TSA pretreatment tended to improve survival after alpha radiation while γH2AX foci were similar or lower; therefore, an increased DNA repair is suggested due to increased access of repair proteins. MDA-MB-231 cells exposed to fractionated gamma radiation (2 Gy × 6) expressed high levels of stem cell markers, elevated heterochromatin H3K9me3 marker, and a trend towards reduced clonogenic survival in response to alpha radiation. There was a higher level of H3K9me3 at baseline, and the ratio of DNA damage induced by alpha vs. gamma radiation was higher in the aggressive MDA-MB-231 cells compared to hormone receptor-positive MCF7 cells. We demonstrate that heterochromatin structure and stemness properties are induced by fractionated radiation exposure. Gamma radiation-exposed cells may be targeted using alpha radiation, and we provide a mechanistic basis for the involvement of chromatin in these effects.
Topics: Acetylation; Alpha Particles; Breast Neoplasms; Cell Line, Tumor; Cell Survival; Clone Cells; Female; Gamma Rays; Heterochromatin; Histones; Humans; Hydroxamic Acids; Lysine; Neoplastic Stem Cells; Radiation Exposure; Spheroids, Cellular
PubMed: 32397212
DOI: 10.3390/cells9051165 -
Nuclear Medicine Communications Sep 2022Actinium-225 (225Ac) has emerged as a promising therapeutic radioisotope for targeted alpha therapy. It emits net four alpha particles during its decay to stable... (Review)
Review
Actinium-225 (225Ac) has emerged as a promising therapeutic radioisotope for targeted alpha therapy. It emits net four alpha particles during its decay to stable daughter bismuth-209, rightly called an in-vivo nano-generator. Compared to the worldwide demand of 225Ac, the amount produced via depleted thorium-229 sources is minimal, making it an expensive radionuclide. However, many research groups are working on optimizing the parameters for the production of 225Ac via different routes, including cyclotrons, reactors and high-energy linear accelerators. The present review article focuses on the various aspects associated with the development of 225Ac radiopharmaceuticals. It includes the challenges and opportunities associated with the production methods, labeling chemistry, in-vivo kinetics and dosimetry of 225Ac radiopharmaceuticals. A brief description is also given about the 225Ac radiopharmaceuticals at preclinical stages, clinical trials and used routinely.
Topics: Actinium; Alpha Particles; Radioisotopes; Radiopharmaceuticals
PubMed: 35950353
DOI: 10.1097/MNM.0000000000001594 -
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 on 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 employ the superposition of single-seed solutions, developed in Part I, to study the alpha dose in DaRT seed lattices and investigate the sensitivity of the required seed activity and spacing to changes in the DL model parameters and to seed placement errors.
RESULTS
We show that the rapid fall-off of the dose, which guarantees sparing healthy tissue already 2-3 mm away from the tumor, strongly favors a hexagonal, rather than square, seed placement pattern. Realistic variations in the seed manufacturing parameters ( Ra activity and emission rate of its daughters) are shown to have a negligible effect on the required lattice spacing. On the other hand, tumor parameters (i.e., diffusion lengths and Pb leakage probability), as well as seed placement errors, have a significant effect.
CONCLUSIONS
In most cases, hexagonal lattice spacing on the scale of ∼3.5-4.5 mm using seeds carrying a few μCi/cm Ra will enable overcoming realistic uncertainties in measured tumor environment parameters, as well as seed placement errors, and result in therapeutically relevant alpha dose levels.
Topics: Humans; Brachytherapy; Neoplasms; Radiotherapy Dosage; Radiotherapy Planning, Computer-Assisted
PubMed: 36517936
DOI: 10.1002/mp.16155 -
Journal of Nuclear Medicine : Official... Oct 2022The application of radiopharmaceutical therapy for the treatment of certain diseases is well established, and the field is expanding. New therapeutic...
The application of radiopharmaceutical therapy for the treatment of certain diseases is well established, and the field is expanding. New therapeutic radiopharmaceuticals have been developed in recent years, and more are in the research pipeline. Concurrently, there is growing interest in the use of internal dosimetry as a means of personalizing, and potentially optimizing, such therapy for patients. Internal dosimetry is multifaceted, and the current state of the art is discussed in this continuing education article. Topics include the context of dosimetry, internal dosimetry methods, the advantages and disadvantages of incorporating dosimetry calculations in radiopharmaceutical therapy, a description of the workflow for implementing patient-specific dosimetry, and future prospects in the field.
Topics: Humans; Radiometry; Radiopharmaceuticals
PubMed: 36192334
DOI: 10.2967/jnumed.121.262305 -
Nuclear Medicine and Biology 2022Current interest in the α-emitting bismuth radionuclides, bismuth-212 (Bi) and bismuth-213 (Bi), stems from their great potential for targeted alpha therapy (TAT), an... (Review)
Review
Current interest in the α-emitting bismuth radionuclides, bismuth-212 (Bi) and bismuth-213 (Bi), stems from their great potential for targeted alpha therapy (TAT), an expanding and promising approach for the treatment of micrometastatic disease and the eradication of single malignant cells. To selectively deliver their emission to the cancer cells, these radiometals must be firmly coordinated by a bifunctional chelator (BFC) attached to a tumour-seeking vector. This review provides a comprehensive overview of the current state-of-the-art chelating agents for bismuth radioisotopes. Several aspects are reported, from their 'cold' chelation chemistry (thermodynamic, kinetic, and structural properties) and radiolabelling investigations to the preclinical and clinical studies performed with a variety of bioconjugates. The aim of this review is to provide both a guide for the rational design of novel optimal platforms for the chelation of these attractive α-emitters and emphasize the prospects of the most encouraging chelating agents proposed so far.
Topics: Humans; Bismuth; Chelating Agents; Immunoconjugates; Neoplasms; Alpha Particles
PubMed: 35753940
DOI: 10.1016/j.nucmedbio.2022.06.002 -
Theranostics 2020This is the initial report of an α-based pre-targeted radioimmunotherapy (PRIT) using Ac and its theranostic pair, In. We call our novel tumor-targeting DOTA-hapten...
This is the initial report of an α-based pre-targeted radioimmunotherapy (PRIT) using Ac and its theranostic pair, In. We call our novel tumor-targeting DOTA-hapten PRIT system "proteus-DOTA" or "Pr." Herein we report the first results of radiochemistry development, radiopharmacology, and stoichiometry of tumor antigen binding, including the role of specific activity, anti-tumor efficacy, and normal tissue toxicity with the Pr-PRIT approach (as α-DOTA-PRIT). A series of α-DOTA-PRIT therapy studies were performed in three solid human cancer xenograft models of colorectal cancer (GPA33), breast cancer (HER2), and neuroblastoma (GD2), including evaluation of chronic toxicity at ~20 weeks of select survivors. Preliminary biodistribution experiments in SW1222 tumor-bearing mice revealed that Ac could not be efficiently pretargeted with current DOTA-Bn hapten utilized for Lu or Y, leading to poor tumor uptake . Therefore, we synthesized Pr consisting of an empty DOTA-chelate for Ac, tethered via a short polyethylene glycol linker to a lutetium-complexed DOTA for picomolar anti-DOTA chelate single-chain variable fragment (scFv) binding. Pr was radiolabeled with Ac and its imaging surrogate, In. studies verified anti-DOTA scFv recognition of [Ac]Pr, and biodistribution and clearance studies were performed to evaluate hapten suitability and targeting efficiency. Intravenously (i.v.) administered Ac- or In-radiolabeled Pr in mice showed rapid renal clearance and minimal normal tissue retention. pretargeting studies show high tumor accumulation of Pr (16.71 ± 5.11 %IA/g or 13.19 ± 3.88 %IA/g at 24 h p.i. for [Ac]Pr and [In]Pr, respectively) and relatively low uptake in normal tissues (all average ≤ 1.4 %IA/g at 24 h p.i.). Maximum tolerated dose (MTD) was not reached for either [Ac]Pr alone or pretargeted [Ac]Pr at administered activities up to 296 kBq/mouse. Single-cycle treatment consisting of α-DOTA-PRIT with either huA33-C825 bispecific anti-tumor/anti-DOTA-hapten antibody (BsAb), anti-HER2-C825 BsAb, or hu3F8-C825 BsAb for targeting GPA33, HER2, or GD2, respectively, was highly effective. In the GPA33 model, no complete responses (CRs) were observed but prolonged overall survival of treated animals was 42 d for α-DOTA-PRIT vs. 25 d for [Ac]Pr only ( < 0.0001); for GD2, CRs (7/7, 100%) and histologic cures (4/7, 57%); and for HER2, CRs (7/19, 37%) and histologic cures (10/19, 56%) with no acute or chronic toxicity. [Ac]Pr and its imaging biomarker [In]Pr demonstrate optimal radiopharmacologic behavior for theranostic applications of α-DOTA-PRIT. For this initial evaluation of efficacy and toxicity, single-cycle treatment regimens were performed in all three systems. Histologic toxicity was not observed, so MTD was not observed. Prolonged overall survival, CRs, and histologic cures were observed in treated animals. In comparison to RIT with anti-tumor IgG antibodies, [Ac]Pr has a much improved safety profile. Ultimately, these data will be used to guide clinical development of toxicity and efficacy studies of [Ac]Pr, with the goal of delivering massive lethal doses of radiation to achieve a high probability of cure without toxicity.
Topics: Actinium; Alpha Particles; Animals; Cell Line, Tumor; Dose-Response Relationship, Radiation; Female; Half-Life; Heterocyclic Compounds, 1-Ring; Humans; Indium Radioisotopes; Mice; Nanoparticles; Neoplasms; Radioimmunotherapy; Radiopharmaceuticals; Radiotherapy Dosage; Theranostic Nanomedicine; Tissue Distribution; Toxicity Tests, Chronic; Xenograft Model Antitumor Assays
PubMed: 33052220
DOI: 10.7150/thno.48810 -
Radiation and Environmental Biophysics Nov 2022Exosomes are spherical membrane nanovesicles secreted from cells, and they play an important role in tumor immune response, metastasis, angiogenesis, and survival....
Exosomes are spherical membrane nanovesicles secreted from cells, and they play an important role in tumor immune response, metastasis, angiogenesis, and survival. Studies investigating exosomes isolated from cells exposed to photon radiation commonly used in conventional radiotherapy demonstrate the influence of this type of radiation on exosome characteristics and secretion. There is currently no research investigating the effects of densely ionizing particles such as protons and alpha radiation on exosomes. Thus we have evaluated the cellular response of human prostate cancer cells exposed to 0, 2, and 6 Gy of alpha radiation emitted from the Am-241 source. Irradiated PC3 and DU145 cell lines, characterized by differences in radiosensitivity, were studied using apoptosis, LDH, and IL-6 assays. Additionally, the corresponding concentration and size of isolated exosomes were measured using NTA. We found that exposure to ionizing radiation resulted in gross changes in viability and cell damage. There were increased amounts of apoptotic or necrotic cells as a function of radiation dose. We demonstrated that irradiated PC3 cells secrete higher quantities of exosomes compared to DU145 cells. Additionally, we also found no statistical difference in exosome size for control and irradiated cells.
Topics: Male; Humans; Exosomes; Alpha Particles; PC-3 Cells; Radiation Tolerance; Cell Line, Tumor
PubMed: 36098819
DOI: 10.1007/s00411-022-00991-5 -
Frontiers in Medicine 2022Osteosarcoma is a high-grade sarcoma characterized by osteoid formation, nearly universal expression of IGF1R and with a subset expressing HER-2. These qualities provide... (Review)
Review
Osteosarcoma is a high-grade sarcoma characterized by osteoid formation, nearly universal expression of IGF1R and with a subset expressing HER-2. These qualities provide opportunities for the use of the alpha particle-emitting isotopes to provide targeted radiation therapy alpha particles precisely to bone-forming tumors in addition to IFG1R or Her-2 expressing metastases. This review will detail experience using the alpha emitter radium-223 (Ra, tradename Xofigo), that targets bone formation, in osteosarcoma, specifically related to patient selection, use of gemcitabine for radio-sensitization, and using denosumab to increasing the osteoblastic phenotype of these cancers. A case of an inoperable left upper lobe vertebral-paraspinal-mediastinal osteoblastic lesion treated successfully with Ra combined with gemcitabine is described. Because not all areas of osteosarcoma lesions are osteoblastic, but nearly all osteosarcoma cells overexpress IGF1R, and some subsets expressing Her-2, the anti-IGF1R antibody FPI-1434 linked to actinium-225 (Ac) or the Her-2 antibody linked to thorium-227 (Th) may become other means to provide targeted alpha particle therapy against osteosarcoma (NCT03746431 and NCT04147819).
PubMed: 36457575
DOI: 10.3389/fmed.2022.1030094