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International Journal of Molecular... Jul 2023Radiopharmaceuticals are rapidly developing as a field, with the successful use of targeted beta emitters in neuroendocrine tumors and prostate cancer serving as... (Review)
Review
Radiopharmaceuticals are rapidly developing as a field, with the successful use of targeted beta emitters in neuroendocrine tumors and prostate cancer serving as catalysts. Targeted alpha emitters are in current development for several potential oncologic indications. Herein, we review the three most prevalently studied conjugated/chelated alpha emitters (actinium, lead, and astatine) and focus on contemporary clinical trials in an effort to more fully appreciate the breadth of the current evaluation. Phase I trials targeting multiple diseases are now underway, and at least one phase III trial (in selected neuroendocrine cancers) is currently in the initial stages of recruitment. Combination trials are now also emerging as alpha emitters are integrated with other therapies in an effort to create solutions for those with advanced cancers. Despite the promise of targeted alpha therapies, many challenges remain. These challenges include the development of reliable supply chains, the need for a better understanding of the relationships between administered dose and absorbed dose in both tissue and tumor and how that predicts outcomes, and the incomplete understanding of potential long-term deleterious effects of the alpha emitters. Progress on multiple fronts is necessary to bring the potential of targeted alpha therapies into the clinic.
Topics: Humans; Male; Alpha Particles; Prostatic Neoplasms; Radiopharmaceuticals; Clinical Trials as Topic
PubMed: 37511386
DOI: 10.3390/ijms241411626 -
Cancer Biotherapy & Radiopharmaceuticals Aug 2020
Topics: Alpha Particles; Antibodies, Monoclonal; Humans; Molecular Targeted Therapy; Neoplasms; Radiation Oncology; Radioisotopes; Radiopharmaceuticals; Radium
PubMed: 32503377
DOI: 10.1089/cbr.2020.29008.mbr -
PET Clinics Jul 2024Targeted radionuclide therapy (TRT) has significantly evolved from its beginnings with iodine-131 to employing carrier molecules with beta emitting isotopes like... (Review)
Review
Targeted radionuclide therapy (TRT) has significantly evolved from its beginnings with iodine-131 to employing carrier molecules with beta emitting isotopes like lutetium-177. With the success of Lu-177-DOTATATE for neuroendocrine tumors and Lu-177-PSMA-617 for prostate cancer, several other beta emitting radioisotopes, such as Cu-67 and Tb-161, are being explored for TRT. The field has also expanded into targeted alpha therapy (TAT) with agents like radium-223 for bone metastases in prostate cancer, and several other alpha emitter radioisotopes with carrier molecules, such as Ac-225, and Pb-212 under clinical trials. Despite these advancements, the scope of TRT in treating diverse solid tumors and integration with other therapies like immunotherapy remains under investigation. The success of antibody-drug conjugates further complements treatments with TRT, though challenges in treatment optimization continue.
Topics: Humans; Beta Particles; Alpha Particles; Radioisotopes; Radiopharmaceuticals; Neoplasms; Prostatic Neoplasms; Male; Lutetium; Radium; Bone Neoplasms
PubMed: 38688775
DOI: 10.1016/j.cpet.2024.03.006 -
Toxics Aug 2023Radon is a carcinogenic factor, but the effects of the potential carcinogenicity of radon progeny on the human body during the prenatal period have not yet been...
Radon is a carcinogenic factor, but the effects of the potential carcinogenicity of radon progeny on the human body during the prenatal period have not yet been explored. Based on data regarding the half-lives of radon-222 and radon-220 and their progeny, this paper considers their potential effects on the human body in the prenatal period. Radon-220 represents a small fraction of the total radon concentration in the air, but the dose of radon-220 progeny may have a significant effect in the prenatal period, as the precursors of polonium-212 exhibit substantially longer half-lives than the corresponding precursors of polonium-214. Theoretically, it is possible that radon-220 decay products, particularly polonium-212, are the predominant emitters of alpha particles in the prenatal period. Studies aiming to establish a relationship between exposure to radon during pregnancy and the subsequently observed incidence of childhood neoplasms should consider this observation.
PubMed: 37624186
DOI: 10.3390/toxics11080681 -
Clinical Cancer Research : An Official... May 2023Radiopharmaceutical therapy is changing the standard of care in prostate cancer and other malignancies. We previously reported high CD46 expression in prostate cancer...
PURPOSE
Radiopharmaceutical therapy is changing the standard of care in prostate cancer and other malignancies. We previously reported high CD46 expression in prostate cancer and developed an antibody-drug conjugate and immunoPET agent based on the YS5 antibody, which targets a tumor-selective CD46 epitope. Here, we present the preparation, preclinical efficacy, and toxicity evaluation of [225Ac]DOTA-YS5, a radioimmunotherapy agent based on the YS5 antibody.
EXPERIMENTAL DESIGN
[225Ac]DOTA-YS5 was developed, and its therapeutic efficiency was tested on cell-derived (22Rv1, DU145), and patient-derived (LTL-545, LTL484) prostate cancer xenograft models. Biodistribution studies were carried out on 22Rv1 tumor xenograft models to confirm the targeting efficacy. Toxicity analysis of the [225Ac]DOTA-YS5 was carried out on nu/nu mice to study short-term (acute) and long-term (chronic) toxicity.
RESULTS
Biodistribution study shows that [225Ac]DOTA-YS5 agent delivers high levels of radiation to the tumor tissue (11.64% ± 1.37%ID/g, 28.58% ± 10.88%ID/g, 29.35% ± 7.76%ID/g, and 31.78% ± 5.89%ID/g at 24, 96, 168, and 408 hours, respectively), compared with the healthy organs. [225Ac]DOTA-YS5 suppressed tumor size and prolonged survival in cell line-derived and patient-derived xenograft models. Toxicity analysis revealed that the 0.5 μCi activity levels showed toxicity to the kidneys, likely due to redistribution of daughter isotope 213Bi.
CONCLUSIONS
[225Ac]DOTA-YS5 suppressed the growth of cell-derived and patient-derived xenografts, including prostate-specific membrane antigen-positive and prostate-specific membrane antigen-deficient models. Overall, this preclinical study confirms that [225Ac]DOTA-YS5 is a highly effective treatment and suggests feasibility for clinical translation of CD46-targeted radioligand therapy in prostate cancer.
Topics: Mice; Male; Animals; Humans; Radioisotopes; Actinium; Bismuth; Radioimmunotherapy; Alpha Particles; Tissue Distribution; Prostatic Neoplasms; Membrane Cofactor Protein
PubMed: 36917693
DOI: 10.1158/1078-0432.CCR-22-3291 -
Frontiers in Medicine 2022According to the 2021 World Health Organization Classification of Tumors of the Central Nervous System, glioblastoma (GB) is a primary brain tumor and presents with the... (Review)
Review
According to the 2021 World Health Organization Classification of Tumors of the Central Nervous System, glioblastoma (GB) is a primary brain tumor and presents with the worst prognosis. Due to its infiltrating characteristic, molecular heterogeneity, and only partly preserved function of the blood-brain barrier, the median overall survival time is short (9-15 months), regardless of comprehensive treatment including surgery, radiotherapy, and chemotherapy. Several novel treatment strategies are under investigation. Unfortunately, none of them produced successful results; 90% of patients have a recurrence of the disease within 6 months. Local administration of the drug could be a promising approach to delivering treatment with minimized side effects, due to the recurrence of 95% glioblastomas in a margin of 2 cm at the primary site. Several ligand-receptor systems have been evaluated, such as targeting tenascin, the extracellular matrix protein, or radiolabeled somatostatin analogs, as it is overexpressed with the SSTR-2 receptor system in around 80% of gliomas. Moreover, this study revealed that the NK-1 receptor is overexpressed in GB, suggesting that substance P (SP) may serve as a ligand. A variety of radioisotopes, beta- (I, Y, or Lu) and alpha emitters (Bi, Ac, or At), with different physical properties were tested for treatment. Alpha particles have many advantages over beta radiation such as short range with higher linear energy transfer. According to that characteristic, it is extremely dose delivered to the targeted cells, while reducing harm to nearby healthy tissue. Additionally, the biological effect of alpha radiation is independent of the cell cycle phase, cell oxygenation and O-6-methylguanine-DNA methyltransferase () gene promoter methylation status. In this article, we summarize the experience with local treatment of primary and secondary GBs with locally used radioisotopes such as [Bi]Bi-DOTA-SP or [Ac]Ac-DOTA-SP.
PubMed: 36590948
DOI: 10.3389/fmed.2022.1085245 -
Health Physics May 2022The human brain dose from radon-222 (222Rn) exposure is calculated here using 222Rn tissue solubility data. A fraction of 222Rn inhaled dissolves in blood and cellular...
The human brain dose from radon-222 (222Rn) exposure is calculated here using 222Rn tissue solubility data. A fraction of 222Rn inhaled dissolves in blood and cellular fluids and circulates to brain and all organs. Radon-222 has a relatively high solubility in blood and body fluids based on human inhalation experiments. The brain dose uses calculated concentrations of 222Rn in blood and cellular fluids from exhaled breath measurements following human exposure in a 222Rn chamber. The annual brain dose from continuous inhalation of a concentration of 100 Bq m-3 is about 450 times less than the dose to bronchial epithelium from inhalation of the same 222Rn concentration. Based on the 222Rn dosimetry here, it is highly unlikely that brain cancer is related to even high 222Rn exposures. Any functional or neurodegenerative issues from exposure to very small doses of 222Rn alpha particles are, at present, unknown.
Topics: Air Pollutants, Radioactive; Brain; Humans; Radiation Monitoring; Radon
PubMed: 35228505
DOI: 10.1097/HP.0000000000001533