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The 7.2-h half life radiohalogen (211)At offers many potential advantages for targeted α-particle therapy; however, its use for this purpose is constrained by its limited availability. Astatine-211 can be produced in reasonable yield from natural bismuth targets via the (209)Bi(α,2n)(211)At nuclear reaction utilizing straightforward methods. There...
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... addition to its half life, 211 At possesses other decay properties that are favorable for targeted α-particle radio-therapy. As shown in Fig. (1), the emission of an α-particle is associated with 100% of 211 At decays, either directly by α-decay to 207 Bi (42%), followed by electron capture decay to stable 207 Pb, or by electron capture decay to 211 Po (58%) followed by α-emission to stable 207 Pb. A potential problem associated with this second decay branch is escape of ...
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Among the α-particle emitting radionuclides, (211)At is considered to be a promising radionuclide for targeted cancer therapy due to its decay properties. The range of alpha particles produced by the decay of (211)At are less than 70 µm in water with a linear energy transfer between 100 and 130 keV µm(-1), which are about the maximum relative biolo...
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Citations
... Astatine-211 ( 211 At) is an easy-to-handle α-emitting radionuclide with a half-life of 7.2 h. It is a versatile α-emitting radionuclide that can be produced using a 30 MeV cyclotron (Nelson et al. 2021;Zalutsky and Pruszynski 2011). Furthermore, because 211 At emits only one alpha particle during decay, the potential radiotoxicity of its daughter radionuclides is negligible. ...
Background
Prostate cancer is a common cancer among men worldwide that has a very poor prognosis, especially when it progresses to metastatic castration-resistant prostate cancer (mCRPC). Therefore, novel therapeutic agents for mCRPC are urgently required. Because prostate-specific membrane antigen (PSMA) is overexpressed in mCRPC, targeted alpha therapy (TAT) for PSMA is a promising treatment for mCRPC. Astatine-211 (²¹¹At) is a versatile α-emitting radionuclide that can be produced using a cyclotron. Therefore, ²¹¹At-labeled PSMA compounds could be useful for TAT; however, ²¹¹At-labeled compounds are unstable against deastatination in vivo. In this study, to develop in vivo stable ²¹¹At-labeled PSMA derivatives, we designed and synthesized ²¹¹At-labeled PSMA derivatives using a neopentyl glycol (NpG) structure that can stably retain ²¹¹At in vivo. We also evaluated their biodistribution in normal and tumor-bearing mice.
Results
We designed and synthesized ²¹¹At-labeled PSMA derivatives containing two glutamic acid (Glu) linkers between the NpG structure and asymmetric urea (NpG-L-PSMA ((L-Glu)2 linker used) and NpG-D-PSMA ((D-Glu)2 linker used)). First, we evaluated the characteristics of ¹²⁵I-labeled NpG derivatives because ¹²⁵I was readily available. [¹²⁵I]I-NpG-L-PSMA and [¹²⁵I]I-NpG-D-PSMA showed low accumulation in the stomach and thyroid, indicating their high in vivo stability against deiodination. [¹²⁵I]I-NpG-L-PSMA was excreted in urine as hydrophilic radiometabolites in addition to the intact form. Meanwhile, [¹²⁵I]I-NpG-D-PSMA was excreted in urine in an intact form. In both cases, no radioactivity was observed in the free iodine fraction. [¹²⁵I]I-NpG-D-PSMA showed higher tumor accumulation than [¹²⁵I]I-NpG-L-PSMA. We then developed ²¹¹At-labeled PSMA using the NpG-D-PSMA structure. [²¹¹At]At-NpG-D-PSMA showed low accumulation in the stomach and thyroid in normal mice, indicating its high stability against deastatination in vivo. Moreover, [²¹¹At]At-NpG-D-PSMA showed high accumulation in tumor similar to that of [¹²⁵I]I-NpG-D-PSMA.
Conclusions
[²¹¹At]At-NpG-D-PSMA showed high in vivo stability against deastatination and high tumor accumulation. [²¹¹At]At-NpG-D-PSMA should be considered as a potential new TAT for mCRPC.
... Furthermore, the potentially destabilizing influence of alpha particle recoil nuclei on chemical stability is irrelevant since 211 Po is not a product of alpha decay. The second branch of decay, which involves electron capture, ultimately results in the emission of polonium K X-rays with energies ranging from 77 to 92 keV, which is a substantial benefit for 211 At [9]. 211 At decays to stable 207 Pb via a branched pathway with a half-life of 7.2 h. ...
... A broad range of 211 At labeled chemicals have shown positive results in the treatment of cancer, and the potential benefits of 211 At for targeted alpha particle irradiation have been known for approximately 40 years. The therapeutic radionuclide of greatest interest is 211 At [9,23]. In addition, the production of 211 At has a low inherent cost as compared to other prospective alpha particle emitters for cancer treatment, such as 225 Ac. ...
... In addition, the production of 211 At has a low inherent cost as compared to other prospective alpha particle emitters for cancer treatment, such as 225 Ac. In addition, the favorable half-life during treatment is among the advantages of this isotope [9]. ...
In this research, the calculations have been done for α -emitters of ²¹¹ At, which is a promising isotope in cyclotrons for radiotherapy. The scope of the study is to investigate the production parameters of ²¹¹ At, which can be produced in the cyclotron by bombarding bismuth with an alpha particle beam for the ²⁰⁹ Bi( α ,2n) ²¹¹ At reaction. The total activity, reaction yield, and production cross–sections of ²⁰⁹ Bi( α ,2n) ²¹¹ At reaction have been calculated by using diverse level density models of the TALYS 1.95 code. Furthermore, recommended data with 95% confidence limits have been obtained. Experimental data available in the literature based on EXFOR compilation are used to compare the findings. Consequently, the required beam energy has been found to be 28 MeV to produce ²¹¹ At.
... Recently, there has been increasing interest in alternative alpha emitters beyond 225 Ac. Astatine ( 211 At), an alpha emitter with a physical half-life of 7.2 h, can be produced using a 30 MeV 4 He cyclotron with a natural bismuth ( 209 Bi) target [18][19][20][21][22]. Given this target material's natural abundance, 211 At can be produced globally by establishing a manufacturing base equipped with a cyclotron that enables a stable and sustainable supply. ...
Astatine (211At) is a cyclotron-produced alpha emitter with a physical half-life of 7.2 h. In our previous study, the 211At-labeled prostate-specific membrane antigen (PSMA) compound ([211At]PSMA-5) exhibited excellent tumor growth suppression in a xenograft model. We conducted preclinical biodistribution and toxicity studies for the first-in-human clinical trial. [211At]PSMA-5 was administered to both normal male ICR mice (n = 85) and cynomolgus monkeys (n = 2). The mice were divided into four groups for the toxicity study: 5 MBq/kg, 12 MBq/kg, 35 MBq/kg, and vehicle control, with follow-ups at 1 day (n = 10 per group) and 14 days (n = 5 per group). Monkeys were observed 24 h post-administration of [211At]PSMA-5 (9 MBq/kg). Blood tests and histopathological examinations were performed at the end of the observation period. Blood tests in mice indicated no significant myelosuppression or renal dysfunction. However, the monkeys displayed mild leukopenia 24 h post-administration. Despite the high accumulation in the kidneys and thyroid, histological analysis revealed no abnormalities. On day 1, dose-dependent single-cell necrosis/apoptosis was observed in the salivary glands of mice and intestinal tracts of both mice and monkeys. Additionally, tingible body macrophages in the spleen and lymph nodes indicated phagocytosis of apoptotic B lymphocytes. Cortical lymphopenia (2/10) in the thymus and a decrease in the bone marrow cells (9/10) were observed in the 35 MBq/kg group in mice. These changes were transient, with no irreversible toxicity observed in mice 14 days post-administration. This study identified no severe toxicities associated with [211At]PSMA-5, highlighting its potential as a next-generation targeted alpha therapy for prostate cancer. The sustainable production of 211At using a cyclotron supports its applicability for clinical use.
... Both 211 At and 225 Ac show promise as alpha-emitting agents for medical purposes, yet they are markedly different in their production and decay characteristics. The generation of 211 At generally requires a cyclotron [97], whereas 225 Ac is typically sourced from nuclear reactors, with its longer half-life of 10 days enhancing its potential for wider distribution [98]. Establishing in-house production of 211 At using a medium-energy cyclotron signifies a significant capital investment for medical or research institutions. ...
In the evolving landscape of precision medicine, NET-targeted radiopharmaceuticals are emerging as pivotal tools for the diagnosis and treatment of a range of conditions, from heart failure and neurodegenerative disorders to neuroendocrine cancers. This review evaluates the advancements offered by 18F-labeled PET tracers and 211At alpha-particle therapy, juxtaposed with current 123I-MIBG SPECT and 131I-MIBG therapies. The enhanced spatial resolution and capability for quantitative analysis render 18F-labeled PET tracers potential candidates for improved detection and management of diseases. Alpha-particle therapy with 211At may offer increased specificity and tumoricidal efficacy, pointing towards a shift in therapeutic protocols. While preliminary data is promising, these innovative approaches require thorough validation against current modalities. Ongoing clinical trials are pivotal to confirm the expected clinical benefits and to address safety concerns. This review underscores the need for rigorous research to verify the clinical utility of NET-targeted radiopharmaceuticals, which may redefine precision medicine paradigms and significantly impact patient care.
... www.nature.com/scientificreports/ of astatine, being a halogen, this also mean that astatinated degradation products in the form of small organic molecules or di-halogens, with unknown properties, can be formed. Historically, few research labs around the world have worked with astatine because of its short half-life that requires relatively close proximity to a medium energy cyclotron, capable of accelerating alpha particles of circa 30 MeV, for producing astatine 9 . In Gothenburg the Targeted Alpha Therapy research group has been working with astatine since 1994 including basic chemistry, preclinical work and a clinical study that was conducted 2005-2012, applying the astatinated Fab2-fragment MX-35 for treatment of ovarian carcinoma 10,11 . ...
Targeted alpha therapy of disseminated cancer is an emerging technique where astatine-211 is one of the most promising candidate nuclides. Astatine-211 can be produced in medium energy cyclotrons by alpha particle bombardment of natural bismuth. The produced astatine is then commonly recovered from the irradiated solid target material through dry distillation. The dry distillation process often includes elution and solvation of condensed astatine with chloroform, forming Chloroform Eluate. In this work the handling and safe use of the high activity concentration Chloroform Eluate has been investigated. Correctly performed, evaporation of Chloroform Eluate results in a dry residue with complete recovery of the astatine. The dry residue can then serve as a versatile starting material, using appropriate oxidizing or reducing conditions, for subsequent downstream chemistry. However, it has been found that when evaporating the Chloroform Eluate, astatine can be volatilized if continuing the process beyond the point of dryness. This behavior is more pronounced when the Chloroform Eluate has received a higher absorbed dose. Upon water phase contact of the Chloroform Eluate, a major part of the astatine activity becomes water soluble, leaving the organic phase. A behavior which is also dependent on dose to the solvent.
... The biological functions, medical applications related to their anticancer activity and toxic effects of s-and p-block metals and metalloids and their compounds are collected in Table 1. [110][111][112][113][114][115] In this review, almost all metals and metalloids of the main group elements are summarized in terms of their efficient anticancer activity. ...
... Among them, 211 At is one of the most promising candidates [110,111]. The radioactive astatine-211 has many advantages for targeted α-therapeutic purposes [112,113]. α-emitters have unique features for removal of focal locations of tumor cells which are close to the normal tissues of the central nervous system (CNS). For example, they may be useful for targeted treatment with no risks of the toxicity that occurs with β-emitters. ...
Cancer is one of the leading causes of human death among all major diseases. Metal-based complexes are considered as the most promising vital part in the existing arsenal of cytotoxic candidates used in cancer therapy and diagnostics. The efforts of many scientific groups resulted in the development of numerous metal-based compounds featuring different biologically active organic ligands in order to modulate their bioactivity. Along with the main representatives as potential therapeutic agents, such as the complexes Pt(II)/Pt(IV), Pd(II), Ru(II)/Ru(III), Ag(I), Au(I)/Au(III), Ti(IV), V(IV) and Ga(III), many other transition metal and lanthanide complexes possessing antiproliferative activity are widely discussed in the literature. However, such drugs remain outside the scope of this review. The main purpose of the current study is to review the potential activity of main group metal- and metalloid-based complexes against the most common cancer cell types, such as carcinomas (lung, liver, breast, kidney, gastric, colorectal, bladder, ovarian, cervical, prostate, etc.); sarcomas; blastomas; lymphomas; multiple myeloma; and melanoma. Overcoming the long disregard of organometallic compounds of metals and metalloids from the main groups, a growing number of emerging anticancer agents remarkably prove this field offers an extensive variety of new options for the design of innovative unexplored chemopharmaceutics. Moreover, some of the metal complexes and organometallic compounds from these elements can exhibit entirely different, specific modes of action and biological targets. Obviously, exploitation of their distinct properties deserves more attention.
... In particular, 211 At provides a better biodistribution and strong labelling of PSMA, decreasing the dose delivered to non-targeted tissue, especially in regard to the salivary glands [193]. Furthermore, 211 At production cost is considerably lower than other alpha emitters, resulting in a clear advantage for future application [194]. However, dosimetry remains the main challenge, requiring a robust body of investigation to optimize the potential of PSMA theragnostics. ...
Simple Summary
The huge armamentarium of currently available theragnostic modalities allows a novel approach to prostate cancer from imaging to therapy. Clinical examination is the starting-point, then radiology and nuclear medicine are often needed to define the illness grading to set up the best therapeutic strategy. Prostate cancer care horizons are opening with the aid of nuclear medicine, which takes advantage of the technological ascendancy of prostate-specific membrane antigen-based imaging and therapy and is currently evolving with machine-learning approaches. We have focused our review on the current state, on the advancements, and on the future prospects of nuclear medicine modalities that could change prostate cancer’s standard of care.
Abstract
Prostate cancer is the most frequent epithelial neoplasia after skin cancer in men starting from 50 years and prostate-specific antigen (PSA) dosage can be used as an early screening tool. Prostate cancer imaging includes several radiological modalities, ranging from ultrasonography, computed tomography (CT), and magnetic resonance to nuclear medicine hybrid techniques such as single-photon emission computed tomography (SPECT)/CT and positron emission tomography (PET)/CT. Innovation in radiopharmaceutical compounds has introduced specific tracers with diagnostic and therapeutic indications, opening the horizons to targeted and very effective clinical care for patients with prostate cancer. The aim of the present review is to illustrate the current knowledge and future perspectives of nuclear medicine, including stand-alone diagnostic techniques and theragnostic approaches, in the clinical management of patients with prostate cancer from initial staging to advanced disease.
... The nuclear reaction 209 Bi(α,2n) 211 At is produced by bombarding solid 209 Bi targets with α-beams at energies below 28.4 MeV [7]. When the energy is <28.4 ...
Alpha emitters are radionuclides with good pharmacological characteristics for the treatment of cancer because they decay by emitting high linear energy transfer particles. Recent advancements in isotope production and purification and the generation of novel techniques for optimum targeting have led to the development of targeted alpha therapy (TAT). The great cytotoxic potential of α‐particle emissions combined with monoclonal antibodies, peptides, small compounds, or nanoparticles has led to investigations of TAT in the pre‐clinical context and more recently, in oncology clinical trials. Numerous studies have shown that TAT is effective both in vitro and in vivo. The first α‐emitter to obtain FDA approval for the treatment of prostate cancer with metastatic bone lesions was radium‐223 dichloride. Many clinical trials are being conducted to evaluate the efficiency and safety of several radionuclides in cancer treatment, including radium‐223, astatine‐211, actinium‐225, bismuth‐213, lead‐212, and thorium‐227. This review provides an overview of the therapeutic use of these radionuclides and a summary of the studies that lay the groundwork for future clinical advancement.
... This means that 210 Po activity assessments based on measured 210 At activities at EOB will lead to a significant underestimation of the total 210 Po activity on the target. Many studies (Feng and Zalutsky, 2021;Henriksen et al., 2001;Larsen et al., 1996;Zalutsky, n. d.;Zalutsky and Pruszynski, 2011) focus on the production of 210 At as the main source of the potential presence of the 210 Po contaminant in 211 At-labeled radiopharmaceuticals. This originates from the assumption that radiochemical separation effectively separates the 210 Po from 211/210 At. ...
... Besides, 211 At can be produced in reasonably high yield via 209 Bi(α,2n) 211 At reaction utilizing inexpensive natural Bi target [19]. The methodology for isolation of 211 At from the irradiated target by dry-distillation or wet chemistry is well established and commercially sustainable [20]. ...
... Overall, this preclinical study amply demonstrated that [ 211 At]PSMA5 or close analogs holds promise for translation if and when TAT is to be considered in the treatment protocol of mCRPCa patients, which for sure is a giant leap towards cost-effective precision oncology. Despite abundant availability of target material and robust radiochemical separation technology, the feasibility of sourcing 211 At and its implementation for widespread clinical use is still a challenge as most accelerators in the world do not have beam characteristics required for producing meaningful levels of 211 At [19,20]. Providing worldwide supply chain of 211 At mandates efficient utilization of existing facilities, installations of new cyclotrons and employment of well-organized chemistry infrastructure. ...
