Abstract:The widespread use of peptide receptor radionuclide therapy (PRRT) represents a major therapeutic breakthrough in nuclear medicine, particularly since the introduction of 177Lu-radiolabeled somatostatin analogs. These radiopharmaceuticals have especially improved progression-free survival and quality of life in patients with inoperable metastatic gastroenteropancreatic neuroendocrine tumors expressing somatostatin receptors. In the case of aggressive or resistant disease, the use of somatostatin derivatives ra… Show more
“…The lower LET of β − -particles from 177 Lu (~ 0.2 keV/μm) compared to α-particles is associated with their primary mechanism of inducing single-strand DNA breaks, which may explain their limited therapeutic effectiveness. Therefore, in anticipation of the efficacy of NETs with TAT, fundamental and clinical studies on the therapeutic effects on NETs of octreotide derivatives labeled with 225 Ac, which can form stable complexes with DOTA as well as 177 Lu, were subsequently conducted [ 8 , 53 ]. Fig.…”
Section: Radiolabeled Octreotide Analogs With High Affinity For Somat...mentioning
Radiotheranostics utilizes a set of radioligands incorporating diagnostic or therapeutic radionuclides to achieve both diagnosis and therapy. Imaging probes using diagnostic radionuclides have been used for systemic cancer imaging. Integration of therapeutic radionuclides into the imaging probes serves as potent agents for radionuclide therapy. Among them, targeted alpha therapy (TAT) is a promising next-generation cancer therapy. The α-particles emitted by the radioligands used in TAT result in a high linear energy transfer over a short range, inducing substantial damage to nearby cells surrounding the binding site. Therefore, the key to successful cancer treatment with minimal side effects by TAT depends on the selective delivery of radioligands to their targets. Recently, TAT agents targeting biomolecules highly expressed in various cancer cells, such as sodium/iodide symporter, norepinephrine transporter, somatostatin receptor, αvβ3 integrin, prostate-specific membrane antigen, fibroblast-activation protein, and human epidermal growth factor receptor 2 have been developed and have made remarkable progress toward clinical application. In this review, we focus on two radionuclides, 225Ac and 211At, which are expected to have a wide range of applications in TAT. We also introduce recent fundamental and clinical studies of radiopharmaceuticals labeled with these radionuclides.
Graphical abstract
“…The lower LET of β − -particles from 177 Lu (~ 0.2 keV/μm) compared to α-particles is associated with their primary mechanism of inducing single-strand DNA breaks, which may explain their limited therapeutic effectiveness. Therefore, in anticipation of the efficacy of NETs with TAT, fundamental and clinical studies on the therapeutic effects on NETs of octreotide derivatives labeled with 225 Ac, which can form stable complexes with DOTA as well as 177 Lu, were subsequently conducted [ 8 , 53 ]. Fig.…”
Section: Radiolabeled Octreotide Analogs With High Affinity For Somat...mentioning
Radiotheranostics utilizes a set of radioligands incorporating diagnostic or therapeutic radionuclides to achieve both diagnosis and therapy. Imaging probes using diagnostic radionuclides have been used for systemic cancer imaging. Integration of therapeutic radionuclides into the imaging probes serves as potent agents for radionuclide therapy. Among them, targeted alpha therapy (TAT) is a promising next-generation cancer therapy. The α-particles emitted by the radioligands used in TAT result in a high linear energy transfer over a short range, inducing substantial damage to nearby cells surrounding the binding site. Therefore, the key to successful cancer treatment with minimal side effects by TAT depends on the selective delivery of radioligands to their targets. Recently, TAT agents targeting biomolecules highly expressed in various cancer cells, such as sodium/iodide symporter, norepinephrine transporter, somatostatin receptor, αvβ3 integrin, prostate-specific membrane antigen, fibroblast-activation protein, and human epidermal growth factor receptor 2 have been developed and have made remarkable progress toward clinical application. In this review, we focus on two radionuclides, 225Ac and 211At, which are expected to have a wide range of applications in TAT. We also introduce recent fundamental and clinical studies of radiopharmaceuticals labeled with these radionuclides.
Graphical abstract
“…The most commonly used chelators in nuclear medicine are the DOTA ((1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid), DTPA (Diethylenetriaminepentaacetic acid) and EDTA (Ethylenediaminetetraacetic acid) chelators, their structure is shown in Fig. 2 (Thiele and Wilson 2018 ; Rubira et al 2023 ; Eychenne et al 2021 ). Due to the characteristics of the DOTA chelator, complexation with Ac-225 as well as the wide availability and known toxicity it often the best option for clinical implementation and is therefore widely used (Thiele and Wilson 2018 ).…”
Section: Radiochemistry Of Ac-225 Radiopharmaceuticalsmentioning
Background
In the past years, there has been a notable increase in interest regarding targeted alpha therapy using Ac-225, driven by the observed promising clinical anti-tumor effects. As the production and technology has advanced, the availability of Ac-225 is expected to increase in the near future, making the treatment available to patients worldwide.
Main body
Ac-225 can be labelled to different biological vectors, whereby the success of developing a radiopharmaceutical depends heavily on the labelling conditions, purity of the radionuclide source, chelator, and type of quenchers used to avoid radiolysis. Multiple (methodological) challenges need to be overcome when working with Ac-225; as alpha-emission detection is time consuming and highly geometry dependent, a gamma co-emission is used, but has to be in equilibrium with the mother-nuclide. Because of the high impact of alpha emitters in vivo it is highly recommended to cross-calibrate the Ac-225 measurements for used quality control (QC) techniques (radio-TLC, HPLC, HP-Ge detector, and gamma counter). More strict health physics regulations apply, as Ac-225 has a high toxicity, thereby limiting practical handling and quantities used for QC analysis.
Conclusion
This overview focuses specifically on the practical and methodological challenges when working with Ac-225 labelled radiopharmaceuticals, and underlines the required infrastructure and (detection) methods for the (pre-)clinical application.
“…In a long-term study of patients with metastatic gastro-pancreatic neuroendocrine tumors receiving both 225 Ac-DOTATATE-TAT and capecitabine, 225 Ac-DOTATATE TAT showed satisfactory outcomes and improved overall survival. In patients previously refractory to 177 Lu-DOTATATE, there were brief and acceptable adverse reactions [73,74].…”
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.
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