In this comprehensive review, we discuss the current consensus regarding the properties of the α-particle-emitting radionuclides that are potentially relevant for use in the clinic the TAT-mediated mechanisms responsible for cell death the different classes of targeting moieties and radiometal chelators available for TAT development current approaches to calculating radiation dosimetry for TATs and lead optimization via medicinal chemistry to improve the TAT radiopharmaceutical properties. We have also summarized the use of TATs in pre-clinical and clinical studies to date. Over the past two decades, radioimmunotherapy (RIT) has proven to be an effective treatment for non-solid tumors (reviewed in ) e.g., radiolabeled anti-CD20 monoclonal antibodies for the treatment of lymphoma. These antibody-radionuclide conjugates have typically used beta (β)-particle emitting radionuclides e.g., 131I, 67Cu, 177Lu or 90Y.
However, due to the relatively long range of the associated β-emissions and the poor tumor penetration of antibodies, there has been concern regarding the use of RIT for treatment of solid tumors, where much of the energy is deposited in the surrounding normal tissues relative to the tumor, particularly in the case of small tumor cell foci or metastases. Alpha (α)-particle-emissions have a much shorter range and greater linear energy transfer (LET) relative to β-emissions, depositing more energy into smaller volumes. Hence, there has been significant interest in the development of targeted alpha-particle therapy (TAT) for the treatment of solid tumors. Recently, the FDA approved the use of 223RaCl 2 (Xofigo ®) for the palliative care of prostate bone metastases, and the efficacy of 223RaCl 2 and 225Ac–PSMA–617 have been demonstrated in the treatment of prostate bone metastases ( Figure 1). These developments have further elevated interest in the development of novel α-emission cancer treatments. Typically, TAT for solid tumors involves attaching an α-particle-emitting radionuclide to a tumor targeting scaffold, followed by the intravenous administration and systemic targeting of tumors and metastases. The α-particle range is only a few cell diameters, ensuring that the greatest effect of tumor TAT remains within the tumor volume.
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