Abstract
Targeted alpha-particle therapy (TAT) aims to selectively deliver radionuclides emitting α-particles (cytotoxic payload) to tumors by chelation to monoclonal antibodies, peptides or small molecules that recognize tumor-associated antigens or cell-surface receptors. Because of the high linear energy transfer (LET) and short range of alpha (α) particles in tissue, cancer cells can be significantly damaged while causing minimal toxicity to surrounding healthy cells. Recent clinical studies have demonstrated the remarkable efficacy of TAT in the treatment of metastatic, castration-resistant prostate cancer. 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.
Highlights
Over the past two decades, radioimmunotherapy (RIT) has proven to be an effective treatment for non-solid tumors; e.g., radiolabeled anti-CD20 monoclonal antibodies for the Molecules 2019, 24, 4314; doi:10.3390/molecules24234314 www.mdpi.com/journal/moleculesMolecules 2019, 24 FOR PEER REVIEW treatment lymphoma.These antibody-radionuclide conjugates have typically usedtreatment beta (β)-particleOverofthe past two decades, radioimmunotherapy (RIT)has proven to be an effective131 I, 67 Cu, 177 Lu or 90 Y
Four and five-fold reductions were observed at 1 and 24 h post-injection, respectively. These data demonstrate that multi-functional, layered nanoparticles have the potential to deliver and retain 225 Ac and its daughter radionuclides at the target site, while minimizing off-target toxicities that can occur from errant daughter products in the 225 Ac decay chain
Many pre-clinical and clinical studies have demonstrated promising anti-tumor efficacy results (Tables 2 and 3)
Summary
Over the past two decades, radioimmunotherapy (RIT) has proven to be an effective treatment for non-solid tumors (reviewed in [1,2]); e.g., radiolabeled anti-CD20 monoclonal antibodies for the Molecules 2019, 24, 4314; doi:10.3390/molecules24234314 www.mdpi.com/journal/molecules. It has been widely accepted that high oxygen levels play a large cycle but is the only means of repair in G1 and early S phases In this error prone repair method, role in a cell’s sensitivity to ionizing radiation, and tumor hypoxia is an established factor in DNA ends are rejoined with no sister templates [22]. A higher proportion of double-strand breaks remain un-rejoined after exposure to high LET radiation [15] When it comes to damage from high LET α-particles in close proximity to the cells being irradiated, the main radiobiological effect is complex and irreparable DNA damage resulting in cell death by either apoptosis or necrosis. Combinations of bystander effects and the abscopal (likely immune) response in vivo are potential mechanisms of the efficacy for tumors that are not venerable to the targeted α-emitter radiotherapy in a patient with heterogeneous target expression
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