Résumé
Receptor-targeted radionuclide therapy refers to a form of intravenously administered pharmaceutical cancer treatment that directs radiation specifically to cancer cells in the body. These radiopharmaceuticals generally comprise vectors (or ligands, e.g., antibodies, peptides, small molecules) that are designed to bind to the external domain of cell surface proteins (e.g., g-protein coupled receptors) that are found in high concentration on cancer cells, with much lower concentrations (to complete absence) on normal cells and tissues. Targeted alpha therapy (TAT) is a form of receptor-targeted radionuclide therapy in which these vectors are radiolabeled with radionuclides that can be used to deliver alpha particle radiation to the tumor microenvironment. Because the mass and energy deposition of alpha particles differ greatly from those of beta particles for this application, the radiobiology of the interactions of alpha particles with cells is distinct from that of beta particles. In this context, TAT represents an exciting direction for the development of tumor-targeted cancer treatments with distinct challenges to the radiobiologist and the interdisciplinary teams developing this approach. In this chapter, the history of the use of alpha particle radiation for cancer treatment is presented to provide a framework and context for the reader. This introductory section is followed by an overview of the radionuclides available for TAT and classes of molecular vectors (or ligands) that have been applied for radiopharmaceuticals designed to direct alpha particle radiation to the tumor microenvironment. The following sections describe the underpinnings of the radiobiology of TAT and the current understanding of alpha particle interactions in the cellular setting along with the physical parameters that influence these interactions and the abscopal effects. For context, comparisons to beta particle emissions are included and new paradigms in the radiobiology of TAT that have arisen over the past two decades are highlighted. The chapter concludes with an in-depth discussion of mathematical formalisms applied for TAT dosimetry (absorbed dose calculations) including microdosimetry and current standards for reporting of dosimetric quantities for TAT. A summary is provided that points to the rich potential for TAT and future needs for research and development