MIRD Monograph: Radiobiology and Dosimetry for Radiopharmaceutical Therapy with Alpha-Particle Emitters

Abstract

Publication of MIRD Monograph: Radiobiology and Dosimetry for Radiopharmaceutical Therapy with Alpha-Particle Emitters was supported by the SNMMI MIRD Committee to provide clinicians with information on radiopharmaceutical therapies that use a-particle emitters. George Sgouros, the MIRD committee chair, stated that the objective of this book is to "provide guidance and recommendations for human dosimetry" in these therapies. The book begins with an introduction to a-particles and an excellent historical overview of the use of radioactivity and a-emitters since 1896, followed by an explanation of the radiobiology of a-particles (how they work) and relative biological effectiveness (what the radiation dose to patients might be). In a section covering radiation dosimetry, readers are told how a-particles affect each part of the body, including the bone marrow and normal organs, as well as the effects at the cellular level. This part of the book can help guide clinicians in tailoring radiopharmaceutical therapy to a specific patient. Challenges concerning detection of a-particles are then discussed, with an important piece of the puzzle being an understanding of the instruments capable of detecting a-particles. It is also important to understand how the different a-particleemitting tracers are delivered, and the book includes a valuable section detailing the different methods of localization.

Advances in Precision Oncology: Targeted Thorium-227 Conjugates As a New Modality in Targeted Alpha Therapy

“…Both slow proliferating as well as actively dividing cells can be targeted by TTCs as long as the target antigen is expressed on the cell surface. [5][6][7] TTCs induce clustered DNA DSBs and cell cycle arrest in the G2/M phase resulting in cell death through apoptotic and necrotic pathways. 3,[5][6][7]35,36 In vitro exposure of cancer cells to TTCs leads to a release of markers of danger-associated molecular patterns (DAMPs), which are upregulated by dying cells to alert the immune system and to initiate immunogenic cell death.…”

“…[5][6][7] TTCs induce clustered DNA DSBs and cell cycle arrest in the G2/M phase resulting in cell death through apoptotic and necrotic pathways. 3,[5][6][7]35,36 In vitro exposure of cancer cells to TTCs leads to a release of markers of danger-associated molecular patterns (DAMPs), which are upregulated by dying cells to alert the immune system and to initiate immunogenic cell death. 36,37 Due to an inherent cross-fire effect of a-particle emitters and their ability to penetrate 2-10 cell layers in tissue, 3 the biological activity of TTCs, in contrast to antibody-drug conjugates, does not strictly depend on antigen internalization and is broadly independent of homogeneity of antigen expression.…”

“…36,37 Due to an inherent cross-fire effect of a-particle emitters and their ability to penetrate 2-10 cell layers in tissue, 3 the biological activity of TTCs, in contrast to antibody-drug conjugates, does not strictly depend on antigen internalization and is broadly independent of homogeneity of antigen expression. 3,[5][6][7] A critical parameter for their optimal efficacy, however, is the efficient delivery, accumulation, and retention in the tumor tissue to ensure treatment efficacy and a minimal damage to the surrounding healthy tissue.…”

“…3,5 The high potency of a particles is further highlighted by the fact that only 1-4 nuclear traversals are necessary to sterilize a bacterial cell, whereas around 2000 b particles are needed to induce an equivalent effect. 6,7 In addition, the longer path length of b-particle emitters may induce more damage to tumor-adjacent normal tissue. 3,5 Over the past two decades, a number of a-particle-emitting radionuclides, including bismuth-213 ( 213 Bi, half-life of 45.6 min), actinium-225 ( 225 Ac, half-life of 9.9 d), astatine-211 (half-life of 7.2 h), radium-223 ( 223 Ra, half-life of 11.4 d), and thorium-227 ( 227 Th, half-life of 18.7 d) have been investigated preclinically as TATs.…”

“…The high potency of α particles is further highlighted by the fact that only 1–4 nuclear traversals are necessary to sterilize a bacterial cell, whereas around 2000 β particles are needed to induce an equivalent effect. 6 , 7 In addition, the longer path length of β − -particle emitters may induce more damage to tumor-adjacent normal tissue. 3 , 5 …”