Targeted alpha therapy: part I

The possibility of pinpointing biological targets, and thereby potentially targeting and eradicating small tumors or even single cancer cells, is a tantalizing concept that has been discussed since the magic-bullet concept was first presented by Paul Erlich in the beginning of the 20th century in connection with his work on tissue staining for histological examinations and the work by Kohler and Milstein on antibody production published in 1975. This concept now seems feasible through the use of highly specific targeting constructs, chemical labeling of radioactive substances to these targeting constructs that results in high specific activities, radioimmunocomplexes with good stability even after injection, and the use of radionuclides emitting alpha( α)-particles having exceedingly high ionizing density and, therefore, a high probability of killing cells along its track in tissue. The short range of the emitted α-particles makes them even more interesting by minimizing unwanted irradiation of normal tissue surrounding the targeted cancer cells of interest, assuming high specificity of the targeting construct and good stability of the chemical bonds between the targeting construct and the α-particle emitter. Targeted Alpha Therapy (TAT), in which an α-particle emitting radionuclide is specifically directed to the biological target, is gaining more attention as new targets, targeting constructs, chemical labeling techniques, and α-particle emitters are, respectively, identified, constructed, developed, and made available. Results and improvements are now being published at an increasing rate and the number of conceivable applications is expanding, especially in the field of cancer treatment. Therefore, it is of utmost importance to provide an overview of the overall progress in the research field of TAT on a regular basis. However, problems such as limited or delayed diffusion of the α-radioimmunocomplex and inhomogeneous activity distributions in the targeted tumors, resulting in inhomogeneous absorbed dose distributions, are challenges that need to be addressed. These challenges need to be overcome before TAT becomes a standard treatment for diseases such as micrometastatic cancer. Hopefully, when enough funding will be provided and, hence, more treatment strategies of TAT will reach the clinical level the importance to conduct controlled, randomized trials with sufficient patient numbers, enabling statistical significance to occur must be emphasized in order to be able to properly compare and evaluate different approaches. In this issue, of the two hot-topic issues for targeted alpha therapy, articles discuss the recent developments in radionuclide availability, biomolecular targeting, labeling chemistry, and dosimetry for the most promising α-particle emitters. In the first article, Zalutsky et al. discuss the possibilities and limitations of using the promising α-particle emitter, 211At, and emphasize the need for funding new cyclotrons and prioritizing beam-times of already existing cyclotrons to improve the availability of 211At. Haddad et al. describe the status of the ARRONAX project through which a number of important nuclear medicine radionuclides will be produced, including some of those suitable for TAT. Relevant targeting constructs and their associated antigens used today and candidates for use in the future are discussed by Olafsen et al. in the third article. The next article, by Scott Wilbur, discusses chemical and radiochemical issues of radiolabeling using α-particle emitting radionuclides, e.g. factors that are important in selecting chelation or bonding reagents during the development of α-particle emitting radiopharmaceuticals. Lindegren at al. continue the discussion of chemical considerations in the following article, but focuses on pre-targeting techniques, which will hopefully enhance both the activity distribution in the targeted tumor and the tumor-to-normal tissue absorbed dose ratio. The two final articles discuss different aspects of the dosimetry related to α-particles. The article by Sgouros et al. discusses how knowledge of the microscopic distribution of α-particle emitters is necessary to perform correct dosimetry, as well as the importance of the translation of activity distributions obtained in pre-clinical studies to the human situation, which requires micro-scale models of the source-target geometry at human dimensions according to the authors. Chouin et al. focus in the following article on the microdosimetry of α-particles. The authors present basic concepts and some applications of the microdosimetry for TAT, and conclude microdosimetry should only be considered when alternative approaches fail to provide an account of a given biological endpoint. The intention of this particular hot-topic issue is to present an up-to-date overview of key areas in the research field of TAT, i.e. radionuclides available, targeting constructs, labeling chemistry, and dosimetry. This issue will hopefully be followed by similar ones jointly produced by contributions from the research community active in the field, of which most researchers are participating in these two particular issues, i.e. Targeted Alpha Therapy - Part I and II.