alpha-Particle emitters in radioimmunotherapy: new and welcome challenges to medical internal dosimetry.

Over the past decade, there has been progressively stronger interest in the use of a-particle emitters for radioimmunotherapy (1–6). With proper localization of the labeled antibody, the high linear energy transfer of a-particles provides a correspondingly high probability of mitotic cell kill when compared with an equivalent number of cellular traversals by lower linear energy transfer b-particles. Consequently, much developmental work has been initiated in the production, chemistry, and preclinical trials of candidates for radioimmunotherapy such as 211At, 212Bi, 212Pb, 225Ac, 213Bi, and 223Ra (7). In general, a-emitters with half-lives that are either relatively short or relatively long compared with transient times in blood as well as diffusion and binding times in disease tissues may be considered. Those a-emitters with relatively short halflives, such as 213Bi, will most likely be restricted in their application to small, readily accessible tumors. For treatment of larger solid tumors, longerlived a-emitters such as 225Ac and 223Ra can also be considered. However, longer-lived radionuclides require more extensive normal organ dosimetry and biokinetics of their multiple unstable daughters in evaluating clinical efficacy. With high probability, the recoil energy of the a-emission will result in destruction of their chemical bonds with the antibody, resulting in the release of the daughter as a free element. Two very different approaches can be applied to the dosimetry of a-particle emitters. One is microdosimetry, in which the probabilistic nature of a-particle emission and its trajectory through the cell and cell nucleus are explicitly considered (1,8–10). In a microdosimetric analysis, probability density functions of specific energy are obtained (stochastic expressions of energy imparted per unit mass to small targets), as well as frequencies of zerodose contribution. Input data for such an analysis, however, require detailed knowledge of geometric features such as the spatial distribution and size of the source and target regions (e.g., cellular and nuclear sizes and subcellular distribution of the radionuclide). Meaningful correlations to biologic response further require data on the timing of the decays within the phases of the cell cycle and the variations of cellular radiosensitivity during these phases. In many cases, such data are not available in the clinical setting. A simpler approach is to extend the MIRD schema to the cellular level and estimate mean absorbed dose to the cells or cell nuclei through the application of cellular S values. In its 1997 monograph, the MIRD committee published extensive tables of cellular S values for a wide range of aand b-emitting radionuclides (11). These tabulations include S values for the cell and cell nucleus as target regions and for the cell, the cell surface, the nucleus, and the cytoplasm as potential source regions. In this issue of The Journal of Nuclear Medicine, Hamacher et al. (12) have provided an elegant extension of the cellular S value methodology to include time-dependent partial contributions of the various daughter emissions in the serial decay chains of 225Ac, 221At, 213Bi, and 223Ra. In their approach, a cutoff time (t0) is selected before which free elemental daughter radionuclides are considered to remain in the same source configuration as that assumed for the parent. At short cutoff times, the daughter radionuclides, which are released as free elements after the a-decay of the parent, diffuse or migrate far from the site of the parent decay and thus the cellular target dose results only from the decay of the parent. The authors note that for parent decays in blood circulation, short values of t0 are applicable. For tumor interstitium, intermediate values of t0 would be appropriate; thus, the total cellular dose is contributed by the parent and a t0-dependent fraction of the cumulative decays of the daughters of the serial decay chain. It is clear that this approach to cellular dosimetry lends itself nicely to broader considerations of the biokinetics and dosimetry of radionuclides with multiple unstable daughters as proposed under a matrix formalism developed by these same authors. Several issues and challenges of a-particle dosimetry are highlighted through this approach. First, what value of t0 is appropriate and under what conditions of the cellular microenvironment? What is the spatial mobility of these daughter radionuclides within tissues and cellular microenvironment that would permit quantitative selections of t0? To correctly perform this analysis, detailed knowledge of the chemical diffusion coefficients for each elemental species within various Received Mar. 30, 2001; revision accepted Apr. 9, 2001. For correspondence or reprints contact: Wesley E. Bolch, PhD, Department of Nuclear and Radiological Engineering, University of Florida, 202 NSC, Gainesville, FL 32611-8300.