Theoretical estimation of absorbed dose to organs in radioimmunotherapy using radionuclides with multiple unstable daughters.

The toxicity and clinical utility of long-lived alpha emitters such as Ac-225 and Ra-223 will depend upon the fate of alpha-particle emitting unstable intermediates generated after decay of the conjugated parent. For example, decay of Ac-225 to a stable element yields four alpha particles and seven radionuclides. Each of these progeny has its own free-state biodistribution and characteristic half-life. Therefore, their inclusion for a more accurate prediction of absorbed dose and potential toxicity requires a formalism that takes these factors into consideration as well. To facilitate the incorporation of such intermediates into the dose calculation, a previously developed methodology (model 1) has been extended. Two new models (models 2 and 3) for allocation of daughter products are introduced and are compared with the previously developed model. Model 1 restricts the transport to a function that yields either the place of origin or the place(s) of biodistribution depending on the half-life of the parent radionuclide. Model 2 includes the transient time within the bloodstream and model 3 incorporates additional binding at or within the tumor. This means that model 2 also allows for radionuclide decay and further daughter production while moving from one location to the next and that model 3 relaxes the constraint that the residence time within the tumor is solely based on the half-life of the parent. The models are used to estimate normal organ absorbed doses for the following parent radionuclides: Ac-225, Pb-212, At-211, Ra-223, and Bi-213. Model simulations are for a 0.1 g rapidly accessible tumor and a 10 g solid tumor. Additionally, the effects of varying radiolabled carrier molecule purity and amount of carrier molecules, as well as tumor cell antigen saturation are examined. The results indicate that there is a distinct advantage in using parent radionuclides such as Ac-225 or Ra-223, each having a half-life of more than 10 days and yielding four alpha particles per parent decay, in that lower doses to normal organs result for a given tumor dose in comparison to those radionuclides yielding fewer alpha particles. In model 2, which accounts for transit time through the blood, a dose of 20 Gy to a rapidly accessible 0.1 g tumor will result in a liver and kidney dose of 1.7 and 0.9 Gy, respectively from Ac-225. An equivalent dose to tumor from Ra-223 would yield a maximum normal organ dose of 0.4 and 0.3 Gy to bone and small intestines, respectively; the corresponding absorbed dose to small intestines from Pb-212 and Bi-213 is 2.2 and 3.0 Gy, respectively.