A feasibility study of the therapeutic application of a mixture of Cu radioisotopes produced by cyclotrons with proton irradiation.

Purpose: Cu and Cu radioisotopes have nuclear characteristics suitable for nuclear medicine applications. The production of Cu is already well established. However, the production of Cu in quantities suitable to conduct clinical trials is more challenging as it leads to the coproduction of other Cu isotopes, in particular Cu. The aim of this study is to investigate the possibility of using a CuCl solution with a mixture of Cu radioisotopes for therapeutic purposes, providing an alternative solution for the cyclotron production problem.

Methods: Copper radioisotopes activities were calculated by considering proton beam irradiation of the following targets: (i) Zn in the energy range 70-45 MeV; (ii) Zn in the energy range 70-35 MeV; (iii) a combination of Zn (70-55 MeV) and Zn (55-35 MeV). The contribution of each copper radioisotope to the human-absorbed dose was estimated with OLINDA/EXM software using the biokinetic model for CuCl published by ICRP 53. The total absorbed dose generated by the CuCl mixture, obtained through different production routes, was calculated at different times after the end of the bombardment (EOB). A simple spherical model was used to simulate tumors of different sizes containing uniformly distributed Cu mixture and to calculate the absorbed dose of self-irradiation. The biological damage produced by Cu and Cu was also evaluated through cellular dosimetry and cell surviving fraction assessment using the MIRDcell code, considering two prostate cancer cell lines with different radiosensitivity.

Results: The absorbed dose to healthy organs and the effective dose (ED) per unit of administered activity of CuCl are higher than those of CuCl . Absorbed dose values per unit of administered activity of CuCl mixture increase with time after the EOB because the amount of Cu in the mixture increases. Survival data showed that the biological damage caused per each decay of Cu is greater than that of Cu, assuming that radionuclides remain accumulated in the cell cytoplasm. Sphere model calculations demonstrated that Cu administered activity must be about five times higher than that of Cu to obtain the same absorbed dose for tumor mass between 0.01 and 10 g and about 10 times higher for very small spheres. Consequently, the CuCl -absorbed dose to healthy organs will reach higher values than those of CuCl . The supplemental activity of the CuCl mixture, required to get the same tumor-absorbed dose produced by CuCl , triggers a dose increment (DI) in healthy organs. The waiting time post-EOB necessary to keep this DI below 10% (t ) depends on the irradiation methods employed for the production of the CuCl mixture.

Conclusions: A mixture of cyclotron produced Cu radioisotopes proved to be an alternative solution for the therapeutic use of CuCl with minimal DI to healthy organs compared with pure Cu. Irradiation of a Zn+ Zn target in the 70-35 MeV proton energy range for 185 h appears to be the best option from among all the production routes investigated, as it gives the maximum amount of activity, the shortest t (10 h), and less than 1% of Cu and Cu impurities.