A feasibility study of the Therapeutic Application of a Mixture of 67/64Cu Radioisotopes produced by cyclotrons with proton irradiation

Purpose: 64Cu and 67Cu radioisotopes have nuclear characteristics suitable for nuclear medicine applications. The production of 64Cu is already well-established. However, the production of 67Cu in quantities suitable to conduct clinical trials is more challenging as it leads to the co-production of other Cu-isotopes, in particular 64Cu. The aim of this study is to investigate the possibility of using a CuCl2 solution with a mixture of 67/64Cu 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) 70Zn in the energy range 70-45 MeV; ii) 68Zn in the energy range 70-35 MeV; iii) a combination of 70Zn (70-55 MeV) and 68Zn (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 CuCl2 published by ICRP 53. The total absorbed dose generated by the 67/64CuCl2 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 tumours of different sizes containing uniformly distributed 67/64Cu mixture and to calculate the absorbed dose of self-irradiation. The biological damage produced by 67Cu and 64Cu 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 67CuCl2 are higher than those of 64CuCl2. Absorbed dose values per unit of administered activity of 67/64CuCl2 mixture increase with time after the EOB, because the amount of 67Cu in the mixture increases. Survival data showed that the biological damage caused per each decay of 67Cu is greater than that of 64Cu, assuming that radionuclides remain accumulated in the cell cytoplasm. Sphere model calculations demonstrated that 64Cu administered activity must be about five times higher than that of 67Cu to obtain the same absorbed dose for tumour mass between 0.01 g and 10 g and about ten times higher for very small spheres. Consequently, the 64CuCl2 absorbed dose to healthy organs will reach higher values than those of 67CuCl2. The supplemental activity of the 67/64CuCl2 mixture, required to get the same tumour absorbed dose produced by 67CuCl2, triggers a dose increment in healthy organs. The waiting time post-EOB necessary to keep this dose increment below 10% (t10%) depends on the irradiation methods employed for the production of the 67/64CuCl2 mixture. Conclusions: A mixture of cyclotron produced 67/64Cu radioisotopes proved to be an alternative solution for the therapeutic use of CuCl2 with minimal dose increment to healthy organs compared to pure 67Cu. Irradiation of a 70Zn+68Zn 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 t10% (10 h), and less than 1% of 61Cu and 60Cu impurities.