A feasibility study of the therapeutic application of a mixture of (67/64) Cu radioisotopes produced by cyclotrons with proton irradiation.
A feasibility study of the therapeutic application of a mixture of (67/64) Cu radioisotopes produced by cyclotrons with proton irradiation.
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DOI：
10.1002/mp.15524
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发表时间：
2022-04
期刊：
影响因子：
3.8
通讯作者：
Melendez-Alafort, Laura
中科院分区：
文献类型：
--
作者：
De Nardo, Laura;Pupillo, Gaia;Mou, Liliana;Esposito, Juan;Rosato, Antonio;Melendez-Alafort, Laura
关键词：
64 Cu和67 Cu放射性同位素具有适合于核医学应用的核特性。64 Cu的生产已经很成熟。然而，以适合进行临床试验的数量生产67 Cu更具挑战性，因为它会导致其他Cu同位素的共同生产，特别是64 Cu。本研究的目的是调查的可能性，使用CuCl 2溶液与67/64 Cu放射性同位素的混合物用于治疗目的，提供了一种替代的解决方案的回旋加速器生产的问题。通过考虑以下靶的质子束辐照来计算铜放射性同位素活性：（i）能量范围为70-45 MeV的70 Zn;（ii）能量范围为70-35 MeV的68 Zn;（iii）70 Zn（70-55 MeV）和68 Zn（55-35 MeV）的组合。使用ICRP 53发布的CuCl 2生物动力学模型，使用OLINDA/EXM软件估计每种铜放射性同位素对人体吸收剂量的贡献。在轰击结束（EOB）后的不同时间计算通过不同生产途径获得的67/64 CuCl 2混合物产生的总吸收剂量。使用简单的球形模型来模拟含有均匀分布的67/64 Cu混合物的不同大小的肿瘤，并计算自照射的吸收剂量。考虑到两种具有不同放射敏感性的前列腺癌细胞系，还通过使用MIRDcell代码的细胞剂量测定和细胞存活分数评估来评估67 Cu和64 Cu产生的生物损伤。67 CuCl 2对健康器官的吸收剂量和每单位给药活性的有效剂量（艾德）高于64 CuCl 2。在EOB后，67/64 CuCl 2混合物的每单位给药活性的吸收剂量值随时间增加，因为混合物中67 Cu的量增加。存活数据显示，假设放射性核素仍然积累在细胞质中，67 Cu每次衰变造成的生物损伤大于64 Cu。球体模型计算表明，64 Cu给药的活性必须比67 Cu高约5倍，以获得0.01至10 g之间肿瘤质量的相同吸收剂量，并且对于非常小的球体高约10倍。因此，健康器官的64 CuCl 2吸收剂量将达到比67 CuCl 2更高的值。67/64 CuCl 2混合物的补充活性，需要获得与67 CuCl 2产生的相同的肿瘤吸收剂量，触发健康器官中的剂量增量（DI）。保持DI低于10%所需的EOB后等待时间（t <10%）取决于生产67/64 CuCl 2混合物所采用的辐照方法。回旋加速器产生的67/64 Cu放射性同位素的混合物被证明是CuCl 2的治疗用途的替代解决方案，与纯67 Cu相比，对健康器官具有最小的DI。在70-35 MeV质子能量范围内照射70 Zn +68 Zn靶185 h似乎是所有研究的生产路线中的最佳选择，因为它提供了最大量的活性，最短的t 10%（10 h），以及小于1%的61 Cu和60 Cu杂质。
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 coproduction 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. 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 tumors 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. 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 tumor mass between 0.01 and 10 g and about 10 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 tumor‐absorbed dose produced by 67CuCl2, triggers a dose increment (DI) in healthy organs. The waiting time post‐EOB necessary to keep this DI below 10% (t 10%) depends on the irradiation methods employed for the production of the 67/64CuCl2 mixture. A mixture of cyclotron produced 67/64Cu radioisotopes proved to be an alternative solution for the therapeutic use of CuCl2 with minimal DI to healthy organs compared with 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 t 10% (10 h), and less than 1% of 61Cu and 60Cu impurities.
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