Process validation for production of copper radioisotopes in a TR-19 variable energy cyclotron

Leonte, Radu A.; Cocioabă, Diana; Chilug, Livia Elena; Baruta, Simona; Eşanu, T.; Burghelea, B.; Chiriacescu, A.; Crăciun, Liviu; Niculae, Dana

doi:10.1063/5.0031538

Cited by 7 publications

(11 citation statements)

References 5 publications

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“…Targets were successfully prepared by electroplating approximately 50 mg of nickel-64 in an aqueous solution at 2.7–2.9 V, with a starting current intensity of 37 mA, for 20–24 h. The end of the electrodeposition process was indicated by the complete change of color of the electroplating solution from dark blue to colorless. After cleaning and drying, we obtained a circular-shaped target on the shuttle, containing 48 ± 1 mg nickel-64, ready for bombardment [ 20 ].…”

Section: Resultsmentioning

confidence: 99%

“…Before irradiation, the target was obtained by electrodeposition of metallic nickel-64 (99.53%) onto platinum support based on the work of Leonte et al, 2020 [ 20 ].…”

Section: Methodsmentioning

confidence: 99%

“…The crude solution obtained at the dissolution step was purified by the ion exchange technique [ 20 ]. The highly acidic solutions were passed through an AG1-X8 anion column aiming to separate the copper-64 from the rest of the metallic impurities and to recover the unreacted nickel-64.…”

Section: Methodsmentioning

confidence: 99%

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Antibody and Nanobody Radiolabeling with Copper-64: Solid vs. Liquid Target Approach

et al. 2023

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Antibody and nanobody-based copper-64 radiopharmaceuticals are increasingly being proposed as theranostic tools in multiple human diseases. While the production of copper-64 using solid targets has been established for many years, its use is limited due to the complexity of solid target systems, which are available in only a few cyclotrons worldwide. In contrast, liquid targets, available in virtually in all cyclotrons, constitute a practical and reliable alternative. In this study, we discuss the production, purification, and radiolabeling of antibodies and nanobodies using copper-64 obtained from both solid and liquid targets. Copper-64 production from solid targets was performed on a TR-19 cyclotron with an energy of 11.7 MeV, while liquid target production was obtained by bombarding a nickel-64 solution using an IBA Cyclone Kiube cyclotron with 16.9 MeV on target. Copper-64 was purified from both solid and liquid targets and used to radiolabel NODAGA-Nb, NOTA-Nb, and DOTA-Trastuzumab conjugates. Stability studies were conducted on all radioimmunoconjugates in mouse serum, PBS, and DTPA. Irradiation of the solid target yielded 13.5 ± 0.5 GBq with a beam current of 25 ± 1.2 μA and an irradiation time of 6 h. On the other hand, irradiation of the liquid target resulted in 2.8 ± 1.3 GBq at the end of bombardment (EOB) with a beam current of 54.5 ± 7.8 μA and an irradiation time of 4.1 ± 1.3 h. Successful radiolabeling of NODAGA-Nb, NOTA-Nb, and DOTA-Trastuzumab with copper-64 from both solid and liquid targets was achieved. Specific activities (SA) obtained with the solid target were 0.11, 0.19, and 0.33 MBq/μg for NODAGA-Nb, NOTA-Nb, and DOTA-trastuzumab, respectively. For the liquid target, the corresponding SA values were 0.15, 0.12, and 0.30 MBq/μg. Furthermore, all three radiopharmaceuticals demonstrated stability under the testing conditions. While solid targets have the potential to produce significantly higher activity in a single run, the liquid process offers advantages such as speed, ease of automation, and the feasibility of back-to-back production using a medical cyclotron. In this study, successful radiolabeling of antibodies and nanobodies was achieved using both solid and liquid targets approaches. The radiolabeled compounds exhibited high radiochemical purity and specific activity, rendering them suitable for subsequent in vivo pre-clinical imaging studies.

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Section: Resultsmentioning

confidence: 99%

“…Before irradiation, the target was obtained by electrodeposition of metallic nickel-64 (99.53%) onto platinum support based on the work of Leonte et al, 2020 [ 20 ].…”

Section: Methodsmentioning

confidence: 99%

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Antibody and Nanobody Radiolabeling with Copper-64: Solid vs. Liquid Target Approach

et al. 2023

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“…The resulting solution was transferred into the electrodeposition module, while the process was performed at a current intensity of 37 mA for 15–24 h to obtain a compact target, without stalagmites or cracks. The target was irradiated at the TR-19 cyclotron (ACSI, Richmond, Canada), via the 64 Ni(p,n) 64 Cu nuclear reaction, using the following parameters: extracted beam energy 14.2 ± 0.3 MeV, energy on target 11.81 ± 0.63 MeV, integrated dose 150 μAh, according to an improved process of that previously described by our group ( 23 , 24 ). After irradiation, the target was retracted and dissolved with 6 M HCl at 90°C.…”

Section: Methodsmentioning

confidence: 99%

Modifications in cellular viability, DNA damage and stress responses inflicted in cancer cells by copper-64 ions

Serban,

Niculae,

Manda

et al. 2023

Front. Med.

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Due to combined therapeutical emissions, a high linear energy transfer Auger-electrons with the longer ranged β− particles, 64Cu-based radiopharmaceuticals raise particular theragnostic interest in cancer, by joined therapeutic and real-time PET imaging properties. The in vitro study aimed to investigate the biological and molecular background of 64CuCl2 therapy by analyzing the damages and stress responses inflicted in various human normal and tumor cell lines. Colon (HT29 and HCT116) and prostate carcinoma (DU145) cell lines, as well as human normal BJ fibroblasts, were treated up to 72 h with 2–40 MBq/mL 64CuCl2. Radioisotope uptake and retention were assessed, and cell viability/death, DNA damage, oxidative stress, and the expression of 84 stress genes were investigated at various time points after [64Cu]CuCl2 addition. All the investigated cells incorporated 64Cu ions similarly, independent of their tumoral or normal status, but their fate after exposure to [64Cu]CuCl2 was cell-dependent. The most striking cytotoxic effects of the radioisotope were registered in colon carcinoma HCT116 cells, for which a substantial decrease in the number of metabolically active cells, and an increased DNA damage and oxidative stress were registered. The stress gene expression study highlighted the activation of both death and repair mechanisms in these cells, related to extrinsic apoptosis, necrosis/necroptosis or autophagy, and cell cycle arrest, nucleotide excision repair, antioxidant, and hypoxic responses, respectively. The in vitro study indicated that 40 MBq/mL [64Cu]CuCl2 delivers a therapeutic effect in human colon carcinoma, but its use is limited by harmful, yet lower effects on normal fibroblasts. The exposure of tumor cells to 20 MBq/mL [64Cu]CuCl2, might be used for a softer approach aiming for a lower radiotoxicity in normal fibroblasts as compared to tumor cells. This radioactive concentration was able to induce a persistent decrease in the number of metabolically active cells, accompanied by DNA damage and oxidative stress, associated with significant changes in stress gene expression in HCT116 colon cancer cells.

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“…Commonly produced in a low to medium energy cyclotron by proton bombardment of a nickel-64 target through (p,n) nuclear reaction, copper-64 can be obtained using either a solid, metallic electrodeposited nickel-64 target or a liquid target, containing a dissolved nickel-64 salt (usually nitrate) solution [ 9 , 10 ].…”

Section: Introductionmentioning

confidence: 99%

Neurotensin (8-13) and Neuromedin N Neuropeptides Radiolabelling with Copper-64 Produced on Solid or Liquid Targets

Cocioabă,

Fonseca,

Leonte

et al. 2024

Molecules

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On the verge of a theranostic approach to personalised medicine, copper-64 is one of the emerging radioisotopes in nuclear medicine due to its exploitable nuclear and biochemical characteristics. The increased demand for copper-64 for preclinical and clinical studies has prompted the development of production routes. This research aims to compare the (p,n) reaction on nickel-64 solid versus liquid targets and evaluate the effectiveness of [64Cu]CuCl2 solutions prepared by the two routes. As new treatments for neurotensin receptor-overexpressing tumours have developed, copper-64 was used to radiolabel Neurotensin (8-13) and Neuromedin N. High-quality [64Cu]CuCl2 solutions were prepared using ACSI TR-19 and IBA Cyclone Kiube cyclotrons. The radiochemical purity after post-irradiation processing reached 99% (LT) and 99.99% (ST), respectively. The irradiation of a solid target with 11.8 MeV protons and 150 μAh led to 704 ± 84 MBq/μA (17.6 ± 2.1 GBq/batch at EOB). At the end of the purification process (1 h, 90.90% activity yield), the solution for peptide radiolabelling had a radioactive concentration of 1340.4 ± 70.1 MBq/mL (n.d.c.). The irradiation of a liquid target with 16.9 MeV protons and 230 μAh resulted in 3.7 ± 0.2 GBq/batch at EOB, which corresponds to an experimental production yield of 6.89 GBq.cm3/(g.µA)sat. Benefiting from a shorter purification process (40 min), the activity yielded 90.87%, while the radioactive concentration of the radiolabelling solution was lower (492 MBq/mL, n.d.c.). The [64Cu]CuCl2 solutions were successfully used for the radiolabelling of DOTA-NT(8-13) and DOTA-NN neuropeptides, resulting in a high RCP (>99%) and high molar activity (27.2 and 26.4 GBq/μmol for LT route compared to 45 and 52 GBq/μmol for ST route, respectively). The strong interaction between the [64Cu]Cu-DOTA-NT(8-13) and the colon cancerous cell lines HT29 and HCT116 proved that the specificity for NTR had not been altered, as shown by the uptake and retention data.

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Process validation for production of copper radioisotopes in a TR-19 variable energy cyclotron

Cited by 7 publications

References 5 publications

Antibody and Nanobody Radiolabeling with Copper-64: Solid vs. Liquid Target Approach

Antibody and Nanobody Radiolabeling with Copper-64: Solid vs. Liquid Target Approach

Modifications in cellular viability, DNA damage and stress responses inflicted in cancer cells by copper-64 ions

Neurotensin (8-13) and Neuromedin N Neuropeptides Radiolabelling with Copper-64 Produced on Solid or Liquid Targets

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