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Zoi, V.; Giannakopoulou, M.; Alexiou, G.A.; Bouziotis, P.; Thalasselis, S.; Tzakos, A.G.; Fotopoulos, A.; Papadopoulos, A.N.; Kyritsis, A.P.; Sioka, C. Radiopharmaceutical Applications of 64Cu Isotope. Encyclopedia. Available online: https://encyclopedia.pub/entry/50437 (accessed on 02 August 2024).
Zoi V, Giannakopoulou M, Alexiou GA, Bouziotis P, Thalasselis S, Tzakos AG, et al. Radiopharmaceutical Applications of 64Cu Isotope. Encyclopedia. Available at: https://encyclopedia.pub/entry/50437. Accessed August 02, 2024.
Zoi, Vasiliki, Maria Giannakopoulou, George A. Alexiou, Penelope Bouziotis, Savvas Thalasselis, Andreas G. Tzakos, Andreas Fotopoulos, Athanassios N. Papadopoulos, Athanassios P. Kyritsis, Chrissa Sioka. "Radiopharmaceutical Applications of 64Cu Isotope" Encyclopedia, https://encyclopedia.pub/entry/50437 (accessed August 02, 2024).
Zoi, V., Giannakopoulou, M., Alexiou, G.A., Bouziotis, P., Thalasselis, S., Tzakos, A.G., Fotopoulos, A., Papadopoulos, A.N., Kyritsis, A.P., & Sioka, C. (2023, October 18). Radiopharmaceutical Applications of 64Cu Isotope. In Encyclopedia. https://encyclopedia.pub/entry/50437
Zoi, Vasiliki, et al. "Radiopharmaceutical Applications of 64Cu Isotope." Encyclopedia. Web. 18 October, 2023.
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Cancer theragnostics is a novel approach that combines diagnostic imaging and radionuclide therapy. It is based on the use of a pair of radiopharmaceuticals, one optimized for positron emission tomography imaging through linkage to a proper radionuclide, and the other bearing an alpha- or beta-emitter isotope that can induce significant damage to cancer cells. The 64Cu isotope has been proposed as an effective metallic radionuclide for the development of theragnostic radiopharmaceuticals. 64CuCl2 is a promising agent for different types of tumors, including prostate cancer and glioblastoma.
theragnostics
nuclear medicine
1. Introduction
Cancer is a primary cause of death globally. Given its recurring and lethal nature, its cure remains unsuccessful for most patients. In recent years, there has been a great expansion of theragnostics, which consists of a comprehensive therapeutic process that encompasses identification of the cancer using a specific radioactive molecule that binds to the tumor, followed by the administration of a similar radioactive molecule designed to kill the malignant cells. In addition, another diagnostic post-therapy scan is usually performed that confirms the therapeutic response of the selected sites [1]. In certain cases, nuclear theragnostic agents with comparable molecular features are utilized, whereas in others, theragnostic compounds that are not biologically similar but have equal biodistribution are used [2]. The rapidly evolving field of theragnostics includes some already approved treatments such as 177Lu-PSMA (prostate-specific membrane antigen) for prostate cancer, 223Ra for osseous metastases, 177Lu-DOTATATE for neuroendocrine tumors, 131I for thyroid cancer, and several others that are under development [3]. The concept of theragnostics was initiated during the early days of nuclear medicine.
One such example represents the administration of iodine-131 followed by SPECT to diagnose thyroid cancer and the subsequent administration of a higher dose of the same radioactive molecule to attack and extinguish the cancer. However, during the last two decades, there has been tremendous progress in the actual construction and development of theragnostic molecules for personalized cancer diagnosis and therapy [4]. Examples of such recent molecules include [68Ga/177Lu]-labeled somatostatin peptides for theragnostics of neuroendocrine tumors. A similar molecule, [68Ga/177Lu] PSMA, may be used for metastatic prostate cancer. The exploitation and the clinical utilization of the range of diagnostic and therapeutic radioisotopes presupposes a deep knowledge of the physics of radiation. For an introductory section, the physical characteristics and the features of the decay schemes of the theragnostic radionuclides that are utilized today are presented in Table 1. Most of the presented radioisotopes are well known, since the large majority of them have been exploited in numerous applications—though not necessarily in clinical areas.
Table 1. The physical characteristics and decay schemes of the theragnostic radioisotopes.
| Radionuclides | Half Life (t1/2) | γ Ray (%) | Emission Type | E Average (keV) |
|---|---|---|---|---|
| 131I | 8.01 d | 360 (6.2%) 720 (10.4%) |
β− (100%) | 192 |
| 18F | 1.83 h | 511 (annihilation) | β+ (97%), EC (3%) | 634 |
| 68Ga | 68 min | 511 (annihilation) | β+ (90%), EC (10%) | 1899 |
| 177Lu | 6.65 d | 113 (6.2%) 208 (10.4%) |
β− 47.7 (11.6%) 111.7 (9.0%) 149.4 (79.4%) |
134 (498 max) |
| 90Y | 2.67 d | Bremsstrahlung | β− | 934 (2280 max) |
| 67Cu | 2.58 d | 91 (7.0%) 93 (16.1%) 185 (48.7%) |
β− | 141 |
| 64Cu | 12.7 h | β+ (17.5%), β− (38.5%) EC (44.0%) |
288 190 1675, 1346 |
|
| 225Ac | 10.0 d | 99.8 (1.0%) | α | α: (89.8%) 5732 5791 5793 5830 |
| 223Ra | 11.44 d | 154 (6%) 269 (14%) |
α & β− (3.6%) |
α: (95.3%) 5606, 6819, 7386, 6623 β−: 445 (1370 max) 492 (1420 max) |
Ιt is essential to mention that the precise knowledge of the interaction of radiation with matter for each isotope lies behind a successful therapeutic approach. The use of different radiation modes, Auger electrons, α-emitters, and β-emitters can cause the desired death of cancer cells. Auger electron emission causes double-strand DNA damage by direct internalization or through an indirect effect caused by the generation of free radicals due to water hydrolysis. The α-emitters with high LET cause high-density ionization effects, resulting in double-stranded DNA breaks. In contrast, the β-emitters mainly cause repairable single-strand DNA damage. The higher path length of β-emitters is approximately equal to 1000 cell diameters, resulting in crossfire radiation, whereas the Auger electron and α-emitters result in less cross-fire radiation due to their shorter path length.
Though these applications are very promising, there are significant practical challenges that must be solved for creative theragnostics to be implemented. For instance, the biodistribution of the theragnostic drugs should demonstrate adequate accumulation in the tumor, but very low concentration in the normal tissues; the diagnostic and therapeutic radionuclide half-lives must be appropriate for imaging and targeted cell killing, respectively; finally, the therapeutic radionuclides should be available to the patient within the time frame suggested by half-life and stability.
2. Radiopharmaceutical Applications of 64Cu Isotope
The 64Cu isotope has been proposed as an effective metallic radionuclide for the development of theragnostic radiopharmaceuticals. 64CuCl2 is a promising agent for different types of tumors, including prostate cancer and glioblastoma. Ferrari et al. investigated the effect of this molecule against U87MG glioma cells using a xenografted GBM tumor mouse model. The investigators demonstrated that 64CuCl2 not only exhibits high affinity for GBM cells compared to normal cells, but it is also a potent anti-cancer agent, with the ability to inhibit cell proliferation after single- or multiple-dose treatments [5]. In another study performed by Qin et al., the use of 64CuCI2 as a theragnostic agent for malignant melanoma was investigated. The authors reported that 64CuCI2 showed high uptake in the studied melanoma cell lines, and the tumors were clearly visualized using 64CuCI2 PET imaging. It was also observed that this molecule could effectively reduce tumor growth in the same cell lines, thus acting as a promising theragnostic agent [6].
The use of 64CuCl2 as a PET imaging tool in a clinical environment was first introduced by Panichelli et al. back in 2016 in glioblastoma patients. The clinical study included 19 patients, of which 18 were diagnosed with glioblastoma and 1 with grade 2 astrocytoma. The findings of this study demonstrated that all 18 patients with high-grade glioma showed a significantly higher tumor uptake of 64CuCl2 compared to the patient with low-grade malignancy [7]. Moreover, recent studies have demonstrated that hCTR1-expressing tumor cells or xenografts show elevated 64CuCl2 uptake, meaning that this compound can be a helpful theragnostic tool for these types of tumors. For example, it has been found that 64CuCl2 can act as a promising imaging tool for the diagnosis of recurrent prostate cancer in small-scale human studies, with the additional benefit that no adverse effects were recorded in those participating in the studies. Back in 2018, Guerreiro et al. investigated the effects of 64CuCl2 on different prostate Ca cell lines compared to normal cells. Interestingly, their results showed that not only was the uptake of this compound higher in tumor cells, but it was significantly more cytotoxic against cancer cells, compared to the non-tumoral prostate cell line [8]. Recently, an inhibitor of SGK1, a serine/threonine protein kinase named SI113, has been investigated in combination with 64CuCl2 for its therapeutic role against glioblastoma cell lines. The results presented by the investigators show that co-treatment with SI113 and 64CuCl2 increases cell death and enhances the effects of ionizing radiation. Thus, such a combination could be the basis of developing novel theragnostic tools for the diagnosis and treatment of GBM [9].
As mentioned above, the radionuclide pair 64Cu/67Cu may be a promising theragnostic solution due to the concurrent PET imaging properties of 64Cu and the therapeutic potential of 67Cu. In a recent study, in which patients with unresectable multifocal meningioma were injected with [64Cu] Cu-SARTATE (with SARTATE being a somatostatin analogue chelated to the sarcophagine MeCOSar chelator) prior to treatment with [67Cu] Cu-SARTATE, nearly identical targeting of tumors was observed between patients, implying that this combination of copper radionuclides can be an effective theragnostic option [10]. In another study, in which the molecular target was the gastrin-releasing peptide receptor (GRPR), which is highly expressed in tumors like prostate cancer, a complex made of the pair of radionuclides 64Cu/67Cu, a bombesin (BBN) analogue, and a sarcophagine-based amine was used in a PC-3 xenograft prostate cancer mouse model. The results showed that [64/67Cu] Cu(SAR-BBN) displayed increased tumor uptake and retention, followed by a significant tumor growth inhibition [11].
References
- Choudhury, P.S.; Gupta, M. Differentiated thyroid cancer theranostics: Radioiodine and beyond. Br. J. Radiol. 2018, 91, 20180136.
- Rizzo, A.; Annunziata, S.; Salvatori, M. Side effects of theragnostic agents currently employed in clinical practice. Q. J. Nucl. Med. Mol. Imaging 2021, 65, 315–326.
- Pomykala, K.; Hadaschik, B.A.; Sartor, O.; Gillessen, S.; Sweeney, C.J.; Maughan, T.; Hofman, M.S.; Herrmann, K. Next generation radiotheranostics promoting precision medicine. Ann. Oncol. 2023, 34, 507–519.
- Koziorowski, J.; Ballinger, J. Theragnostic radionuclides: A clinical perspective. Q. J. Nucl. Med. Mol. Imaging 2021, 65, 306–314.
- Ferrari, C.; Niccoli, A.; Villano, C.; Giacobbi, B.; Coccetti, D.; Panichelli, P.; Giuseppe, R. Copper-64 Dichloride as Theranostic Agent for Glioblastoma Multiforme: A Preclinical Study. BioMed. Res. Int. 2015, 2015, 129764.
- Qin, C.; Liu, H.; Chen, K.; Hu, X.; Ma, X.; Lan, X. Theranostics of malignant melanoma with 64CuCl2. J. Nucl. Med. 2014, 55, 812–817.
- Panichelli, P.; Villano, C.; Cistaro, A.; Bruno, A.; Barbato, F.; Piccardo, A. Imaging of brain tumors with copper-64 chloride: Early experience and results. Cancer Biother. Radiopharm. 2016, 31, 159–167.
- Guerreiro, J.F.; Alves, V.; Abrunhosa, A.J.; Paulo, A.; Gil, O.M.; Mendes, F. Radiobiological characterization of 64CuCl2 as a simple tool for prostate cancer theranostics. Molecules 2018, 23, 2944.
- Catalogna, G.; Talarico, C.; Dattilo, V.; Gangemi, V.; Calabria, F.; D’Antona, L.; Schenone, S.; Musumeci, F.; Bianco, C.; Perrotti, N.; et al. The SGK1 kinase inhibitor SI113 sensitizes theranostic effects of the 64CuCl2 in human glioblastoma Multiforme cells. Cell Physiol. Biochem. 2017, 43, 108–119.
- Bailey, D.L.; Willowson, K.P.; Harris, M.; Biggin, C.; Aslani, A.; Lengkeek, N.A.; Stoner, J.; Eslick, M.E.; Marquis, H.; Parker, M.; et al. 64Cu Treatment Planning and 67Cu Therapy with Radiolabeled MeCOSar-Octreotate in Subjects with Unresectable Multifocal Meningioma: Initial Results for Human Imaging, Safety, Biodistribution, and Radiation Dosimetry. J. Nucl. Med. 2023, 64, 704–710.
- Huynh, T.; Van Dam, E.; Houston, Z.; McInnes, L.; Mpoy, C.; Harris, M.; Thurecht, K.; Donnelly, P.; Rogers, B. A Cu-64/Cu-67 Bombesin ligand as a theranostic for cancer. J. Nucl. Med. 2021, 62 (Suppl. S1), 1237.
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