Synthesis, Bio-Evaluation, and HumanAbsorbed Dose Estimation of 68Ga-Zoledronic Derivative for PET

Document Type : Research Article

Authors

1 Radiation Application Department, Shahid Beheshti University, Tehran, I.R. IRAN

2 Radiation Application Research School, Nuclear Science and Technology Research Institute, Tehran, I.R. IRAN

3 Faculty of Engineering, Science and Research Branch, Islamic Azad University, Tehran, I.R. IRAN

Abstract

Today, the development of PET-based diagnostic radiopharmaceuticals is essential due to their accessibility by generators such as gallium-68 radioisotope. In this study, due to the distinctive properties of the bone-seeking agent of DOTA-ZOL, an effort is created to synthesize this valuable compound and use it in labeling with gallium-68. Further preclinical studies of  68Ga-DOTA-ZOL are performed, and therefore the human absorbed dose after injection of the labeled compound was estimated based on rat biodistribution data. DOTA-ZOL was synthesized and characterized by FT-IR, NMR, and MS analyses. A tin-based in-house 68Ge /68Ga generator was used for labeling studies. To get the simplest labeling condition of DOTA-ZOL, completely different experiments were performed by variable labeling parameters together with concentration, time, pH, and time. The radiochemical purity of the radiolabeled complex was examined using RTLC methodology by totally different solvent systems. The steadiness of the final complex was assessed in PBS and human serum. The biodistribution of the radiolabeled complex as well as 68GaCl3 was evaluated in normal rats up to 120 min post-injection. The human-absorbed dose of the complex was estimated using animal data 68Ga-DOTA-ZOL and was prepared with radiochemical purity of quite 97 at optimized conditions using synthesized DOTA-ZOL and an in-house generator. The complex was stable in both PBS (4 °C) and in human blood serum (37 °C). The biodistribution studies in normal rats showed a high accumulation of 68Ga-DOTA-ZOL injection with the most uptake at 30 min. The human absorbed dose estimation of the radiolabeled compound showed the highest absorbed dose is received by the bone tissue with the equivalent dose of 0.052 mGy/MBq. The results showed the attainable preparation of a new emerging bone-seeking agent of 68Ga- DOTA-ZOL using an in-house generator. Also, the radiolabeled compound is considered an approximately safe radiopharmaceutical in terms of radiation absorbed dose.

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Main Subjects

References

[1] Kuźnik A., Październiok-Holewa A., Jewula P., Kuźnik N., Bisphosphonates—Much More than Only Drugs for Bone Disease, European Journal of Pharmacology, 866: 172773 (2020).
[2] Yang M., Yu X., Management of Bone Metastasis with Intravenous Bisphosphonates in Breast Cancer: A Systematic Review and Meta-Analysis of Dosing Frequency, Supportive Care in Cancer, 28: 2533-2540 (2020).
[3] Abdussalam-Mohammed W., Review of Therapeutic Applications of Nanotechnology in Medicine Field and its Side Effects, Journal of Chemical Reviews, 1: 243-251 (2019).
[4] Hosseinzadeh Z., Ramazani A., Razzaghi-Asl N, Plants of the Genus Heracleum as a Source of Coumarin and Furanocoumarin, Journal of Chemical Reviews, 1: 78-98 (2019).
[5] Peddagundam B., Abdul Ahad H., Chinthaginjala H., Ksheerasagare T., Ganthala A K., Gummadisani G.R., The Design of Soft Drugs: Basic Principles, Energetic Metabolite Methods, Approved Compounds, and Pharmaceutical Applications, Journal of Chemical Reviews, 4: p. 241-254 (2022).
[6] Menschutkin N., Ueber Die Einwirkung Des Chloracetyls Auf Phosphorige Säure, Justus Liebigs Annalen der Chemie, 133: 317-320 (1865).
[7] Smith R., Russell R., Bishop M., Diphosphonates and Paget's Disease of Bone, The Lancet, 297, p. 945-947 (1971).
[8] Von Baeyer H., Hofmann K., Acetodiphosphorige Saure, Beitr Dtsch Chem Ges, 30: 1973-1978 (1897).
[9] Fleish H., Neuman W.F., Mechanisms of Calcification: Role of Collagen, Polyphosphates, and Phosphatase, American Journal of Physiology-Legacy Content, 200: 1296-1300 (1961).
[10] Fleisch H., Russell R., A Review of the Physiological and Pharmacological Effects of Pyrophosphate and Diphosphonates on Bones and Teeth, Journal of Dental Research, 51: 323-332 (1972).
[11] Russell R., Hodgkinson A., The Urinary Excretion of Inorganic Pyrophosphate by Normal Subjects and Patients with Renal Calculus, Clinical Science,  31: 51-62 (1966).
[12] Farrell K B., Karpeisky A., Thamm D H., Zinnen S., Bisphosphonate Conjugation for Bone Specific Drug Targeting, Bone Reports, 9: 47-60 (2018).
[13] Maghsoudi S., Hosseini S.A., Ravandi S., A Review on Phospholipid and Liposome Carriers: Synthetic Methods and Their Applications in Drug Delivery, Journal of Chemical Reviews, 4: 346-363 (2022).
[14] Kakanejadifard A., Synthesis, Characterization, Crystal Structure and Density Functional Investigation of Dialkyl(Phenyl((4-(Phenyl Diazenyl)Phenyl) Amino)Methyl) Phosphonate, 333174: (2021).
[15] Faghihian H.,Yaghobb Nejadasl H., Synthesis, Characterization and Application of a Novel Zirconium Phosphonate Ion-Exchanger for Removal of Ni2+, Cu2+ and Zn2+ from Aqueous Solutions, 333174. 30: 23-31 (2011).
[16] Russell R.G.G., Bisphosphonates: From Bench to bedside, Annals of the New York Academy of Sciences, 1068: 367-401 (2006).
[17] J. Roelofs A., Thompson K., H. Ebetino F., J. Rogers M., P. Coxon F., Bisphosphonates: Molecular Mechanisms of Action and Effects on Bone Cells, Monocytes and Macrophages, Current Pharmaceutical Design, 16: 2950-2960 (2010).
[18] Edwards B.J., Gounder M., McKoy J.M., Boyd I., Farrugia M., Migliorati C., Marx R., Ruggiero S., Dimopoulos M., Raisch D.W, Pharmacovigilance and Reporting Oversight in US FDA Fast-Track Process: Bisphosphonates and Osteonecrosis of the Jaw, The Lancet Oncology, 9: 1166-1172 (2008).
[19] Heymann D., Ory B., Gouin F., Green J.R., Rédini F., Bisphosphonates: New Therapeutic Agents for the Treatment of Bone Tumors, Trends in Molecular Medicine, 10: 337-343 (2004).
[20] Ponte Fernández N., Estefania Fresco R., Aguirre Urizar J.M., Bisphosphonates and Oral Pathology I. General and Preventive Aspects, Medicina Oral, Patologia Oral Y Cirugia Bucal, 11: E396-400 (2006).
[21] Mbese Z., Aderibigbe B.A., Bisphosphonate-Based Conjugates and Derivatives as Potential Therapeutic Agents in Osteoporosis, Bone Cancer and Metastatic Bone Cancer, International Journal of Molecular Sciences, 22: 6869 (2021).
[22] Isla D., Afonso R., Bosch-Barrera J., Martínez N., Zoledronic Acid in Lung Cancer with Bone Metastases: A Review, Expert Review of Anticancer Therapy, 13: 421-426 (2013).
[23] Coleman R., Cook R., Hirsh V., Major P., Lipton A., Zoledronic Acid Use in Cancer Patients: More than Just Supportive Care? Cancer, 117: 11-23 (2011).
[24] Wadsak W., Mitterhauser M., Basics and Principles of Radiopharmaceuticals for PET/CT, European Journal of Radiology, 73:  -469 (2010).
[25] Sudbrock F., Fischer T., Zimmermann B., Guliyev M., Dietlein M., Drzezga A., Schomäcker K., Characterization of SnO2-Based 68Ge/68Ga Generators and 68Ga-DOTATATE Preparations: Radionuclide Purity, Radiochemical Yield and Long-Term Constancy, EJNMMI Research, 4: 1-10 (2014).
[26] Velikyan I., Prospective of 68Ga-Radiopharmaceutical Development, Theranostics, 4: 47 (2014).
[27] Ogawa K., Saji H., Advances in Drug Design of Radiometal-Based Imaging Agents for Bone Disorders, International Journal of Molecular Imaging, 2011 (2011).
[28] Bandoli G., Dolmella A., Tisato F., Porchia M., Refosco F., Mononuclear Six-Coordinated Ga (III) Complexes: A Comprehensive Survey, Coordination Chemistry Reviews, 253: 56-77 (2009).
[29] Farhanghi M., Holmes R.A., Volkert W.A., Logan K.W., Singh A., Samarium-153-EDTMP: Pharmacokinetic, Toxicity and Pain response Using an Escalating Dose Schedule in Treatment of Metastatic Bone Cancer, J. Nucl. Med., 33: 1451-1458 (1992).
[30] Pfannkuchen N., Bausbacher N., Pektor S., Miederer M., Rosch F., In Vivo Evaluation of [225Ac] Ac-DOTAZOL for α-Therapy of Bone Metastases, Current Radiopharmaceuticals, 11: 223-230 (2018).
[31] Yadav M.P., Ballal S., Meckel M., Roesch F., Bal C., [177Lu] Lu-DOTA-ZOL Bone Pain Palliation in Patients with Skeletal Metastases from Various Cancers: Efficacy and Safety Results, EJNMMI Research, 10: 1-13 (2020).
[32] Yen N., Azahari K., Wan H.B.W.K., Choong K.K., Radiolabelling and Preliminary Biodistribution Study of Samarium-153-Zoledronic Acid as a Novel Bone Pain Palliative Agent. 
Iranian Journal of Chemistry and Chemical Engineering
Volume 42, Issue 8 - Serial Number 130
August 2023
Pages 2483-2493

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