Synthesis, validation and quality controls of [68Ga]-DOTA-Pentixafor for PET imaging of chemokine receptor CXCR4 expression
Synthesis and CQ of [68Ga]-DOTA-Pentixafor
Keywords:
CXCR4 targeting, PET, radiopharmaceutical validation, [68Ga]-DOTA-Pentixafor.Abstract
Background. Chemokine receptor-4 (CXCR4) is involved in tumor growth and progression in several types of human cancer.
Recently, [68Ga]-DOTA-Pentixafor has been assessed as an excellent imaging probe targeting CXCR4-expression using positron emission tomography (PET).
Here we report on the entire production cycle of [68Ga]-DOTA-Pentixafor, including quality control development and process validation.
Methods. Synthesis of [68Ga]-DOTA-Pentixafor was validated via three independent and consecutive production runs using an automated synthesis system. All validation runs must pass the pre-set quality control (QC) limits. Validation was performed for established QC tests to ensure that methods were reproducible and reliable in routine use. Germanium-68 breakthrough was determined for each sample. Production yield was calculated for each synthesis to assess the performance and efficiency of the radiolabeling process. The quality of the final product was determined by ITLC and HPLC methods after each synthesis.
Results. The average ITLC‐measured radiochemical purity was above 98.5% and HPLC‐measured radiochemical purity was 99.86%, 99,83% and 100% in the three validation runs. Germanium breakthrough was 4.8*10-5%, 4.9*10-5% and 4.7*10-5% of total activity, far below the recommended level of 0.001%. Residual ethanol resulted 5.22%, 5.58% and 5.32%V/V; spot of HEPES impurity was not more intense than spot of reference solution (200µg/V). Endotoxin level resulted <17.5EU/ml. pH of the final product was 7 in all samples.
Conclusion: [68Ga]-DOTA-Pentixafor fit requirements of the pre-set quality parameters of purity, efficacy and safety in the batches considered for this study and fulfilled all the acceptance criteria for injectable radiopharmaceutical products. The results demonstrated a batch-to-batch reproducibility providing high radiochemical purity.
References
Buck AK, Stolzenburg A, Hänscheid H, Schirbel A, Lückerath K, Schottelius M, Wester HJ, Lapa C. Chemokine receptor - Directed imaging and therapy. Methods. 2017 Nov 1;130:63-71. doi: 10.1016/j.ymeth.2017.09.002. Epub 2017 Sep 12. Review.
Burger JA and Kipps TJ. CXCR4: a key receptor in the crosstalk between tumor cells and their microenvironment. Blood. 2006; 107:1761-1767.
Burger JA and Peled A. CXCR4 antagonists: targeting the microenvironment in leukemia and other cancers. Leukemia. 2009; 23:43-52.
Muller A, Homey B, Soto H, Ge N, Catron D, Buchanan ME, McClanahan T, Murphy E, Yuan W, Wagner SN, Barrera JL, Mohar A, Verastegui E and Zlotnik A. Involvement of chemokine receptors in breast cancer metastasis. Nature. 2001; 410:50-56.
Zhang B, Wu T, Wang Z, Zhang Y, Wang J, Yang B, Zhao Y, Rao Z and Gao J. p38MAPK activation mediates tumor necrosis factor-alpha-induced apoptosis in glioma cells. Molecular medicine reports. 2015; 11:3101-3107.
Kaemmerer D, Reimann C, Specht E, Wirtz RM, Sayeg M, Baum RP, Schulz S and Lupp A. Differential expression and prognostic value of the chemokine receptor CXCR4 in bronchopulmonary neuroendocrine neoplasms. Oncotarget. 2015; 6:3346-3358. doi: 10.18632/oncotarget.3242.
Andreas Johannes Poschenrieder. Development of Diagnostic and Therapeutic Radiopharmaceuticals targeting the Chemokine Receptor 4. https://d-nb.info/1142376478/34
Poschenrieder, A., Schottelius, M., Schwaiger, M. et al. Preclinical evaluation of [68Ga]NOTA-pentixafor for PET imaging of CXCR4 expression in vivo — a comparison to [68Ga]pentixafor. EJNMMI Res 6, 70 (2016) doi:10.1186/s13550-016-0227-2
A. Sammartano, S. Migliari, M. Scarlattei, G. Baldari, L. Ruffini. Synthesis and Quality Control of a new probe [68Ga]- Pentixafor for PET imaging of CXCR4 expression. https://link.springer.com/content/pdf/10.1007%2Fs00259-018-4148-3.pdf
Eur J Nucl Med Mol Imaging (2018) 45(Suppl 1): 1. https://doi.org/10.1007/s00259-018-4148-3
Guidelines on current good Radio‐ pharmacy Practice (cGRPP) in the Preparation of Radiopharmaceuticals. European Association of Nuclear Medicine. (2007). Version 2., http:// www.eanm.org/publications/guidelines/gl_radioph_cgrpp.pdf.
Elsinga P, Todde S, Penuelas I, Meyer G, Farstad B, Faivre-Chauvet A, Mikolajczak R, Westera G, Gmeiner-Stopar T, Decristoforo C. Guidance on current good radiopharmacy practice (cGRPP) for the small-scale preparation of radiopharmaceuticals. Radiopharmacy Committee of the EANM. Eur J Nucl Med Mol Imaging. 2010 May;37(5):1049-62
International atomic energy agency. Quality control bin the Production of Radiopharmaceuticals. IAEA-TECDOC-1856 https://www-pub.iaea.org/MTCD/Publications/PDF/TE-1856web.pdf
World Health Organization. WHO Expert Committee on Specifications for Pharmaceutical Preparations-WHO Technical Report Series, 908-Thirtyseventh Report., (2003). http:// whqlibdoc.who.int/trs/who_trs_908.pdf.
Kung-Tien Liu, Jian-Hua Zhao, Lee-Chung Men and Chien-Hsin Chen. Quality by Design and Risk Assessment for Radiopharmaceutical Manufacturing and Clinical Imaging. Chapter 13 http://dx.doi.org/10.5772/51112
Barbet, J., Kraeber-Bodéré, F., & Chatal, J. F. Review: What Can Be Expected from Nuclear Medicine Tomorrow? Cancer biotherapy and radiopharmaceuticals, (2008). 23(4), 483-504
Blois, E., Zanger, R.M.S., Chan, H.S. et al. Radiochemical and analytical aspects of inter-institutional quality control measurements on radiopharmaceuticals. EJNMMI radiopharm. chem. 4, 3 (2019)
Decristoforo C, Penuelas I, Patt M, Todde S. European regulations for the introduction of novel radiopharmaceuticals in the clinical setting. Q J Nucl Med Mol Imaging. 2017 Jun;61(2):135-144.
Todde S, Peitl PK, Elsinga P, Koziorowski J, Ferrari V, Ocak EM, Hjelstuen O, Patt M, Mindt TL, Behe M. Guidance on validation and qualification of processes and operations involving radiopharmaceuticals. EJNMMI Radiopharm Chem. 2017;2(1):8
Aslani A, Snowdon GM, Bailey DL, Schembri GP, Bailey EA, Roach PJ. Gallium-68 DOTATATE Production with Automated PET Radiopharmaceutical Synthesis System: A Three Year Experience. Asia Ocean J Nucl Med Biol. 2014;2(2):75–86.
Migliari S, Sammartano A, Scarlattei M, Serreli G, Ghetti C, Cidda C, Baldari G, Ortenzia O, Ruffini L. Development and Validation of a High-Pressure Liquid Chromatography Method for the Determination of Chemical Purity and Radiochemical Purity of a [(68)Ga]-Labeled Glu-Urea-Lys(Ahx)-HBED-CC (Positron Emission Tomography) Tracer. ACS Omega. 2017 Oct 31;2(10):7120-7126.
ICH Q2(R1) Validation of Analytical Procedures: Text and Methodology - International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) https://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q2_R1/Step4/Q2_R1__Guideline.pdf
Annex 15 (EU) of Good Manufacturing Practice (GMP) guidelines: EDQM Guidelines: Guide for the elaboration of monographs on RADIOPHARMACEUTICAL PREPARATIONS European Pharmacopoeia Edition 2018
European Pharmacopoeia, 9th Edition, volume 1: chapter 2.2.66; Detection and measurement of radioactivity, 01/2017.
Shukla J, Vatsa R, Garg N, Bhusari P, Watts A, Mittal BR. Quality control of positron emission tomography radiopharmaceuticals: An institutional experience. Indian J Nucl Med. 2013 Oct;28(4):200-6.
Migliari S, Sammartano A, Cidda C, Baldari G, Scarlattei M, Serreli G, Ghetti C, Pipitone S, Lippi G, Ruffini L. Novel approach for quality assessment and improving diagnostic accuracy in cell-based infection imaging using 99mTc-HMPAO labeled leukocytes. Acta Biomed. 2018 Oct 8;89(3):355-364. doi: 10.23750/abm.v89i3.7064. PubMed PMID: 30333459.
Sammartano, A.; Scarlattei, M.; Migliari, S.; Baldari, G.; Ruffini, L. Validation of in Vitro Labeling Method for Human Use of Heat-Damage Red Blood Cells to Detect Splenic Tissue and Hemocateretic Function. Acta Bio Med 2019, 90, 275-280
Migliari S, Sammartano A, Scarlattei M, Serreli G, Ghetti C, Cidda C, et al. Development and Validation of a High-Pressure Liquid Chromatography Method for the Determination of Chemical Purity and Radiochemical Purity of a [68Ga]-Labeled Glu-Urea-Lys(Ahx)-HBEDCC (Positron Emission Tomography) Tracer. ACS Omega. American Chemical Society; 2017 Oct 31;2(10):7120–6.
Andrea Sartori, Francesca Bianchini, Silvia Migliari, Paola Burreddu, Claudio Curti, Federica Vacondio, Daniela Arosio, Livia Ruffini, Gloria Rassu, Lido Calorini, Alberto Pupi, Franca Zanardi and Lucia Battistini. Synthesis and Preclinical Evaluation of a Novel, Selective 111In-labelled Aminoproline-RGD-peptide For Non-invasive Melanoma Tumor Imaging. Med. Chem. Commun., 2015,6, 2175-2183
Decker MD and Turner JH. Automated Module Radiolabeling of Peptides and Antibodies with Gallium-68, Lutetium-177 and Iodine-131. Cancer Biother Radiopharm 2012; 27: 72-76
Decristoforo C, Knopp R, von Guggenberg E, Rupprich M, Dreger T, Hess A, Virgolini I and Haubner R. A fully automated synthesis for the preparation of 68Ga-labelled peptides. Nucl Med Commun 2007; 28: 870-875.
Ocak M, Antretter M, Knopp R, Kunkel F, Petrik M, Bergisadi N and Decristoforo C. Full automation of 68Ga labelling of DOTA-peptides including cation exchange prepurification. Appl Radiat Isot 2010; 68: 297-302.
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