Login Register Cart 0
Generic placeholder image

Current Radiopharmaceuticals

Editor-in-Chief

ISSN (Print): 1874-4710
ISSN (Online): 1874-4729

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Oxidant and Antioxidant Effects of Gentisic Acid in a 177Lu-Labelled Methionine-Containing Minigastrin Analogue

Author(s): Victoria Trindade* and Henia Balter

Volume 13, Issue 2, 2020

Page: [107 - 119] Pages: 13

DOI: 10.2174/1874471012666190916112904

Abstract

Background: The radiolabelling of receptor-binding peptides for therapy is a challenge since the peptide itself is exposed (during labelling, storage and transport) to radiation-induced damage, directly or indirectly, in aqueous solution. Hence, the use of radiostabilizers seems to be mandatory, especially in peptide molecules that contain radiation-sensitive amino acids.

Objective: The aim of this study was to investigate the effect of two stabilizers, gentisic acid and methionine, to delve into how each of them affects the radiolabelling and stability of the minigastrin analogue [177Lu]Lu-DOTA-His-His-Glu-Ala-Tyr-Gly-Trp-Met-Asp-Phe-NH2 through the analysis of the 22 species distinguished over time by an optimized HPLC system.

Methods: The stabilizers, in different combinations, were present from the beginning of the labelling process carried out at 96 °C for 15 min. The stability was studied for up to 7 days.

Results: The unexpected selective oxidation of the methionine residue of the radiolabelled peptide, promoted by gentisic acid, led to studying the effect of pH, from 3.5 to 6.0, in the presence of only this stabilizer. A pH-dependent antioxidant behaviour was revealed, showing a decrease in peptide impurities but an increase in the selective oxidation as the pH was increased.

Conclusion: The selective oxidation of the methionine residue could be induced by oxidizing species probably produced in the reaction between gentisic acid and free radicals of water, during the protection of the radiolabelled peptide from the attack of these harmful species. Therefore, the addition of methionine becomes necessary to effectively decrease this selective oxidation in the methioninecontaining peptide.

Keywords: Lutetium-177, minigastrin analogue, oxidation, radiolysis, gentisic acid, methionine.

Next »
Graphical Abstract

[1]
de Jong, M.; Verwijnen, S.M.; de Visser, M.; Kwekkeboom, D.J.; Valkema, R.; Krenning, E.P. Peptides for Radionuclide Therapy. Targeted Radionuclide Tumor Therapy. Biological Aspects, 1st ed; Stigbrand, T.; Carlsson, J.; Adams, G.P., Eds.; Springer 2008, 117-144.
[http://dx.doi.org/10.1007/978-1-4020-8696-0_7]
[2]
Roman, S.; Lin, R.; Sosa, J.A. Prognosis of medullary thyroid carcinoma: demographic, clinical, and pathologic predictors of survival in 1252 cases. Cancer, 2006, 107(9), 2134-2142.
[http://dx.doi.org/10.1002/cncr.22244] [PMID: 17019736]
[3]
Šabani, M.; Jelovac, D.B.; Petrović, M.B.; Gavrić, M. Management of advanced medullary thyroid carcinoma. J. Tumor, 2014, 2, 202-207.
[4]
Pawlak, D.; Rangger, C.; Kolenc Peitl, P.; Garnuszek, P.; Maurin, M.; Ihli, L.; Kroselj, M.; Maina, T.; Maecke, H.; Erba, P.; Kremser, L.; Hubalewska-Dydejczyk, A.; Mikołajczak, R.; Decristoforo, C. From preclinical development to clinical application: Kit formulation for radiolabelling the minigastrin analogue CP04 with In-111 for a first-in-human clinical trial. Eur. J. Pharm. Sci., 2016, 85, 1-9.
[http://dx.doi.org/10.1016/j.ejps.2016.01.023] [PMID: 26826279]
[5]
Reubi, J.C.; Schaer, J-C.; Waser, B. Cholecystokinin(CCK)-A and CCK-B/gastrin receptors in human tumors. Cancer Res., 1997, 57(7), 1377-1386.
[PMID: 9102227]
[6]
Tolmachev, V. Choice of Radionuclides and Radiolabelling Techniques. Targeted Radionuclide Tumor Therapy. Biological Aspects, 1st ed; Stigbrand, T.; Carlsson, J.; Adams, G.P., Eds.; Springer 2008, 145-174.
[http://dx.doi.org/10.1007/978-1-4020-8696-0_8]
[7]
Chen, J.; Linder, K.E.; Cagnolini, A.; Metcalfe, E.; Raju, N.; Tweedle, M.F.; Swenson, R.E. Synthesis, stabilization and formulation of [177Lu]Lu-AMBA, a systemic radiotherapeutic agent for Gastrin Releasing Peptide receptor positive tumors. Appl. Radiat. Isot., 2008, 66(4), 497-505.
[http://dx.doi.org/10.1016/j.apradiso.2007.11.007] [PMID: 18178448]
[8]
Garrison, W.M. Reaction mechanisms in the radiolysis of peptides, polypeptides, and proteins. Chem. Rev., 1987, 87, 381-398.
[http://dx.doi.org/10.1021/cr00078a006]
[9]
de Blois, E.; Chan, H.S.; Konijnenberg, M.; de Zanger, R.; Breeman, W.A.P. Effectiveness of quenchers to reduce radiolysis of (111)In- or (177)Lu-labelled methionine-containing regulatory peptides. Maintaining radiochemical purity as measured by HPLC. Curr. Top. Med. Chem., 2012, 12(23), 2677-2685.
[http://dx.doi.org/10.2174/1568026611212230005] [PMID: 23339763]
[10]
Breeman, W.A.P.; Fröberg, A.C.; de Blois, E.; van Gameren, A.; Melis, M.; de Jong, M.; Maina, T.; Nock, B.A.; Erion, J.L.; Mäcke, H.R.; Krenning, E.P. Optimised labeling, preclinical and initial clinical aspects of CCK-2 receptor-targeting with 3 radiolabeled peptides. Nucl. Med. Biol., 2008, 35(8), 839-849.
[http://dx.doi.org/10.1016/j.nucmedbio.2008.09.006] [PMID: 19026945]
[11]
Grob, N.M.; Behe, M.; von Guggenberg, E.; Schibli, R.; Mindt, T.L. Methoxinine - an alternative stable amino acid substitute for oxidation-sensitive methionine in radiolabelled peptide conjugates. J. Pept. Sci., 2017, 23(1), 38-44.
[http://dx.doi.org/10.1002/psc.2948] [PMID: 28054429]
[12]
Liu, S.; Edwards, D.S. Stabilization of (90)y-labeled DOTA-biomolecule conjugates using gentisic acid and ascorbic acid. Bioconjug. Chem., 2001, 12(4), 554-558.
[http://dx.doi.org/10.1021/bc000145v] [PMID: 11459460]
[13]
de Blois, E.; Chan, H.S.; de Zanger, R.; Konijnenberg, M.; Breeman, W.A.P. Application of single-vial ready-for-use formulation of 111In- or 177Lu-labelled somatostatin analogs. Appl. Radiat. Isot., 2014, 85, 28-33.
[http://dx.doi.org/10.1016/j.apradiso.2013.10.023] [PMID: 24365877]
[14]
Davies, M.J. Protein oxidation and peroxidation. Biochem. J., 2016, 473(7), 805-825.
[http://dx.doi.org/10.1042/BJ20151227] [PMID: 27026395]
[15]
Gebicki, S.; Gebicki, J.M. Formation of peroxides in amino acids and proteins exposed to oxygen free radicals. Biochem. J., 1993, 289(Pt 3), 743-749.
[http://dx.doi.org/10.1042/bj2890743] [PMID: 8435071]
[16]
Sarmadi, B.H.; Ismail, A. Antioxidative peptides from food proteins: A review. Peptides, 2010, 31(10), 1949-1956.
[http://dx.doi.org/10.1016/j.peptides.2010.06.020] [PMID: 20600423]
[17]
Verlackt, C.C.W.; Van Boxem, W.; Dewaele, D.; Lemière, F.; Sobott, F.; Benedikt, J.; Neyts, E.C.; Bogaerts, A. Mechanisms of Peptide Oxidation by Hydroxyl Radicals: Insight at the Molecular Scale. J. Phys. Chem. C, 2017, 121, 5787-5799.
[http://dx.doi.org/10.1021/acs.jpcc.6b12278]
[18]
Moerlein, S.M.; Welch, M.J. The chemistry of gallium and indium as related to radiopharmaceutical production. Int. J. Nucl. Med. Biol., 1981, 8(4), 277-287.
[http://dx.doi.org/10.1016/0047-0740(81)90034-6] [PMID: 6460006]
[19]
Clarke, E.T.; Martell, A.E. Stabilities of trivalent metal ion complexes of the tetraacetate derivatives of 12-, 13- and 14-membered tetraazamacrocycles. Inorg. Chim. Acta, 1991, 190, 37-46.
[http://dx.doi.org/10.1016/S0020-1693(00)80229-7]
[20]
Wang, X.; Jin, T.; Comblin, V.; Lopez-Mut, A.; Merciny, E.; Desreux, J.F. A Kinetic investigation of the lanthanide dota chelates. stability and rates of formation and of dissociation of a macrocyclic gadolinium (III) polyaza polycarboxylic MRI contrast agent. Inorg. Chem., 1992, 31, 1095-1099.
[http://dx.doi.org/10.1021/ic00032a034]
[21]
Viola-Villegas, N.; Doyle, R.P. The coordination chemistry of 1,4,7,10-tetraazacyclododecane-N, N′,N”,N”’-tetraacetic acid (H4DOTA): Structural overview and analyses on structure–stability relationships. Coord. Chem. Rev., 2009, 253, 1906-1925.
[http://dx.doi.org/10.1016/j.ccr.2009.03.013]
[22]
Choe, E.; Min, D.B. Mechanisms of Antioxidants in the Oxidation of Foods. Compr. Rev. Food Sci. Food Saf., 2009, 8, 345-358.
[http://dx.doi.org/10.1111/j.1541-4337.2009.00085.x]
[23]
Amorati, R.; Pedulli, G.F.; Cabrini, L.; Zambonin, L.; Landi, L. Solvent and pH effects on the antioxidant activity of caffeic and other phenolic acids. J. Agric. Food Chem., 2006, 54(8), 2932-2937.
[http://dx.doi.org/10.1021/jf053159+] [PMID: 16608211]
[24]
Erdemgil, F.Z.; Sanli, S.; Sanli, N.; Özkan, G.; Barbosa, J.; Guiteras, J.; Beltrán, J.L. Determination of pK(a) values of some hydroxylated benzoic acids in methanol-water binary mixtures by LC methodology and potentiometry. Talanta, 2007, 72(2), 489-496.
[http://dx.doi.org/10.1016/j.talanta.2006.11.007] [PMID: 19071645]
[25]
Sazou, D.; Papadopoulos, N. The electrochemical oxidation of 2,5-dihydroxybenzoic acid on a mercury electrode in aqueous solutions. Can. J. Chem., 1986, 64, 11-14.
[http://dx.doi.org/10.1139/v86-003]
[26]
Taylor, A.J.; Clydesdale, F.M. Potential of oxidised phenolics as food colourants. Food Chem., 1987, 24, 301-313.
[http://dx.doi.org/10.1016/0308-8146(87)90105-1]
[27]
Robards, K.; Prenzler, P.D.; Tucker, G.; Swatsitang, P.; Glover, W. Phenolic compounds and their role in oxidative processes in fruits. Food Chem., 1999, 66, 401-436.
[http://dx.doi.org/10.1016/S0308-8146(99)00093-X]
[28]
Serra, H.M.; Cafaro, T.A. Ascorbic acid: from chemistry to its crucial protective role in the eye. Acta Bioquim. Clin. Latinoam., 2007, 41, 525-532.
[29]
Kramarenko, G.G.; Hummel, S.G.; Martin, S.M.; Buettner, G.R. Ascorbate reacts with singlet oxygen to produce hydrogen peroxide. Photochem. Photobiol., 2006, 82(6), 1634-1637.
[http://dx.doi.org/10.1111/j.1751-1097.2006.tb09823.x] [PMID: 16898858]
[30]
Li, S.; Schöneich, C.; Wilson, G.S.; Borchardt, R.T. Chemical pathways of peptide degradation. V. Ascorbic acid promotes rather than inhibits the oxidation of methionine to methionine sulfoxide in small model peptides. Pharm. Res., 1993, 10(11), 1572-1579.
[http://dx.doi.org/10.1023/A:1018960300769] [PMID: 8290469]
[31]
Li, S.; Schöneich, C.; Borchardt, R.T. Chemical pathways of peptide degradation. VIII. Oxidation of methionine in small model peptides by prooxidant/transition metal ion systems: influence of selective scavengers for reactive oxygen intermediates. Pharm. Res., 1995, 12(3), 348-355.
[http://dx.doi.org/10.1023/A:1016240115675] [PMID: 7617519]
[32]
Joshi, R.; Gangabhagirathi, R.; Venu, S.; Adhikari, S.; Mukherjee, T. Antioxidant activity and free radical scavenging reactions of gentisic acid: in-vitro and pulse radiolysis studies. Free Radic. Res., 2012, 46(1), 11-20.
[http://dx.doi.org/10.3109/10715762.2011.633518] [PMID: 22023109]
[33]
LaVerne, J.A. OH radicals and oxidizing products in the gamma radiolysis of water Radiat. Res., 2000, 153(2), 200.
[http://dx.doi.org/10.1667/0033- 7587(2000)153[0196:ORAOPI]2.0.CO;2] [PMID: 10629619]
[34]
Le Caër, S. Water radiolysis: influence of oxide surfaces on H2 production under ionizing radiation. Water, 2011, 3, 235-253.
[http://dx.doi.org/10.3390/w3010235]
[35]
Fawdry, R.M. Radiolysis of 2-[18F]fluoro-2-deoxy-D-glucose (FDG) and the role of reductant stabilisers. Appl. Radiat. Isot., 2007, 65(11), 1193-1201.
[http://dx.doi.org/10.1016/j.apradiso.2007.05.011] [PMID: 17669662]

Rights & Permissions Print Cite
Article Metrics
11
3
© 2024 Bentham Science Publishers | Privacy Policy