Pre-Study on Radiolabeling of Colistin with Lutetium-177 to Develop Theranostic Infection Agent

Merve Karpuz; Emre Özgenç; Evren Gündoğdu; Zeynep Burak

Pre-Study on Radiolabeling of Colistin with Lutetium-177 to Develop Theranostic Infection Agent

Abstract

Infection is one of the important burdens on the health care system, not only due to leading morbidity and mortality but also because of the development of antibiotic resistance. Although the infection can be diagnosed by imaging techniques, more effective agents including radiopharmaceuticals may be required to image deep-seated infections. Imaging also plays a critical role in the choosing of optimum treatment options and following treatment. Theranostic agents offer many advantages such as monitoring the biodistribution and targeting of therapeutic agents, as well as rapid diagnosis and treatment. Colistin, a cationic peptide, leads to bacterial death through interaction with lipopolysaccharides in the cell wall of bacteria. In our study, 177Lu as radionuclide part and colistimethate sodium (a prodrug of colistin, CMS) as pharmaceutic part were chosen to prepare a radiopharmaceutical for imaging and treatment of infections. 177Lu-CMS complex was formed under room condition, and radiolabeling efficiency was determined by paper and high-performance liquid chromatography. The effect of the filtration process on radiolabeling was evaluated among the labeling efficiencies of filtered and un-filtered complexes. The different incubation times (5, 30, and 60 min) effect on the radiolabeling process was also evaluated. Moreover, in vitro stability of 177Lu-CMS complex in saline solution was assessed during 7 days. According to the results, desired radiolabeling efficiency was not obtained under tested conditions and stability studies. Therefore, various modifications such as the addition of chelating agents or stabilizers in the radiolabeling procedure should be made to increase the radiolabeling stability. Further studies regarding radiolabeling are surely needed, and our studies are continuing.

Keywords

References

[1] Mathers C. Global Burden of Disease. In: Quah SR. (Ed). International Encyclopedia of Public Health (Second Edition). Academic Press, Oxford, 2017, pp.256-267. [CrossRef]
[2] Lieberman JM. Appropriate antibiotic use and why it is important: the challenges of bacterial resistance. Pediatr Infect Dis J. 2003; 22(12): 1143-1151. [CrossRef]
[3] Wu M, Shu J. Multimodal Molecular Imaging: Current Status and Future Directions. Contrast Media Mol Imaging. 2018; 2018: 1382183. [CrossRef]
[4] Kumar V, Boddeti DK. (68)Ga-radiopharmaceuticals for PET imaging of infection and inflammation. Recent Results Cancer Res. 2013; 194: 189-219. [CrossRef]
[5] Goldsmith SJ, Vallabhajosula S. Clinically proven radiopharmaceuticals for infection imaging: mechanisms and applications. Semin Nucl Med. 2009; 39(1): 2-10. [CrossRef]
[6] Chaturvedi S, Mishra AK. Small Molecule Radiopharmaceuticals - A Review of Current Approaches. Front Med (Lausanne). 2016; 3: 5. [CrossRef]
[7] Hughes DK. Nuclear medicine and infection detection: the relative effectiveness of imaging with 111In-oxine-, 99mTc-HMPAO-, and 99mTc-stannous fluoride colloid-labeled leukocytes and with 67Ga-citrate. J Nucl Med Technol. 2003; 31(4): 196-201. [CrossRef]
[8] Richter WS, Ivancevic V, Meller J, Lang O, Le Guludec D, Szilvazi I, et al. 99mTc-besilesomab (Scintimun) in peripheral osteomyelitis: comparison with 99mTc-labelled white blood cells. Eur J Nucl Med Mol Imaging. 2011; 38(5): 899-910. [CrossRef]

[9] Britton KE, Wareham DW, Das SS, Solanki KK, Amaral H, Bhatnagar A, Katamihardja AH, Malamitsi J, Moustafa HM, Soroa VE, Sundram FX, Padhy AK. Imaging bacterial infection with (99m)Tc-ciprofloxacin (Infection). J Clin Pathol. 2002; 55(11): 817-823. [CrossRef]
[10] Bleeker-Rovers CP, Vos FJ, Corstens FH, Oyen WJ. Imaging of infectious diseases using [18F] fluorodeoxyglucose PET. Q J Nucl Med Mol Imaging. 2008; 52(1): 17-29. [CrossRef]
[11] Nanni C, Errani C, Boriani L, Fantini L, Ambrosini V, Boschi S, Rubello D, Pettinato C, Mercuri M, Gasbarrini A, Fanti S. 68Ga-citrate PET/CT for evaluating patients with infections of the bone: preliminary results. J Nucl Med. 2010; 51(12): 1932-1936. [CrossRef]
[12] Kumar V, Boddeti DK, Evans SG, Roesch F, Howman-Giles R. Potential use of 68Ga-apo-transferrin as a PET imaging agent for detecting Staphylococcus aureus infection. Nucl Med Biol. 2011; 38(3): 393-398. [CrossRef]
[13] Karpuz M, Silindir-Gunay M, Ozer AY. Clinical Applications of Nanosized Drug-Delivery Systems in Lung Cancer Imaging and Therapy. Crit Rev Ther Drug Carrier Syst. 2020; 37(5): 435-471. [CrossRef]
[14] Das T, Pillai MR. Options to meet the future global demand of radionuclides for radionuclide therapy. Nucl Med Biol. 2013; 40(1): 23-32. [CrossRef]
[15] Michel RB, Andrews PM, Rosario AV, Goldenberg DM, Mattes MJ. 177Lu-antibody conjugates for single-cell kill of B-lymphoma cells in vitro and for therapy of micrometastases in vivo. Nucl Med Biol. 2005; 32(3): 269-278. [CrossRef]
[16] Das T, Banerjee S. Theranostic Applications of Lutetium-177 in Radionuclide Therapy. Curr Radiopharm. 2016; 9(1): 94-101. [CrossRef]
[17] Shahzad MA, Naqvi SAR, Rasheed R, Yameen M, Anjum F, Ahmed MT, Hussain Z, Gilliani SJH. Radiolabeling of benzylpenicillin with lutetium-177: Quality control and biodistribution study to develop theranostic infection imaging agent. Pak J Pharm Sci. 2017; 30(6): 2349-2354. [CrossRef]
[18] Akbar MU, Bokhari TH, Khalid M, Ahmad MR, Roohi S, Hina S, Mehmood S, Sohaib M, Jabbar T. Radiolabeling, quality control, and biological characterization of (177) Lu-labeled kanamycin. Chem Biol Drug Des. 2017; 90(3): 425-431. [CrossRef]
[19] Naqvi SAR, Rasheed R, Ahmed MT, Zahoor AF, Khalid M, Mahmood S. Radiosynthesis and preclinical studies of 177Lu-labeled sulfadiazine: a possible theranostic agent for deep-seated bacterial infection. J Radioanal Nucl Chem. 2017; 314(2): 1023-1029. [CrossRef]
[20] Bialvaei AZ, Samadi Kafil H. Colistin, mechanisms and prevalence of resistance. Curr Med Res Opin. 2015; 31(4): 707-721. [CrossRef]
[21] Falagas ME, Kasiakou SK. Colistin: the revival of polymyxins for the management of multidrug-resistant gram-negative bacterial infections. Clin Infect Dis. 2005; 40(9): 1333-1341. [CrossRef]
[22] Velikyan I. Prospective of (6)(8)Ga-radiopharmaceutical development. Theranostics. 2013; 4(1): 47-80. [CrossRef]
[23] Kunos CA, Rubinstein LV, Capala J, McDonald MA. Phase 0 Radiopharmaceutical-Agent Clinical Development. Front Oncol. 2020; 10: 1310. [CrossRef]
[24] Niece KL, Akers KS. Preliminary method for direct quantification of colistin methanesulfonate by attenuated total reflectance Fourier transform infrared spectroscopy. Antimicrob Agents Chemother. 2015; 59(9): 5542-5547. [CrossRef]
[25] Aerts J, Ballinger JR, Behe M, Decristoforo C, Elsinga PH, Faivre-Chauvet A, Mindt TL, Kolenc Peitl P, Todde SC, Koziorowski J; European Association of Nuclear Medicine. Guidance on current good radiopharmacy practice for the small-scale preparation of radiopharmaceuticals using automated modules: a European perspective. J Labelled Comp Radiopharm. 2014; 57(10): 615-620. [CrossRef]
[26] Breeman WA, De Jong M, Visser TJ, Erion JL, Krenning EP. Optimising conditions for radiolabelling of DOTA-peptides with 90Y, 111In and 177Lu at high specific activities. Eur J Nucl Med Mol Imaging. 2003; 30(6): 917-920. [CrossRef]
[27] Xu Q, Zhang S, Zhao Y, Feng Y, Liu L, Cai L, et al. Radiolabeling, quality control, biodistribution, and imaging studies of (177) Lu-ibandronate. J Labelled Comp Radiopharm. 2019; 62(1): 43-51. [CrossRef]
[28] Yousefnia H, Jalilian AR, Zolghadri S, Bahrami-Samani A, Shirvani-Arani S, Ghannadi-Maragheh M. Preparation and quality control of lutetium-177 bleomycin as a possible therapeutic agent. Nukleonika. 2010; 55(3): 285-291. [CrossRef]
[29] Banerjee S, Pillai MR, Knapp FF. Lutetium-177 therapeutic radiopharmaceuticals: Linking chemistry, radiochemistry, and practical applications. Chem Rev. 2015; 115(8): 2934-2374. [CrossRef]
[30] Yousefnia H, Jalilian AR, Zolghadri S, Bahrami-Samani A, Shirvani-Arani S, Ghannadi-Maragheh M. Preparation and quality control of (1)(7)(7)Lu-[tris(1,10-phenanthroline) lutetium(III)] complex for therapy. Nucl Med Rev Cent East Eur. 2010; 13(2): 49-54. [CrossRef]
[31] de Blois E, de Zanger RMS, Chan HS, Konijnenberg M, Breeman WAP. Radiochemical and analytical aspects of inter-institutional quality control measurements on radiopharmaceuticals. EJNMMI Radiopharm Chem. 2019; 4(1): 3. [CrossRef]
[32] Watanabe S, Hashimoto K, Ishioka NS. Lutetium-177 complexation of DOTA and DTPA in the presence of competing metals. J Radioanal Nucl Chem. 2015; 303(2): 1519-1521. [CrossRef]
[33] Kang CS, Chen Y, Lee H, Liu D, Sun X, Kweon J, Lewis MR, Chong H-S. Synthesis and evaluation of a new bifunctional NETA chelate for molecular targeted radiotherapy using(90)Y or(177)Lu. Nucl Med Biol. 2015; 42(3): 242-249. [CrossRef]
[34] Hu F, Cutler CS, Hoffman T, Sieckman G, Volkert WA, Jurisson SS. Pm-149 DOTA bombesin analogs for potential radiotherapy: in vivo comparison with Sm-153 and Lu-177 labeled DO3A-amide-βAla-BBN(7–14)NH2. Nucl Med Biol. 2002; 29(4): 423-430. [CrossRef]
[35] Beckford Vera DR, Eigner S, Henke KE, Lebeda O, Melichar F, Beran M. Preparation and preclinical evaluation of 177Lu-nimotuzumab targeting epidermal growth factor receptor overexpressing tumors. Nucl Med Biol. 2012; 39(1): 3-13. [CrossRef]
[36] Guleria M, Das T, Kumar C, Amirdhanayagam J, Sarma HD, Banerjee S. Preparation of clinical-scale (177) Lu-Rituximab: Optimization of protocols for conjugation, radiolabeling, and freeze-dried kit formulation. J Labelled Comp Radiopharm. 2017; 60(5): 234-241. [CrossRef]

Details

Primary Language

English

Subjects

Radiopharmacy

Journal Section

Research Article

Authors

Merve Karpuz ^*
0000-0001-6681-2448
Türkiye

Emre Özgenç
0000-0002-7586-8520
Türkiye

Evren Gündoğdu
0000-0003-2111-101X
Türkiye

Zeynep Burak
0000-0002-3187-9447
Türkiye

Publication Date

June 28, 2025

Submission Date

October 3, 2021

Acceptance Date

December 30, 2021

Published in Issue

Year 2022 Volume: 26 Number: 2

IZ

https://izlik.org/JA55DH32RZ

Cite

RIS / Bibtex

APA

Karpuz, M., Özgenç, E., Gündoğdu, E., & Burak, Z. (2025). Pre-Study on Radiolabeling of Colistin with Lutetium-177 to Develop Theranostic Infection Agent. Journal of Research in Pharmacy, 26(2), 397-407. https://izlik.org/JA55DH32RZ

AMA

1.Karpuz M, Özgenç E, Gündoğdu E, Burak Z. Pre-Study on Radiolabeling of Colistin with Lutetium-177 to Develop Theranostic Infection Agent. J. Res. Pharm. 2025;26(2):397-407. https://izlik.org/JA55DH32RZ

Chicago

Karpuz, Merve, Emre Özgenç, Evren Gündoğdu, and Zeynep Burak. 2025. “Pre-Study on Radiolabeling of Colistin With Lutetium-177 to Develop Theranostic Infection Agent”. Journal of Research in Pharmacy 26 (2): 397-407. https://izlik.org/JA55DH32RZ.

EndNote

Karpuz M, Özgenç E, Gündoğdu E, Burak Z (June 1, 2025) Pre-Study on Radiolabeling of Colistin with Lutetium-177 to Develop Theranostic Infection Agent. Journal of Research in Pharmacy 26 2 397–407.

IEEE

[1]M. Karpuz, E. Özgenç, E. Gündoğdu, and Z. Burak, “Pre-Study on Radiolabeling of Colistin with Lutetium-177 to Develop Theranostic Infection Agent”, J. Res. Pharm., vol. 26, no. 2, pp. 397–407, June 2025, [Online]. Available: https://izlik.org/JA55DH32RZ

ISNAD

Karpuz, Merve - Özgenç, Emre - Gündoğdu, Evren - Burak, Zeynep. “Pre-Study on Radiolabeling of Colistin With Lutetium-177 to Develop Theranostic Infection Agent”. Journal of Research in Pharmacy 26/2 (June 1, 2025): 397-407. https://izlik.org/JA55DH32RZ.

JAMA

1.Karpuz M, Özgenç E, Gündoğdu E, Burak Z. Pre-Study on Radiolabeling of Colistin with Lutetium-177 to Develop Theranostic Infection Agent. J. Res. Pharm. 2025;26:397–407.

MLA

Karpuz, Merve, et al. “Pre-Study on Radiolabeling of Colistin With Lutetium-177 to Develop Theranostic Infection Agent”. Journal of Research in Pharmacy, vol. 26, no. 2, June 2025, pp. 397-0, https://izlik.org/JA55DH32RZ.

Vancouver

1.Merve Karpuz, Emre Özgenç, Evren Gündoğdu, Zeynep Burak. Pre-Study on Radiolabeling of Colistin with Lutetium-177 to Develop Theranostic Infection Agent. J. Res. Pharm. [Internet]. 2025 Jun. 1;26(2):397-40. Available from: https://izlik.org/JA55DH32RZ