Radiolabeled methotrexate as a diagnostic agent of inflammatory target sites: A proof-of-concept study

Papachristou,Maria; Kastis,George A.; Stavrou,Petros  Z.; Xanthopoulos,Stavros; Furenlid,Lars  R.; Datseris,Ioannis  E.; Bouziotis,Penelope

doi:10.3892/mmr.2017.8166

February-2018 Volume 17 Issue 2

Full Size Image

Journals

International Journal of Molecular Medicine

International Journal of Molecular Medicine is an international journal devoted to molecular mechanisms of human disease.

International Journal of Oncology

International Journal of Oncology is an international journal devoted to oncology research and cancer treatment.

Molecular Medicine Reports

Covers molecular medicine topics such as pharmacology, pathology, genetics, neuroscience, infectious diseases, molecular cardiology, and molecular surgery.

Oncology Reports

Oncology Reports is an international journal devoted to fundamental and applied research in Oncology.

Experimental and Therapeutic Medicine

Experimental and Therapeutic Medicine is an international journal devoted to laboratory and clinical medicine.

Oncology Letters

Oncology Letters is an international journal devoted to Experimental and Clinical Oncology.

Biomedical Reports

Explores a wide range of biological and medical fields, including pharmacology, genetics, microbiology, neuroscience, and molecular cardiology.

Molecular and Clinical Oncology

International journal addressing all aspects of oncology research, from tumorigenesis and oncogenes to chemotherapy and metastasis.

World Academy of Sciences Journal

Multidisciplinary open-access journal spanning biochemistry, genetics, neuroscience, environmental health, and synthetic biology.

International Journal of Functional Nutrition

Open-access journal combining biochemistry, pharmacology, immunology, and genetics to advance health through functional nutrition.

International Journal of Epigenetics

Publishes open-access research on using epigenetics to advance understanding and treatment of human disease.

Medicine International

An International Open Access Journal Devoted to General Medicine.

February-2018 Volume 17 Issue 2

Full Size Image

Article Open Access

Radiolabeled methotrexate as a diagnostic agent of inflammatory target sites: A proof-of-concept study

Authors:
- Maria Papachristou
- George A. Kastis
- Petros Z. Stavrou
- Stavros Xanthopoulos
- Lars R. Furenlid
- Ioannis E. Datseris
- Penelope Bouziotis
View Affiliations / Copyright

Affiliations: Department of Nuclear Medicine‑PET/CT, General Hospital of Athens ‘Evaggelismos’, 10676 Athens, Greece, Research Center of Mathematics, Academy of Athens, 11527 Athens, Greece, Institute for Nuclear and Radiological Sciences and Technology, Energy and Safety, National Center for Scientific Research ‘Demokritos’, 15310 Athens, Greece, Center for Gamma‑Ray Imaging, Department of Medical Imaging, University of Arizona, Tucson, AZ 85724, USA

Copyright: © Papachristou et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
Pages: 2442-2448
|
Published online on: November 27, 2017

https://doi.org/10.3892/mmr.2017.8166
Expand metrics +

Abstract

Methotrexate (MTX), as a pharmaceutical, is frequently used in tumor chemotherapy and is also a part of the established treatment of a number of autoimmune inflammatory disorders. Radiolabeled MTX has been studied as a tumor‑diagnostic agent in a number of published studies. In the present study, the potential use of technetium‑99m‑labelled MTX (99mTc‑MTX) as a radiotracer was investigated for the identification of inflammatory target sites. The labelling of MTX was carried out via a 99mTc‑gluconate precursor. Evaluation studies included in vitro stability, plasma protein binding assessment, partition‑coefficient estimation, in vivo scintigraphic imaging and ex vivo animal experiments in an animal inflammation model. MTX was successfully labelled with 99mTc, with a radiochemical purity of >95%. Stability was assessed in plasma, where it remained intact up to 85% at 4 h post‑incubation, while protein binding of the radiotracer was observed to be ~50% at 4 h. These preclinical ex vivo and in vivo studies indicated that 99mTc‑MTX accumulates in inflamed tissue, as well as in the spinal cord, joints and bones; all areas with relatively high remodeling activity. The results are promising, and set the stage for further work on the development and application of 99mTc‑MTX as a radiotracer for inflammation associated with rheumatoid arthritis.

View Figures

View References

1	Rang HP, Dale MM, Ritter JM, Flower RH and Henderson G: Anticancer drugsPharmacology. 7th. Rang HP and Dale MM: Churchill Livingstone Elsevier; London: pp. 673–688. 2011
2	Weinblatt ME: Methotrexate in rheumatoid arthritis: A quarter century of development. Trans Am Clin Climatol Assoc. 124:16–25. 2013.PubMed/NCBI
3	Chan ES and Cronstein BN: Mechanisms of action of methotrexate. Bull Hosp Jt Dis. 71 Suppl 1:S5–S8. 2013.
4	Cutolo M, Sulli A, Pizzorni C, Seriolo B and Straub RH: Anti-inflammatory mechanisms of methotrexate in rheumatoid arthritis. Ann Rheum Dis. 60:729–735. 2001. View Article : Google Scholar : PubMed/NCBI
5	Tian H and Cronstein BN: Understanding the mechanisms of action of methotrexate: Implications for the treatment of rheumatoid arthritis. Bull NYU Hosp Jt Dis. 65:168–173. 2007.PubMed/NCBI
6	Wessels JA, Huizinga TW and Guchelaar HJ: Recent insights in the pharmacological actions of methotrexate in the treatment of rheumatoid arthritis. Rheumatology (Oxford). 47:249–255. 2008. View Article : Google Scholar : PubMed/NCBI
7	Dar UK, Khan IU, Javed M, Ahmad F, Ali M and Hyder SW: Preparation and biodistribution in mice of a new radiopharmaceutical-technetium-99m labeled methotrexate, as a tumor diagnostic agent. Hell J Nucl Med. 15:120–124. 2012.PubMed/NCBI
8	Rasheed R, Javed M, Ahmad F, Sohail A, Murad S, Masood M and Rasheed S and Rasheed S: Preparation of (99m)Tc-labelled methotraxate by a direct labeling technique as a potential diagnostic agent for breast cancer and preliminary clinical results. Hell J Nucl Med. 16:33–37. 2013.PubMed/NCBI
9	Ozgenc E, Ekinci M, Ilem-Ozdemir D, Gundoglu E and Asikoglu M: Radiolabeling and in vitro evaluation of 99mTc-methotrexate on breast cancer cell line. J Radioanal Nucl Chem. 307:627–633. 2016. View Article : Google Scholar
10	Okarvi SM and Jammaz IA: Preparation and in vitro and in vivo evaluation of technetium-99m-labeled folate and methotrexate conjugates as tumor imaging agents. Cancer Biother Radiopharm. 21:49–60. 2006. View Article : Google Scholar : PubMed/NCBI
11	Mirzaei A, Jalilian AR, Akhlaghi M and Beiki D: Production of 68Ga-citrate based on a SnO2 generator for short-term turpentine oil-induced inflammation imaging in rats. Curr Radiopharm. 9:208–214. 2016. View Article : Google Scholar : PubMed/NCBI
12	Rivera S and Ganz T: Animal models of anemia of inflammation. Semin Hematol. 46:351–357. 2009. View Article : Google Scholar : PubMed/NCBI
13	Furenlid LR, Wilson DW, Chen YC, Kim H, Pietraski PJ, Crawford MJ and Barrett HH: FastSPECT II: A second-generation high-resolution dynamic SPECT imager. IEEE Trans Nucl Sci. 51:631–635. 2004. View Article : Google Scholar : PubMed/NCBI
14	Furenlid LR, Chen YC and Kim H: SPECT Imager Design and Data-Acquisition SystemsSmall-Animal SPECT Imaging. Kupinski MA and Barrett HH: Springer US; Boston, MA: pp. 115S–138S. 2005, View Article : Google Scholar
15	Chen YC, Furenlid LR, Wilson DW and Barrett HH: Calibration of Scintillation Cameras and Pinhole SPECT Imaging SystemsSmall-Animal SPECT Imaging. Kupinski MA and Barrett HH: Springer US; Boston, MA: pp. 195–201. 2005, View Article : Google Scholar
16	Rasheed R, Gillani J, Jielani A, Irum F, Lodhi N and Rasheed S and Rasheed S: Tc99m methotrexate (MTX): A novel complex for imaging of rheumatoid arthritis (RA): First clinical trials. Gen Med (Los Angel) Personalized Medicine. S2132016.
17	Naidoo J, Cappelli LC, Forde PM, Marrone KA, Lipson EJ, Hammers HJ, Sharfman WH, Le DT, Baer AN, Shah AA, et al: Inflammatory arthritis: A newly recognized adverse event of immune checkpoint blockade. Oncologist. 22:627–630. 2017. View Article : Google Scholar : PubMed/NCBI
18	Cole LE, Vargo-Gogola T and Roeder RK: Targeted delivery to bone and mineral deposits using bisphosphonate ligands. Adv Drug Deliv Rev. 99:12–27. 2016. View Article : Google Scholar : PubMed/NCBI
19	Raichur V, Vemula KD, Bhadri N and Razdan R: Zolendronic acid-conjugated PLGA ultrasmall nanoparticle loaded with methotrexate as a supercarrier for bone-targeted drug delivery. AAPS PharmSciTech. 18:2227–2239. 2017. View Article : Google Scholar : PubMed/NCBI

Journals

International Journal of Molecular Medicine

International Journal of Oncology

Molecular Medicine Reports

Oncology Reports

Experimental and Therapeutic Medicine

Oncology Letters

Biomedical Reports

Molecular and Clinical Oncology

World Academy of Sciences Journal

International Journal of Functional Nutrition

International Journal of Epigenetics

Medicine International

Radiolabeled methotrexate as a diagnostic agent of inflammatory target sites: A proof-of-concept study

This article is mentioned in:

Abstract

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Related Articles