Skip to main content

Advertisement

SpringerLink
Log in

Synthesis and evaluation of Tc-99m DTPA–glutathione as a non-invasive tumor imaging agent in a mouse colon cancer model

  • Original Article
  • Published:
Annals of Nuclear Medicine Aims and scope Submit manuscript

Abstract

Purpose

Glutathione (GSH) plays a critical role in detoxification reactions by reducing the levels of reactive oxygen species in cancer cells. This study aimed to develop technetium (Tc)-99m diethylenetriaminepentaacetic acid (DTPA)–GSH as a tumor imaging agent, and to evaluate the diagnostic performance of Tc-99m DTPA–GSH in terms of its ability to differentiate tumors from inflammatory lesions.

Methods

DTPA–GSH was synthesized by reaction of GSH with DTPA anhydride under anhydrous conditions in a nitrogen atmosphere. DTPA–GSH was then reacted with Tc-99m sodium pertechnetate in a tin (II) chloride (SnCl2) solution. Gamma camera imaging was performed after intravenous injection of Tc-99m DTPA–GSH into a mouse CT-26 colon cancer model, or a mouse model of inflammation induced by the intramuscular injection of Freund’s complete adjuvant.

Results

DTPA–GSH was successfully prepared via a straightforward synthetic procedure and radiolabeled with Tc-99m at a high labeling efficiency (>95 %). Tc-99m DTPA–GSH was strongly internalized by tumors in colon cancer model mice, with the tumor-to-normal muscle ratio of the complex reaching 4.3 ± 0.9 at 4 h. By contrast, Tc-99m DTPA–GSH showed relatively weak uptake in inflammatory lesions (target-to-non-target ratio = 2.0 ± 0.3 at 4 h). A competition study showed that the uptake of Tc-99m DTPA–GSH into tumors was blocked by co-injection with high concentrations of free GSH.

Conclusions

The results of this work indicate that Tc-99m DTPA–GSH is a good candidate for development as a non-invasive tumor imaging agent. Furthermore, Tc-99m DTPA–GSH effectively distinguished between cancerous tissue and inflammatory lesions.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Endo K, Oriuchi N, Higuchi T, Iida Y, Hanaoka H, Miyakubo M, et al. PET and PET/CT using 18F-FDG in the diagnosis and management of cancer patients. Int J Clin Oncol. 2006;11:286–96.

    Article  PubMed  Google Scholar 

  2. Kim DW, Park SA, Kim CG. Dual-time-point positron emission tomography findings of benign mediastinal fluorine-18-fluorodeoxyglucose uptake in tuberculosis-endemic region. Indian J Nucl Med. 2011;26:3–6.

    PubMed Central  PubMed  Google Scholar 

  3. Takamochi K, Yoshida J, Murakami K, Niho S, Ishii G, Nishimura M, et al. Pitfalls in lymph node staging with positron emission tomography in non-small cell lung cancer patients. Lung Cancer. 2005;47:235–42.

    Article  PubMed  Google Scholar 

  4. Kubota R, Kubota K, Yamada S, Tada M, Ido T, Tamahashi N. Microautoradiographic study for the differentiation of intratumoral macrophages, granulation tissues and cancer cells by the dynamics of fluorine-18-fluorodeoxyglucose uptake. J Nucl Med. 1994;35:104–12.

    CAS  PubMed  Google Scholar 

  5. Pelicano H, Carney D, Huang P. ROS stress in cancer cells and therapeutic implications. Drug Resist Updat. 2004;7:97–110.

    Article  CAS  PubMed  Google Scholar 

  6. Estrela JM, Ortega A, Obrador E. Glutathione in cancer biology and therapy. Crit Rev Clin Lab Sci. 2006;43:143–81.

    Article  CAS  PubMed  Google Scholar 

  7. Cook JA, Gius D, Wink DA, Krishna MC, Russo A, Mitchell JB. Oxidative stress, redox, and the tumor microenvironment. Semin Radiat Oncol. 2004;14:259–66.

    Article  PubMed  Google Scholar 

  8. Zhang K, Wong KP. Active transport of glutathione S-conjugate in human colon adenocarcinoma cells. Cancer Lett. 1996;108:143–51.

    Article  CAS  PubMed  Google Scholar 

  9. Ortega AL, Carretero J, Obrador E, Gambini J, Asensi M, Rodilla V, et al. Tumor cytotoxicity by endothelial cells. Impairment of the mitochondrial system for glutathione uptake in mouse B16 melanoma cells that survive after in vitro interaction with the hepatic sinusoidal endothelium. J Biol Chem. 2003;278:13888–97.

    Article  CAS  PubMed  Google Scholar 

  10. Ortega AL, Mena S, Estrela JM. Oxidative and nitrosative stress in the metastatic microenvironment. Cancers (Basel). 2010;2:274–304.

    Article  CAS  Google Scholar 

  11. Chen G, Izzo J, Demizu Y, Wang F, Guha S, Wu X, et al. Different redox states in malignant and nonmalignant esophageal epithelial cells and differential cytotoxic responses to bile acid and honokiol. Antioxid Redox Signal. 2009;11:1083–95.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  12. Baba K, Moretti JL, Weinmann P, Senekowitsch-Schmidtke R, Ercan MT. Tc-Glutathione Complex (Tc-GSH): labelling, chemical characterization and biodistribution in rats. Met Based Drugs. 1999;6:329–36.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  13. Caglar M, Ciftci I, Hosal S, Kilinc K, Ercan MT. Detection of head and neck cancer with 99Tc(m) glutathione: a correlative study with tissue glutathione and glutathione S-transferase levels. Nucl Med Commun. 2001;22:33–8.

    Article  CAS  PubMed  Google Scholar 

  14. Ercan MT, Senekowitsch-Schmidtke R, Bernatz S. Biodistribution of 99mTc-glutathione in mice with osteosarcoma: effect of gamma irradiation on tumour uptake. Res Exp Med (Berl). 2000;199:359–67.

    Article  CAS  Google Scholar 

  15. Valko M, Rhodes CJ, Moncol J, Izakovic M, Mazur M. Free radicals, metals and antioxidants in oxidative stress-induced cancer. Chem Biol Interact. 2006;160:1–40.

    Article  CAS  PubMed  Google Scholar 

  16. Valko M, Leibfritz D, Moncol J, Cronin MT, Mazur M, Telser J. Free radicals and antioxidants in normal physiological functions and human disease. Int J Biochem Cell Biol. 2007;39:44–84.

    Article  CAS  PubMed  Google Scholar 

  17. Ma YC, Zuo L, Zhang CL, Wang M, Wang RF, Wang HY. Comparison of 99mTc-DTPA renal dynamic imaging with modified MDRD equation for glomerular filtration rate estimation in Chinese patients in different stages of chronic kidney disease. Nephrol Dial Transplant. 2007;22:417–23.

    Article  PubMed  Google Scholar 

  18. van Waarde A, Jager PL, Ishiwata K, Dierckx RA, Elsinga PH. Comparison of sigma-ligands and metabolic PET tracers for differentiating tumor from inflammation. J Nucl Med. 2006;47:150–4.

    PubMed  Google Scholar 

  19. Sugae S, Suzuki A, Takahashi N, Minamimoto R, Cheng C, Theeraladanon C, et al. Fluorine-18-labeled 5-fluorouracil is a useful radiotracer for differentiation of malignant tumors from inflammatory lesions. Ann Nucl Med. 2008;22:65–72.

    Article  PubMed  Google Scholar 

  20. Min JJ, Biswal S, Deroose C, Gambhir SS. Tetraphenylphosphonium as a novel molecular probe for imaging tumors. J Nucl Med. 2004;45:636–43.

    CAS  PubMed  Google Scholar 

  21. Karihtala P, Soini Y. Reactive oxygen species and antioxidant mechanisms in human tissues and their relation to malignancies. APMIS. 2007;115:81–103.

    Article  CAS  PubMed  Google Scholar 

  22. Awasthi S, Singhal SS, Awasthi YC, Martin B, Woo JH, Cunningham CC, et al. RLIP76 and cancer. Clin Cancer Res. 2008;14:4372–7.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

Download references

Acknowledgments

This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (2013R1A1A2059262).

Author information

Authors and Affiliations

  1. Department of Nuclear Medicine and Institute of Wonkwang Medical Science, Wonkwang University School of Medicine, Iksan, Korea

    Dae-Weung Kim, Woo Hyoung Kim, Myoung Hyoun Kim & Chang Guhn Kim

  2. Research Unit of Molecular Imaging Agent (RUMIA), Wonkwang University School of Medicine, Iksan, Jeollabuk-do, Korea

    Dae-Weung Kim

  3. Department of Experimental Diagnostic Imaging, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA

    Chang-Sok Oh

  4. Department of Nuclear Medicine, Chonnam National University Hwasun Hospital, Hwasun, Korea

    Jung-Joon Min

Authors
  1. Dae-Weung Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Woo Hyoung Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Myoung Hyoun Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Chang Guhn Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Chang-Sok Oh
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jung-Joon Min
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jung-Joon Min.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kim, DW., Kim, W.H., Kim, M.H. et al. Synthesis and evaluation of Tc-99m DTPA–glutathione as a non-invasive tumor imaging agent in a mouse colon cancer model. Ann Nucl Med 28, 447–454 (2014). https://doi.org/10.1007/s12149-014-0835-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12149-014-0835-8

Keywords

Search

Navigation