Skip to main content
SpringerLink
Log in

Preclinical evaluation of isostructural Tc-99m- and Re-188-folate-Gly-Gly-Cys-Glu for folate receptor-positive tumor targeting

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

Abstract

Objective

The purpose of the present study was to prepare isostructural Tc-99m- and Re-188-folate-Gly-Gly-Cys-Glu (folate-GGCE), and to evaluate the feasibility of their use for folate receptor (FR)-targeted molecular imaging and as theranostic agents in a mouse tumor model.

Methods

Folate-GGCE was synthesized using solid-phase peptide synthesis and radiolabeled with Tc-99m or Re-188. Radiochemical characterization was performed by radio-high-performance liquid chromatography. The biodistribution of Tc-99m-folate-GGCE was studied, with or without co-injection of excess free folate, in mice bearing both FR-positive (KB cell) and FR-negative (HT1080 cell) tumors. Biodistribution of Re-188-folate-GGCE was studied in mice bearing KB tumors. Serial planar scintigraphy was performed in the dual tumor mouse model after intravenous injection of Tc-99m-folate-GGCE. Serial micro-single photon emission computed tomography/computed tomography (SPECT/CT) studies were performed, with or without co-injection of excess free folate, in the mouse tumor model after injection of Tc-99m-folate-GGCE or Re-188-folate-GGCE.

Results

The radiolabeling efficiency and radiochemical stability of Tc-99m- and Re-188-folate-GGCE were more than 95 % for up to 4 h after radiolabeling. Uptake of Tc-99m-folate-GGCE at 1, 2, and 4 h after injection in KB tumor was 16.4, 23.2, and 17.6 % injected dose per gram (%ID/g), respectively. This uptake was suppressed by 97.4 % when excess free folate was co-administered. Tumor:normal organ ratios at 4 h for blood, liver, lung, muscle, and kidney were 54.3, 25.2, 38.3, 97.8, and 0.3, respectively. Tumor uptake of Re-188-folate-GGCE at 2, 4, 8, and 16 h after injection was 17.4, 21.7, 24.1, and 15.6 %ID/g, respectively. Tumor:normal organ ratios at 8 h for blood, liver, lung, muscle, and kidney were 126.8, 21.9, 54.8, 80.3, and 0.4, respectively. KB tumors were clearly visualized at a high intensity using serial scintigraphy and micro-SPECT/CT in mice injected with Tc-99m- or Re-188-folate-GGCE. The tumor uptake of these molecules was completely suppressed when excess free folate was co-administered.

Conclusion

Isostructural Tc-99m- and Re-188-folate-GGCE showed high and FR-specific uptake by tumors and generally favorable tumor:normal organ ratios. The tumor targeting capabilities of Tc-99m- and Re-188-folate-GGCE were clearly evident on serial imaging studies. This isostructural pair may have potential diagnostic and theranostic applications for FR-positive tumors.

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
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Salazar MDA, Ratnam M. The folate receptor: what does it promise in tissue-targeted therapeutics? Cancer Metastasis Rev. 2007;26:141–52.

    Article  CAS  PubMed  Google Scholar 

  2. Parker N, Turk MJ, Westrick E, Lewis JD, Low PS, Leamon CP. Folate receptor expression in carcinomas and normal tissues determined by a quantitative radioligand binding assay. Anal Biochem. 2005;338:284–93.

    Article  CAS  PubMed  Google Scholar 

  3. Müller C, Schibli R. Prospects in folate receptor-targeted radionuclide therapy. Front Oncol. 2013;3:249.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Hilgenbrink AR, Low PS. Folate receptor-mediated drug targeting: from therapeutics to diagnostics. J Pharm Sci. 2005;94:2135–46.

    Article  CAS  PubMed  Google Scholar 

  5. Krall N, Scheuermann J, Neri D. Small targeted cytotoxics: current state and promises from DNA-encoded chemical libraries. Angew Chem Int Ed Engl. 2013;52:1384–402.

    Article  CAS  PubMed  Google Scholar 

  6. Muller C. Folate based radiopharmaceuticals for imaging and therapy of cancer and inflammation. Curr Pharm Des. 2012;18:1058–83.

    Article  CAS  PubMed  Google Scholar 

  7. Muller C, Struthers H, Winiger C, Zhernosekov K, Schibli R. DOTA conjugate with an albumin-binding entity enables the first folic acid-targeted 177Lu-radionuclide tumor therapy in mice. J Nucl Med. 2013;54:124–31.

    Article  CAS  PubMed  Google Scholar 

  8. Muller C, Reber J, Haller S, Dorrer H, Bernhardt P, Zhernosekov K, et al. Direct in vitro and in vivo comparison of Tb-161 and Lu-177 using a tumour-targeting folate conjugate. Eur J Nucl Med Mol Imaging. 2014;41:476–85.

    Article  CAS  PubMed  Google Scholar 

  9. Leamon CP, Parker MA, Vlahov IR, Xu LC, Reddy JA, Vetzel M, et al. Synthesis and biological evaluation of EC20: a new folate-derived, (99m)Tc-based radiopharmaceutical. Bioconjug Chem. 2002;13:1200–10.

    Article  CAS  PubMed  Google Scholar 

  10. Reddy JA, Xu LC, Parker N, Vetzel M, Leamon CP. Preclinical evaluation of (99m)Tc-EC20 for imaging folate receptor-positive tumors. J Nucl Med. 2004;45:857–66.

    CAS  PubMed  Google Scholar 

  11. Kim MH, Kim WH, Kim CG, Kim DW. Synthesis and evaluation of (99m)Tc-labeled folate-tripeptide conjugate as a folate receptor-targeted imaging agent in a tumor-bearing mouse model. Nucl Med Mol Imaging. 2015;49:200–7.

    Article  CAS  PubMed  Google Scholar 

  12. Yamada Y, Nakatani H, Yanaihara H, Omote M. Phase I clinical trial of (99m)Tc-etarfolatide, an imaging agent for folate receptor in healthy Japanese adults. Ann Nucl Med. 2015;29:792–8.

    Article  CAS  PubMed  Google Scholar 

  13. Morris RT, Joyrich RN, Naumann RW, Shah NP, Maurer AH, Strauss HW, et al. Phase II study of treatment of advanced ovarian cancer with folate-receptor-targeted therapeutic (vintafolide) and companion SPECT-based imaging agent (99mTc-etarfolatide). Ann Oncol. 2014;25:852–8.

    Article  CAS  PubMed  Google Scholar 

  14. Muller C, Reddy JA, Leamon CP, Schibli R. Effects of the antifolates pemetrexed and CB3717 on the tissue distribution of (99m)Tc-EC20 in xenografted and syngeneic tumor-bearing mice. Mol Pharm. 2010;7:597–604.

    Article  PubMed  Google Scholar 

  15. Vegt E, de Jong M, Wetzels JF, Masereeuw R, Melis M, Oyen WJ, et al. Renal toxicity of radiolabeled peptides and antibody fragments: mechanisms, impact on radionuclide therapy, and strategies for prevention. J Nucl Med. 2010;51:1049–58.

    Article  CAS  PubMed  Google Scholar 

  16. Muller C, Mindt TL, de Jong M, Schibli R. Evaluation of a novel radiofolate in tumour-bearing mice: promising prospects for folate-based radionuclide therapy. Eur J Nucl Med Mol Imaging. 2009;36:938–46.

    Article  PubMed  Google Scholar 

  17. Müller C, Schubiger PA, Schibli R. Isostructural folate conjugates radiolabeled with the matched pair 99mTc/188Re: a potential strategy for diagnosis and therapy of folate receptor-positive tumors. Nucl Med Biol. 2007;34:595–601.

    Article  PubMed  Google Scholar 

  18. Muller C, Hohn A, Schubiger PA, Schibli R. Preclinical evaluation of novel organometallic 99mTc-folate and 99mTc-pteroate radiotracers for folate receptor-positive tumour targeting. Eur J Nucl Med Mol Imaging. 2006;33:1007–16.

    Article  PubMed  Google Scholar 

  19. Muller C, Forrer F, Schibli R, Krenning EP, de Jong M. SPECT study of folate receptor-positive malignant and normal tissues in mice using a novel 99mTc-radiofolate. J Nucl Med. 2008;49:310–7.

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

This study was supported by Wonkwang University in 2014.

Author information

Authors and Affiliations

  1. Department of Nuclear Medicine, Seoul National University Hospital, Seoul, Republic of Korea

    Woo Hyoung Kim & Keon Wook Kang

  2. Department of Nuclear Medicine, Institute of Wonkwang Medical Science, Wonkwang University School of Medicine, 895 Moowangro, Iksan, 54538, Republic of Korea

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

  3. Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea

    Cho Rong Park, Ji Yong Park, Yun-Sang Lee, Hyewon Youn, Keon Wook Kang, Jae Min Jeong & June-Key Chung

  4. Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, and College of Medicine or College of Pharmacy, Seoul National University, Seoul, Republic of Korea

    Yun-Sang Lee

  5. Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea

    Hyewon Youn, Keon Wook Kang & June-Key Chung

  6. Tumor Microenvironment Global Core Research Center, Seoul National University, Seoul, Republic of Korea

    Hyewon Youn & June-Key Chung

  7. Cancer Imaging Center, Seoul National University Hospital, Seoul, Republic of Korea

    Hyewon Youn

  8. Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea

    Keon Wook Kang & June-Key Chung

Authors
  1. Woo Hyoung Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Chang Guhn 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. Dae-Weung Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Cho Rong Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ji Yong Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yun-Sang Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Hyewon Youn
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Keon Wook Kang
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Jae Min Jeong
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. June-Key Chung
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Chang Guhn Kim.

Ethics declarations

Conflict of interest

No potential conflicts of interest were disclosed.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (TIFF 668 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kim, W.H., Kim, C.G., Kim, M.H. et al. Preclinical evaluation of isostructural Tc-99m- and Re-188-folate-Gly-Gly-Cys-Glu for folate receptor-positive tumor targeting. Ann Nucl Med 30, 369–379 (2016). https://doi.org/10.1007/s12149-016-1072-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12149-016-1072-0

Keywords

Search

Navigation