Skip to main content

Advertisement

SpringerLink
Log in

SPECT Imaging of Treatment-Related Tumor Necrosis Using Technetium-99m-Labeled Rhein

  • Research Article
  • Published:
Molecular Imaging and Biology Aims and scope Submit manuscript

Abstract

Purpose

Noninvasive imaging of treatment-induced necrosis is important to distinguish early responders from patients resistant to the treatment plan, enabling the tailored-made therapeutic intervention. The purpose of this study was to explore the feasibility of [99mTc]EDDA-HYNIC-2C-rhein for early assessment of tumor response to treatment.

Procedures

In vitro necrosis avidity of [99mTc]EDDA-HYNIC-2C-rhein was evaluated in human lung cancer A549 cells treated with hyperthermia. Single photon emission–computed tomography/X-ray-computed tomography (SPECT/CT) imaging was performed in rats bearing subcutaneous W256 tumor treated with combretastatin A-4 disodium phosphate (CA4P) and rats bearing orthotopic liver W256 tumor treated with a single microwave ablation. All rats were euthanized immediately after the imaging session for biodistribution and histology studies. The mechanism of necrosis avidity for the tracer was further explored by in vivo blocking experiment and in vitro histochemistry and fluorescence staining.

Results

The uptake of [99mTc]EDDA-HYNIC-2C-rhein in necrotic cells was significantly higher than that in viable cells (p < 0.05). SPECT/CT imaging showed that an obvious “hot spot” was observed in the CA4P-treated tumor while not in the control tumor at 5 h after tracer injection. Ex vivo γ-counting revealed that the uptake of [99mTc]EDDA-HYNIC-2C-rhein in tumor was increased 3.5-fold in rats treated with CA4P compared with rats treated with vehicle. Autoradiography and corresponding H&E staining suggested that the higher overall radiotracer uptake in the treated tumors was attributed to the increased necrosis. Blocking with unlabeled HYNIC-2C-rhein demonstrated the specific binding of the radiotracer to necrotic tissues. The perfect match of autoradiograph and histochemistry staining and PI fluorescence staining revealed that necrosis avidity of the tracer may be attributable to intercalation with exposed DNA in necrotic tissues.

Conclusion

[99mTc]EDDA-HYNIC-2C-rhein can image necrosis induced by anticancer therapy and holds potential for early assessment of treatment response.

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

Similar content being viewed by others

References

  1. Elvas F, Vangestel C, Pak K, Vermeulen P, Gray B, Stroobants S, Staelens S, Wyffels L (2016) Early prediction of tumor response to treatment: preclinical validation of 99mTc-duramycin. J Nucl Med 57:805–811

    Article  CAS  PubMed  Google Scholar 

  2. Elvas F, Boddaert J, Vangestel C, Pak K, Gray B, Kumar-Singh S, Staelens S, Stroobants S, Wyffels L (2017) 99mTc-Duramycin SPECT imaging of early tumor response to targeted therapy: a comparison with 18F-FDG PET. J Nucl Med 58:665–670

    Article  CAS  PubMed  Google Scholar 

  3. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J (2009) New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 45:228–247

    Article  CAS  Google Scholar 

  4. Wahl RL, Jacene H, Kasamon Y, Lodge MA (2009) From RECIST to PERCIST: evolving considerations for PET response criteria in solid tumors. J Nucl Med 50:122S–150S

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Weissleder R (2006) Molecular imaging in cancer. Science 312:1168–1171

    Article  CAS  Google Scholar 

  6. Chang JM, Lee HJ, Goo JM, Lee HY, Lee JJ, Chung JK, Im JG (2006) False positive and false negative FDG-PET scans in various thoracic diseases. Korean J Radiol 7:57–69

    Article  PubMed  PubMed Central  Google Scholar 

  7. Ben-Haim S, Ell P (2009) 18F-FDG PET and PET/CT in the evaluation of cancer treatment response. J Nucl Med 50:88–99

    Article  PubMed  Google Scholar 

  8. Siemann DW (2011) The unique characteristics of tumor vasculature and preclinical evidence for its selective disruption by tumor-vascular disrupting agents. Cancer Treat Rev 37:63–74

    Article  CAS  PubMed  Google Scholar 

  9. Pérez-Pérez MJ, Priego EM, Bueno O, Martins MS, Canela MD, Liekens S (2016) Blocking blood flow to solid tumors by destabilizing tubulin: an approach to targeting tumor growth. J Med Chem 59:8685–8711

    Article  CAS  PubMed  Google Scholar 

  10. Siemann DW, Chaplin DJ, Walicke PA (2009) A review and update of the current status of the vasculature-disabling agent combretastatin-A4 phosphate (CA4P). Expert Opin Investig Drugs 18:189–197

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Jaroch K, Karolak M, Górski P, Jaroch A, Krajewski A, Ilnicka A, Sloderbach A, Stefański T, Sobiak S (2016) Combretastatins: in vitro structure-activity relationship, mode of action and current clinical status. Pharmacol Rep 68:1266–1275

    Article  CAS  PubMed  Google Scholar 

  12. Pisetsky DS, Fairhurst AM (2007) The origin of extracellular DNA during the clearance of dead and dying cells. Autoimmunity 40:281–284

    Article  CAS  PubMed  Google Scholar 

  13. Vlassov VV, Laktionov PP, Rykova EY (2007) Extracellular nucleic acids. Bioessays 29:654–667

    Article  CAS  PubMed  Google Scholar 

  14. Luo Q, Jin Q, Su C et al (2016) Radiolabeled rhein as novel small-molecule necrosis avid agents for rapid imaging of necrotic myocardium. Anal Chem 89:1260–1266

    Article  CAS  PubMed  Google Scholar 

  15. Perek N, Sabido O, Le Jeune N et al (2008) Could 99mTc-glucarate be used to evaluate tumour necrosis? Eur J Nucl Med Mol Imaging 35:1290–1298

    Article  CAS  PubMed  Google Scholar 

  16. Brader P, Riedl CC, Woo Y, Ponomarev V, Zanzonico P, Wen B, Cai S, Hricak H, Fong Y, Blasberg R, Serganova I (2007) Imaging of hypoxia-driven gene expression in an orthotopic liver tumor model. Mol Cancer Ther 6:2900–2908

    Article  CAS  PubMed  Google Scholar 

  17. Olive PL, Banáth JP (2006) The comet assay: a method to measure DNA damage in individual cells. Nat Protoc 1:23–29

    Article  CAS  PubMed  Google Scholar 

  18. Thorpe PE (2004) Vascular targeting agents as cancer therapeutics. Clin Cancer Res 10:415–427

    Article  PubMed  Google Scholar 

  19. Ni Y, Chen F, Mulier S, Sun X, Yu J, Landuyt W, Marchal G, Verbruggen A (2006) Magnetic resonance imaging after radiofrequency ablation in a rodent model of liver tumor: tissue characterization using a novel necrosis-avid contrast agent. Eur Radiol 16:1031–1040

    Article  PubMed  Google Scholar 

  20. Dasari M, Lee S, Sy J, Kim D, Lee S, Brown M, Davis M, Murthy N (2010) Hoechst-IR: an imaging agent that detects necrotic tissue in vivo by binding extracellular DNA. Org Lett 12:3300–3303

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Smith BA, Smith BD (2012) Biomarkers and molecular probes for cell death imaging and targeted therapeutics. Bioconjug Chem 23:1989–2006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Khan RS, Martinez MD, Sy JC et al (2014) Targeting extracellular DNA to deliver IGF-1 to the injured heart. Sci Rep 4:4257

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Zhang D, Gao M, Yao N et al (2018) Preclinical evaluation of radioiodinated Hoechst 33258 for early prediction of tumor response to treatment of vascular-disrupting agents. Contrast Media Mol Imaging 2018:5237950

    PubMed  PubMed Central  Google Scholar 

  24. Huang S, Chen HH, Yuan H, Dai G, Schule D, Ngoy S, Liao R, Caravan P, Josephson L, Sosnovik D (2011) Molecular MRI of acute necrosis with a novel DNA-binding gadolinium chelate: kinetics of cell death and clearance in infarcted myocardium. J Cardiovasc Magn Reson 13:O23

    Article  PubMed Central  Google Scholar 

  25. Witney TH, Hoehne A, Reeves RE, Ilovich O, Namavari M, Shen B, Chin FT, Rao J, Gambhir SS (2015) A systematic comparison of 18F-C-SNAT to established radiotracer imaging agents for the detection of tumor response to treatment. Clin Cancer Res 21:3896–3905

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Wang K, Purushotham S, Lee JY, Na MH, Park H, Oh SJ, Park RW, Park JY, Lee E, Cho BC, Song MN, Baek MC, Kwak W, Yoo J, Hoffman AS, Oh YK, Kim IS, Lee BH (2010) In vivo imaging of tumor apoptosis using histone H1-targeting peptide. J Control Release 148:283–291

    Article  CAS  PubMed  Google Scholar 

  27. Kwak W, Ha YS, Soni N, Lee W, Park SI, Ahn H, An GI, Kim IS, Lee BH, Yoo J (2015) Apoptosis imaging studies in various animal models using radio-iodinated peptide. Apoptosis 20:110–121

    Article  CAS  PubMed  Google Scholar 

  28. Kim S, Kim D, Lee Y, Jeon H, Lee BH, Jon S (2015) Conversion of low-affinity peptides to high-affinity peptide binders by using a β-hairpin scaffold-assisted approach. Chembiochem 16:43–46

    Article  CAS  PubMed  Google Scholar 

  29. Belhocine T, Steinmetz N, Hustinx R, Bartsch P, Jerusalem G, Seidel L, Rigo P, Green A (2002) Increased uptake of the apoptosis-imaging agent 99mTc recombinant human Annexin V in human tumors after one course of chemotherapy as a predictor of tumor response and patient prognosis. Clin Cancer Res 8:2766–2774

    CAS  PubMed  Google Scholar 

  30. Kemerink GJ, Liu X, Kieffer D, Ceyssens S, Mortelmans L, Verbruggen AM, Steinmetz ND, Vanderheyden JL, Green AM, Verbeke K (2003) Safety, biodistribution, and dosimetry of 99mTc-HYNIC-annexin V, a novel human recombinant annexin V for human application. J Nucl Med 44:947–952

    CAS  PubMed  Google Scholar 

  31. Blankenberg FG (2008) In vivo detection of apoptosis. J Nucl Med 49:81S–95S

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We thank Mr. Changwen Fu for his kind work in SPECT/CT scanning.

Funding

This study was partially sponsored by the National Natural Science Foundation of China (No. 81473120, 81501536, 81771870).

Author information

Authors and Affiliations

  1. Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210028, Jiangsu Province, People’s Republic of China

    Jiajia Liang, Qi Luo, Dongjian Zhang, Qiaomei Jin, Lichao Liu, Meng Gao & Jian Zhang

  2. Department of TCMs Pharmaceuticals & State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, No.24, Tongjiaxiang, Gulou District, Nanjing, 210009, Jiangsu Province, People’s Republic of China

    Jiajia Liang, Qi Luo, Lichao Liu & Zhiqi Yin

  3. Laboratories of Translational Medicine, Jiangsu Province Academy of Traditional Chinese Medicine, No.100, Shizi Street, Hongshan Road, Qixia District, Nanjing, 210028, Jiangsu Province, People’s Republic of China

    Jiajia Liang, Qi Luo, Dongjian Zhang, Qiaomei Jin, Lichao Liu, Meng Gao & Jian Zhang

  4. Department of Nuclear Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu Province, People’s Republic of China

    Wei Liu

Authors
  1. Jiajia Liang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Qi Luo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Dongjian Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Qiaomei Jin
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Lichao Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Wei Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Meng Gao
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jian Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Zhiqi Yin
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Jian Zhang or Zhiqi Yin.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflicts of interest. Jiajia Liang and Qi Luo contributed equally to this paper.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Liang, J., Luo, Q., Zhang, D. et al. SPECT Imaging of Treatment-Related Tumor Necrosis Using Technetium-99m-Labeled Rhein. Mol Imaging Biol 21, 660–668 (2019). https://doi.org/10.1007/s11307-018-1285-9

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11307-018-1285-9

Key words

Search

Navigation