Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Technical Report
  • Published:

Monitoring photodynamic therapy of solid tumors online by BOLD-contrast MRI

Nature Medicine volume 9, pages 1327–1331 (2003)Cite this article

Abstract

Antivascular photodynamic therapy (PDT) of tumors with palladium-bacteriopheophorbide (TOOKAD) relies on in situ photosensitization of the circulating drug by local generation of cytotoxic reactive oxygen species, which leads to rapid vascular occlusion, stasis, necrosis and tumor eradication. Intravascular production of reactive oxygen species is associated with photoconsumption of O2 and consequent evolution of paramagnetic deoxyhemoglobin. In this study we evaluate the use of blood oxygenation level–dependent (BOLD) contrast magnetic resonance imaging (MRI) for real-time monitoring of PDT efficacy. Using a solid tumor model, we show that TOOKAD-PDT generates appreciable attenuation (25–40%) of the magnetic resonance signal, solely at the illuminated tumor site. This phenomenon is independent of, though augmented by, ensuing changes in blood flow. These results were validated by immunohistochemistry and intravital microscopy. The concept of photosensitized BOLD-contrast MRI may have intraoperative applications in interactive guidance and monitoring of antivascular cancer therapy, PDT treatment of macular degeneration, interventional cardiology and possibly other biomedical disciplines.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: TOOKAD-PDT of M2R mouse melanoma.
Figure 2: Photochemical reduction in sPO2, recorded in human blood using TOOKAD and light.
Figure 3: TOOKAD-PDT of M2R melanoma: online BOLD-contrast MRI.
Figure 4: Kinetics of changes in BOLD-contrast MRI during TOOKAD-PDT.

Similar content being viewed by others

References

  1. Zilberstein, J. et al. Light-dependent oxygen consumption in bacteriochlorophyll-serine-treated melanoma tumors: on-line determination using a tissue-inserted oxygen microsensor. Photochem. Photobiol. 65, 1012–1019 (1997).

    Article  CAS  Google Scholar 

  2. Sitnik, T.M., Hampton, J.A. & Henderson, B.W. Reduction of tumor oxygenation during and after photodynamic therapy in vivo: effects of fluence rate. Br. J. Cancer 77, 1386–1394 (1998).

    Article  CAS  Google Scholar 

  3. Zilberstein, J. et al. Antivascular treatment of solid melanoma tumors with bacteriochlorophyll-serine-based photodynamic therapy. Photochem. Photobiol. 73, 257–266 (2001).

    Article  CAS  Google Scholar 

  4. Dolmans, D.E. et al. Vascular accumulation of a novel photosensitizer, MV6401, causes selective thrombosis in tumor vessels after photodynamic therapy. Cancer Res. 62, 2151–2156 (2002).

    CAS  PubMed  Google Scholar 

  5. Hopper, C. Photodynamic therapy: a clinical reality in the treatment of cancer. Lancet Oncol. 1, 212–219 (2000).

    Article  CAS  Google Scholar 

  6. Dougherty, T.J. An update on photodynamic therapy applications. J. Clin. Laser Med. Surg. 20, 3–7 (2002).

    Article  Google Scholar 

  7. Scherz, A., Salomon, Y., Scheer, H. & Brandis, A. Palladium-substituted bacteriochlorophyll derivatives and use thereof. US Patent 6,569,846 (2003).

  8. Schreiber, S., Gross, S., Harmelin, A., Scherz, A. & Salomon, Y. Local photodynamic therapy (PDT) of rat C6 glioma xenografts with Pd-bacteriopheophorbide leads to decreased metastases and increase of animal cure compared to surgery. Int. J. Cancer 99, 279–285 (2002).

    Article  CAS  Google Scholar 

  9. Kelleher, D.K. et al. Water-filtered infrared-A radiation: a novel technique for localized hyperthermia in combination with bacteriochlorophyll-based photodynamic therapy. Int. J. Hyperthermia 15, 467–474 (1999).

    Article  CAS  Google Scholar 

  10. Chen, Q. et al. Preclinical studies in normal canine prostate of a novel palladium-bacteriopheophorbide (WST09) photosensitizer for photodynamic therapy of prostate cancer. Photochem. Photobiol. 76, 88–95 (2002).

    Google Scholar 

  11. Koudinova, N. et al. Photodynamic therapy with Pd-bacteriopheophorbide (TOOKAD): successful in vivo treatment of human prostatic small cell carcinoma xenografts. Int. J. Cancer 104, 782–789 (2003).

    Article  CAS  Google Scholar 

  12. Preise, D. et al. Bypass of tumor drug resistance by antivascular therapy. Neoplasia (in the press).

  13. Ogawa, S. & Lee, T.M. Magnetic resonance imaging of blood vessels at high fields: in vivo and in vitro measurements and image simulation. Magn. Reson. Med. 16, 9–18 (1990).

    Article  CAS  Google Scholar 

  14. Turner, R. Signal sources in BOLD contrast fMRI. Adv. Exp. Med. Biol. 413, 19–25 (1997).

    Article  CAS  Google Scholar 

  15. Taylor, N.J. et al. BOLD MRI of human tumor oxygenation during carbogen breathing. J. Magn. Reson. Imaging 14, 156–163 (2001).

    Article  CAS  Google Scholar 

  16. Abramovitch, R., Marikovsky, M., Meir, G. & Neeman, M. Stimulation of tumour angiogenesis by proximal wounds: spatial and temporal analysis by MRI. Br. J. Cancer 3, 440–447 (1998).

    Article  Google Scholar 

  17. Gilead, A. & Neeman, M. Dynamic remodeling of the vascular bed precedes tumor growth: MLS ovarian carcinoma spheroids implanted in nude mice. Neoplasia 1, 226–230 (1999).

    Article  CAS  Google Scholar 

  18. Howe, F.A. et al. Issues in flow and oxygenation dependent contrast (FLOOD) imaging of tumours. Effects of different levels of hypercapnic hyperoxia on tumour R(2)* and arterial blood gases. NMR Biomed. 14, 497–506 (2001).

    Article  CAS  Google Scholar 

  19. Uchida, K. et al. Characterization of epitopes recognized by 4-hydroxy-2-nonenal specific antibodies. Arch. Biochem. Biophys. 324, 241–248 (1995).

    Article  CAS  Google Scholar 

  20. Detre, J.A. & Floyd, T.F. Functional MRI and its applications to the clinical neurosciences. Neuroscientist 7, 64–79 (2001).

    Article  CAS  Google Scholar 

  21. Turner, R. How much cortex can a vein drain? Downstream dilution of activation-related cerebral blood oxygenation changes. Neuroimage 16, 1062–1067 (2002).

    Article  Google Scholar 

  22. Jolesz, F.A. Interventional and intraoperative MRI: a general overview of the field. J. Magn. Reson. Imaging 8, 3–7 (1998).

    Article  CAS  Google Scholar 

  23. Yang, M. et al. direct external imaging of nascent cancer, tumor progression, angiogenesis, and metastasis on internal organs in the fluorescent orthotopic model. Proc. Natl. Acad. Sci. USA 99, 3824–3829 (2002).

    Article  CAS  Google Scholar 

  24. Neeman, M., Dafni, H., Bukhari, O., Braun, R.D. & Dewhirst, M.W. In vivo BOLD contrast MRI mapping of subcutaneous vascular function and maturation: validation by intravital microscopy. Magn. Reson. Med. 45, 887–898 (2001).

    Article  CAS  Google Scholar 

  25. Braun, R.D., Dewhirst, M.W. & Hatchell, D.L. Quantification of erythrocyte flow in the choroid of the albino rat. Am. J. Physiol. 272, H1444–H1453 (1997).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Y.S. is the incumbent of the Tillie and Charles Lubin Professorial Chair in Biochemical Endocrinology. A.S. is the incumbent of the Robert and Yadele Sklare Professional Chair in Biochemistry. S.G and A.G. are in partial fulfilment of their Ph.D. theses at the Feinberg Graduate School of the Weizmann Institute of Science. We wish to acknowledge the technical help of I. Meerovitch and Y. Machluf. This work was supported by Steba Biotech.

Author information

Author notes

  1. Shimon Gross and Assaf Gilead: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Biological Regulation, The Weizmann Institute of Science, Rehovot, 76100, Israel

    Shimon Gross, Assaf Gilead, Michal Neeman & Yoram Salomon

  2. Department of Plant Sciences, The Weizmann Institute of Science, Rehovot, 76100, Israel

    Shimon Gross & Avigdor Scherz

Authors
  1. Shimon Gross
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Assaf Gilead
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Avigdor Scherz
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Michal Neeman
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yoram Salomon
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yoram Salomon.

Ethics declarations

Competing interests

This study was funded by Steba Biotech, France, which obtained licenses for TOOKAD (the sensitizer; US Patent no. 6,569,846) and the BOLD imaging technology (PCT/IL03/00371) from Yeda Research and Development, the technology transfer company of the Weizmann Institute of Science in Rehovot, Israel.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Gross, S., Gilead, A., Scherz, A. et al. Monitoring photodynamic therapy of solid tumors online by BOLD-contrast MRI. Nat Med 9, 1327–1331 (2003). https://doi.org/10.1038/nm940

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm940

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing