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

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.

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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.

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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.

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Correspondence to Yoram Salomon.

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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.

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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

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