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Fluence rate-dependent intratumor heterogeneity in physiologic and cytotoxic responses to Photofrin photodynamic therapy

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Abstract

Photodynamic therapy (PDT) can lead to the creation of heterogeneous, response-limiting hypoxia during illumination, which may be controlled in part through illumination fluence rate. In the present report we consider (1) regional differences in hypoxia, vascular response, and cell kill as a function of tumor depth and (2) the role of fluence rate as a mediator of depth-dependent regional intratumor heterogeneity. Intradermal RIF murine tumors were treated with Photofrin PDT using surface illumination at an irradiance of 75 or 38 mW cm-2. Regional heterogeneity in tumor response was examined through comparison of effects in the surfacevs. base of tumors, i.e. along a plane parallel to the skin surface and perpendicular to the incident illumination. 75 mW cm-2 PDT created significantly greater hypoxia in tumor bases relative to their surfaces. Increased hypoxia in the tumor base could not be attributed to regional differences in Photofrin concentration nor effects of fluence rate distribution on photochemical oxygen consumption, but significant depth-dependent heterogeneity in vascular responses and cytotoxic response were detected. At a lower fluence rate of 38 mW cm-2, no detectable regional differences in hypoxia or cytotoxic responses were apparent, and heterogeneity in vascular response was significantly less than that during 75 mW cm-2 PDT. This research suggests that the benefits of low-fluence-rate PDT are mediated in part by a reduction in intratumor heterogeneity in hypoxic, vascular and cytotoxic responses.

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Abbreviations

DCS:

Diffuse correlation spectroscopy

EF3:

[(2-(2-Nitroimidazol-1H-yl)-N-(3,3,3-trifluoropropyl) acetamide)

HPPH:

2-(1-Hexyloxyethyl)-2-devinyl pyropheophorbide-a

PDT:

Photodynamic therapy

THC:

Total hemoglobin concentration

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Authors and Affiliations

  1. Department of Radiation Oncology, School of Medicine, University of Pennsylvania, B13 Anatomy and Chemistry, 3620 Hamilton Walk, Philadelphia, PA, 19104-6072, USA

    Theresa M. Busch, Arjun Yodh, Hsing-Wen Wang, Timothy C. Zhu & Ken Kang-Hsin Wang

  2. Department of Physics and Astronomy, School of Arts and Sciences, University of Pennsylvania, Philadelphia, PA, 19104, USA

    Xiaoman Xing, Guoqiang Yu, Arjun Yodh, Hsing-Wen Wang & Turgut Durduran

  3. Department of Psychiatry, School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA

    E. Paul Wileyto

  4. Department of Radiology, School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA

    Turgut Durduran

  5. Center for Biomedical Engineering, University of Kentucky, Lexington, KY, 40506, USA

    Guoqiang Yu

  6. Institute of Biophotonics, National Yang-Ming University, Taipei, 11221, Taiwan

    Hsing-Wen Wang

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  1. Theresa M. Busch
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Correspondence to Theresa M. Busch.

Additional information

† Electronic supplementary information (ESI) available: Fig. S1 (fluence rate as a function of tumor depth); Fig. S2 (EF3 binding level). See DOI: 10.1039/b9pp00004f

‡ These authors contributed equally to this work

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Busch, T.M., Xing, X., Yu, G. et al. Fluence rate-dependent intratumor heterogeneity in physiologic and cytotoxic responses to Photofrin photodynamic therapy. Photochem Photobiol Sci 8, 1683–1693 (2009). https://doi.org/10.1039/b9pp00004f

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  • DOI: https://doi.org/10.1039/b9pp00004f

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