The role of strong hypoxia in tumors after treatment in the outcome of bacteriochlorin-based photodynamic therapy

Free Radic Biol Med. 2014 Aug;73:239-51. doi: 10.1016/j.freeradbiomed.2014.05.003. Epub 2014 May 14.

Abstract

Blood flow and pO2 changes after vascular-targeted photodynamic therapy (V-PDT) or cellular-targeted PDT (C-PDT) using 5,10,15,20-tetrakis(2,6-difluoro-3-N-methylsulfamoylphenyl) bacteriochlorin (F2BMet) as photosensitizer were investigated in DBA/2 mice with S91 Cloudman mouse melanoma, and correlated with long-term tumor responses. F2BMet generates both singlet oxygen and hydroxyl radicals under near-infrared radiation, which consume oxygen. Partial oxygen pressure was lowered in PDT-treated tumors and this was ascribed both to oxygen consumption during PDT and to fluctuations in oxygen transport after PDT. Similarly, microcirculatory blood flow changed as a result of the disruption of blood vessels by the treatment. A novel noninvasive approach combining electron paramagnetic resonance oximetry and laser Doppler blood perfusion measurements allowed longitudinal monitoring of hypoxia and vascular function changes in the same animals, after PDT. C-PDT induced parallel changes in tumor pO2 and blood flow, i.e., an initial decrease immediately after treatment, followed by a slow increase. In contrast, V-PDT led to a strong and persistent depletion of pO2, although the microcirculatory blood flow increased. Strong hypoxia after V-PDT led to a slight increase in VEGF level 24h after treatment. C-PDT caused a ca. 5-day delay in tumor growth, whereas V-PDT was much more efficient and led to tumor growth inhibition in 90% of animals. The tumors of 44% of mice treated with V-PDT regressed completely and did not reappear for over 1 year. In conclusion, mild and transient hypoxia after C-PDT led to intense pO2 compensatory effects and modest tumor inhibition, but strong and persistent local hypoxia after V-PDT caused tumor growth inhibition.

Keywords: Bacteriochlorins; Blood flow; Free radicals; Hydroxyl radical; Oxymetry; Photodynamic therapy; Phototoxicity; Singlet oxygen; Superoxide; Vascular-targeted PDT.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Cell Hypoxia / drug effects*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Male
  • Melanoma / blood supply*
  • Melanoma / metabolism
  • Melanoma / therapy*
  • Mice
  • Mice, Inbred DBA
  • Microcirculation / drug effects
  • Oxygen / metabolism
  • Oxygen Consumption / drug effects
  • Photochemotherapy / methods*
  • Photosensitizing Agents / pharmacology
  • Porphyrins / pharmacology*
  • Reactive Oxygen Species
  • Vascular Endothelial Growth Factor A / metabolism

Substances

  • Photosensitizing Agents
  • Porphyrins
  • Reactive Oxygen Species
  • Vascular Endothelial Growth Factor A
  • bacteriochlorin
  • vascular endothelial growth factor A, mouse
  • Oxygen