The role of strong hypoxia in tumors after treatment in the outcome of bacteriochlorin-based photodynamic therapy.
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.
Faculty of Biochemistry, Biophysics, and Biotechnology, Jagiellonian University, 30-387 Krakow, Poland.
Martyna
M
Krzykawska-Serda
Faculty of Chemistry, Jagiellonian University, 30-060 Krakow, Poland. Electronic address: jdabrows@chemia.uj.edu.pl.
Janusz M
JM
Dąbrowski
Chemistry Department, University of Coimbra, 3004-535 Coimbra, Portugal; Luzitin SA, 3045-016 Coimbra, Portugal. Electronic address: lgarnaut@ci.uc.pt.
Luis G
LG
Arnaut
Faculty of Biochemistry, Biophysics, and Biotechnology, Jagiellonian University, 30-387 Krakow, Poland.
Małgorzata
M
Szczygieł
Faculty of Biochemistry, Biophysics, and Biotechnology, Jagiellonian University, 30-387 Krakow, Poland.
Krystyna
K
Urbańska
Faculty of Chemistry, Jagiellonian University, 30-060 Krakow, Poland.
Grażyna
G
Stochel
Faculty of Biochemistry, Biophysics, and Biotechnology, Jagiellonian University, 30-387 Krakow, Poland. Electronic address: martyna.elas@uj.edu.pl.
Martyna
M
Elas
D000818:Animals; D017209:Apoptosis; D015687:Cell Hypoxia / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D008297:Male; D008545:Melanoma / Q000098:blood supply* / Q000378:metabolism / Q000628:therapy*; D051379:Mice; D008811:Mice, Inbred DBA; D008833:Microcirculation / Q000187:drug effects; D010100:Oxygen / Q000378:metabolism; D010101:Oxygen Consumption / Q000187:drug effects; D010778:Photochemotherapy / Q000379:methods*; D017319:Photosensitizing Agents / Q000494:pharmacology; D011166:Porphyrins / Q000494:pharmacology*; D017382:Reactive Oxygen Species; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D017319:Photosensitizing Agents; D011166:Porphyrins; D017382:Reactive Oxygen Species; D042461:Vascular Endothelial Growth Factor A; C452433:bacteriochlorin; C467480:vascular endothelial growth factor A, mouse; D010100:Oxygen
Bacteriochlorins; Blood flow; Free radicals; Hydroxyl radical; Oxymetry; Photodynamic therapy; Phototoxicity; Singlet oxygen; Superoxide; Vascular-targeted PDT