Analysis of the Heterogeneity of pO2 Dynamics During Photodynamic Therapy with Verteporfin¶

Abstract

Photodynamic therapy (PDT) with verteporfin provides a reliable way to destroy malignant tissues. Changes in the blood flow and oxygen partial pressure (pO2) during verteporfin-PDT were studied here in the tumor tissue of the rat mammary R3230Ac carcinoma model. Oxygen microelectrodes (6-12 microns tip diameter) were used to measure the transients locally within tumors during intravenous injection of 1.0 mg/kg verteporfin followed by irradiation 15 min later with 690 nm light at 200 mW/cm2, for a cumulative dose of 144 J/cm2. The observed changes in pO2 were heterogeneous and there was a difference in the response of low-pO2 regions relative to higher-pO2 regions. The change in pO2 in hypoxic tissue regions (pO2 < 8 mmHg) had acute pO2 loss after treatment, whereas the response in regions of higher pO2 (> 8 mm Hg) was more heterogeneous with some areas maintaining their pO2 value after treatment was completed. Blood flow measurements taken on a subset of the animals indicated a significant loss in flow during the initial light delivery that remained low after treatment, indicating some vascular stasis. The results suggest that hypoxic or poorly perfused vessels may be more susceptible to acute stasis than normoxic vessels in this treatment protocol.

Effects of light fractionation and different fluence rates on photodynamic therapy with 5-aminolaevulinic acid in vivo

“…Unfortunately, measurements in surrounding normal tissue were not taken. Nevertheless, using laser Doppler measurements in the same experiments, a significant reduction of blood flow during the initial phase of irradiation could be shown (Pogue et al, 2001).…”

“…Using pO 2 -electrodes, Pogue et al (2001) could show in the rat R3230Ac mammary adenocarcinoma after fractionated PDT with Verteporfin s directly after completion of the irradiation a heterogeneous reduction of tissue pO 2 , but not complete anoxia. Unfortunately, measurements in surrounding normal tissue were not taken.…”

“…Therefore, direct tumour cell toxicity by PDT with ALA is expected. Further evidence is given by measurements of NADH fluorescence to assess acute cellular PDT-induced damage in vivo, showing a significant reduction directly after the first fraction of irradiation using Verteporfin s as photosensitiser (Pogue et al, 2001). Comparing continuous vs fractionated irradiation for lowdose PDT, no difference can be measured regarding pO 2 24 h after treatment in tumour tissue, but as for high-dose PDT only in the surrounding tissue, difference can be measured.…”

“…To improve efficacy of ALA -PDT fractionating the light dose or reducing the light intensity might be a possibility (Gibson et al, 1990;Messmann et al, 1995;de Bruijn et al, 1999;Iinuma et al, 1999). Splitting the light dose into fractions by pausing the light source for a certain time is supposed to enable reoxygenation of the irradiated tissue and may increase the generation of singlet oxygen thus enhancing PDT (Hua et al, 1995;Robinson et al, 2000;Pogue et al, 2001). In addition, new PpIX might be formed during the irradiation break further contributing to the generation of reactive oxygen species during the second irradiation turn (de Bruijn et al, 1999;Robinson et al, 2000).…”

“…In addition, new PpIX might be formed during the irradiation break further contributing to the generation of reactive oxygen species during the second irradiation turn (de Bruijn et al, 1999;Robinson et al, 2000). A low-dose PDT is supposed to result in a slower oxygen consumption and therefore allows oxygen to be continuously supplied compared with high-dose PDT (Hua et al, 1995;Robinson et al, 2000;Pogue et al, 2001). Therefore, the oxygen concentration, for example, partial oxygen pressure (pO 2 ), in the tissue is critical and the measurement of tissue oxygenation is of great importance.…”