Photodynamic effects in perifocal, oedematous brain tissue

Background. Photodynamic therapy (PDT) has been under discussion as additional treatment option for malignant gliomas. However, damage not only to tumour tissue but also to normal brain has been demonstrated. The mechanisms of this unwanted side effect have not yet been clearly identified. Spreading of photosensitiser with oedema after disruption of the blood-brain-barrier and potential sensitisation of normal tissue has been found previously. The present study investigates the time- and dose-dependency of normal tissue damage to photodynamic therapy using Photofrin II (R) after disruption of the blood-brain-barrier. Methods. Male wistar rats anaesthetised with chloral hydrate were subjected to focal, cerebral cold lesions. Simultaneously, Photofrin II (R) (PFII) was injected (2,5 or 5 mg/kg b.w.). Laser irradiation (630 nm) was performed after 4 h, 12 h and 24 h with varying light doses. Control groups were subjected to focal cold lesion alone, cold lesion with laser irradiation, PFII followed by laser irradiation, or laser irradiation alone (n = 6 all groups). 24 h later, brains were removed for assessment of necrosis in coronal sections. Findings. Light dose had a significant impact on the extent of necrosis. Compared to control animals (lesion only: 0.84 +/- 0.2 mm(2); lesion and irradiation alone: 0.7 +/- 0.3 mm(2)), the area of necrosis was increased to 2.8 +/- 0.5 (50 J/cm(2)), 3.5 +/- 1,1 (100 J/cm(2)) and: 4.3 +/- 0.7 mm(2) (200 J/cm(2) 5 mg/kg b.w.; P < 0.01). This effect was time-dependent. Maximal necrosis (6.3 +/- 1,6 mm(2)) was observed when brains were irradiated 12 h after PFII injection, with less necrosis occurring at 24 h (2.8 +/- 0.4 mm(2), p < 0.01). Reducing sensitiser dose to 2.5 mg/kg b.w. resulted in a reduction of necrosis (2.09 +/- 0.2 mm(2), p < 0.05). Interpretations. Damage to oedematous tissue after photodynamic therapy using i.v. PFII and laser light at 630 nm depends on laser dose, sensitiser dose and the time point of laser irradiation. The time point of PDT should be considered to prevent unwanted tissue reactions. In the clinical setting however, defined damage to peritumoural tissue may be advantageous. This should be achievable by optimised timing and dosage of photodynamic therapy.