Comparison of Normal Piglet Bladder Damage after PDT with Oral or Intravesical Administration of ALA

Abstract

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5-Aminolaevulinic-acid (ALA) can be used as an alternative drug in photodynamic therapy of the bladder, since the selective formation of protoporphyrin IX (PpIX) in the tumour and the virtual absence of induced skin photosensitivity are theoretically advantageous for clinical use. A preclinical study was performed, using an in vivo normal piglet bladder model, in order to determine the maximum drug and light doses for reversible tissue damage. Various ALA doses were administered either orally or instilled in the bladder and different radiant exposures were applied. Bladder biopsies were taken at regular intervals and tissue damage was investigated histologically. After oral ALA-administration the PpIX concentration was determined in plasma, erythrocytes and various tissues. In the case of oral administration, reversible bladder damage was observed using 60–75 mg/kg ALA combined with a radiant exposure of 100 J/cm² (direct radiant exposure plus scattered 632 nm light) 5–7 h later. For an oral ALA dose of up to 150 mg/kg, the maximum PpIX concentration is reached at ≈5 h following administration and in neither skin nor bladder tissue is PpIX present at 10–11 h after administration. This ALA dose combined with a radiant exposure of 200 J/cm² produces irreversible bladder damage (extensive necrosis and ulceration). In the case of intravesical instillation for 4–4.75 h, an ALA dose of 2.5 g in 50 ml phosphate buffered saline and a radiant exposure of 100 J/cm² are still too high to obtain reversible tissue damage; at this dose one of the 13 pigs developed a shrunken bladder with a fibrotic, thickened bladder wall. These drug and light combinations reported above should be regarded as upper limits in pigs and can serve as an indication for the toxicity of the treatment in a clinical setting.