The efficacy of an iron chelator (CP94) in increasing cellular protoporphyrin IX following intravesical 5-aminolaevulinic acid administration: an in vivo study

Abstract

5-Aminolaevulinic acid (ALA)-induced protoporphyrin IX (PpIX) is proving to be a useful photosensitizer for photodynamic therapy (PDT). Conversion of PpIX to haem requires catalysed chelation with iron, and thus the presence of an iron chelator should, in theory, lead to an increase in cellular PpIX accumulation. This paper assesses the in vivo effect of a new iron chelator, 1,2-diethyl-3-hydroxypyridin-4-one (CP94), on the kinetics of PpIX in different layers of the bladder wall. Wistar rats were given 1% or 10% ALA intravesically with or without intraperitoneal CP94. The biodistribution of ALA-induced PpIX in the bladder was evaluated using fluorescence microscopy. Photodynamic effects on the bladder were compared in rats receiving various drug dosimetries. In CP94-treated rats, 5-7 h after administration of 10% ALA solution, the fluorescence intensity of PpIX in the urothelium was doubled compared with animals given ALA alone, whereas in the muscle layer PpIX remained at a low level similar to that found without the iron chelator. At an ALA concentration of 1%, although the PpIX concentration was not increased with CP94, the urothelial selectivity of PDT compared with the muscle layer was enhanced. In conclusion, by using CP94, a further reduction in skin photosensitization may be possible as similar photodynamic effects can be achieved with a lower dose of ALA. The addition of CP94 seems to be an effective and convenient way to potentiate ALA-induced PpIX tissue selectivity between the urothelium and the underlying layers of the bladder wall.