Enhancing protoporphyrin IX-induced photodynamic therapy with a topical iron chelating agent in a normal skin model

Abstract

Protoporphyrin IX (PpIX)-induced photodynamic therapy (PDT) is being utilised within dermatological practice as a topical method of localised ablation of non-melanoma skin cancer/precancer. Standardised protocols have been implemented to good effect when the disease remains superficial but improvement is required to widen the application of this light activated drug therapy to treat thicker or acrally located conditions. As innate haem biosynthesis is exploited to accumulate the light sensitive PpIX from a topically applied inert prodrug (aminolaevulinic acid; ALA), this pathway can be further manipulated through the concurrent administration of an iron chelating agent to hyper-accumulate PpIX by temporarily reducing its iron dependent conversion to haem. A topical preparation of ALA was applied to normal rat skin with or without the hydroxypyridinone iron chelator, CP94. Image analysis quantification of tissue fluorescence following excision indicated that ALA plus CP94 produced 29.0% more fluorescence than ALA alone (p < 0.09), peaking at 5 hours. Furthermore, fluorescence spectroscopy of frozen skin samples from each treatment group were characteristic of PpIX (maxima 636 +/- 2 nm), indicating that topical CP94 administration elevated PpIX levels without significantly producing any other fluorescent species. When PDT efficacy was considered post irradiation, a substantial three-fold increase in effect was observed 4 days after treatment when the iron chelator CP94 was co-administered topically with the prodrug (p < 0.07). It has therefore been established that the hydroxypyridinone CP94, is topically active within normal rat skin, effectively chelating iron to elevate PpIX accumulation and thus improve PDT efficacy.