Curnow, Alison; (1999) Photodynamic therapy with 5-aminolaevulinic acid: Techniques for enhancement. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Photodynamic therapy (PDT) is a non-thermal technique which can be used to create localised tissue damage. It requires the activation of a pre-administered photosensitiser (in the presence of molecular oxygen) with light of a specific wavelength to form a cytotoxic species. 5-Aminolaevulinic acid (ALA) is an attractive photosensitising agent for PDT as its photoreactive derivative protoporphyrin IX (PPIX), is metabolised within one to two days, eliminating prolonged skin photosensitivity (the major side effect of other clinically used photosensitisers). However, at the maximum dose patients tolerate by mouth (60 mg/kg) only superficial effects are seen. A need exists for the outcome of this treatment modality to be enhanced without increasing the administered dose of ALA. ALA PDT manipulates the haem biosynthesis pathway to create an accumulation of PPIX. By chelating iron (using a hydroxypyridinone iron chelator), this thesis shows that it is possible to amplify this PPIX accumulation and thus significantly enhance the effect of ALA PDT. This is demonstrated in normal and malignant rat colon, normal rat skin and normal rabbit uterus, using several routes of administration. Various light dose fractionation regimes were also investigated in this thesis. A single 150 second interruption to the illumination, when placed appropriately, was found to significantly enhance ALA PDT in normal and malignant rat colon. The reasons for this are unclear but marked differences in tissue oxygenation were observed during continuous and fractionated treatments. Additionally, relocalisation of PPIX during the dark interval was detected and the inhibition of reperfusion injury was found to prevent the tissue damage normally produced in this model. This thesis has investigated two different methods of ALA PDT enhancement and found that the addition of a hydroxypyridinone iron chelator and the technique of light dose fractionation can both be used successfully in vivo, to significantly enhance ALA induced PDT.

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