Novel methodologies to enhance the effectiveness of clinical photodynamic therapy

• Main Author: Blake, Emma
• Published: Exeter and Plymouth Peninsula Medical School 2012
• Subjects: 616.994770631
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.556512

Protoporphyrin IX (PpIX)-induced photodynamic therapy (POT) utilises the combined interaction of the photosensitiser PpIX, light of a specific wavelength and molecular oxygen to produce cytotoxic species which ultimately leads to the ablation of tumour cells. Dermatological PpIX-PDT, although established for superficial lesions, would be a more attractive treatment modality if its efficacy for the removal of thicker cancerous and precancerous skin lesions could be improved. Additionally, an excessive accumulation of naturally fluorescent PplX can be clinically useful for photodiagnosis (PO) or fluorescence guided resection (FGR) as adjuvant aids in the surgical resection of primary brain tumours. The aims of this thesis were therefore to i) increase and/or accelerate PplX photosensitiser accumulation and thus POT efficacy following irradiation and to ii) investigate the effects of oxygen manipulation on the POT process. In vitro experimentation demonstrated that 5-aminolaevulinic acid (ALA) and its ester methyl aminolevulinate (MAL) coincubated with the iron chelator CP94, significantly enhanced levels of PplX fluorescence in U-87 MG human glioma cells. Following irradiation the greatest cytotoxicity was observed when each congener was coincubated with CP94. Further investigation compared dexrazoxane, an already approved drug used clinically known for its iron chelating properties, with CP94. ALA, MAL and in addition hexyl aminolevulinate (HAL) coincubated with iron chelation, significantly enhanced and accelerated PplX fluorescence in both A431 squamous epithelial carcinoma cells and U-87 MG human glioma cells. Employing CP94 to increase and/or accelerate MAL-induced Pp IX accumulation in nodular basal cell carcinomas (nBCC) was investigated clinically. The results suggest that the clinical utilisation of CP94 may offer a simple modification to potentially increase the efficacy of MAL-POT by temporarily increasing PplX accumulation. Furthermore, in vitro manipulation of the oxygen environment was found to affect PplX fluorescence levels pre- and post-irradiation and thus subsequent cell viability. Oxygen manipulation requires further investigation but employment of an oxygen pressure injection (OPI) device during dermatological MAL-PDT was not found to be an effective method to improve tissue oxygenation during irradiation. However, the positive effects of employing an OPI device to drive MAL cream deeper into nBCC on cream application were confirmed. It is therefore clear that much can be done to further improve PDT treatment protocols for different clinical applications and one of the most straight forward methods of enhancement that can be employed is the concurrent application of the iron chelating agent, CP94.