INSIGHTS INTO PHOTODYNAMIC THERAPY AND ITS DOSIMETRY USING A DYNAMIC MODEL FOR ALA-PDT OF NORMAL HUMAN SKIN

Abstract

<p>Photodynamic therapy (PDT) is a rapidly developing clinical treatment modality involving a light-activatable photosensitizer, tissue oxygen and light of an appropriate wavelength to generate cytotoxic reactive molecular species - primarily singlet oxygen (¹O₂). Singlet oxygen readily reacts with surrounding biomolecules leading to different biological effects and subsequent therapeutic outcomes. Over the last decades, many standard PDT treatments have been approved worldwide to treat different medical conditions ranging from a variety of cancer conditions to age-related macular degeneration (AMD). Meanwhile, many active clinical trials and pre-clinical studies are underway for other clinical indications. The therapeutic outcomes of PDT are difficult to predict reliably even with many years of research. The fundamental cause for this is the inherent complexity of PDT mechanisms. As PDT involves three main components, the outcomes of PDT are determined by the combination of all components. Each component varies temporally and spatially during PDT, and the variations are mutually dependent on each other. Moreover, components such as the photosensitizer can have great variations in their initial distribution among patients even before PDT treatment. Given this, no well accepted standard PDT dose metric method has been recognized in clinics, although different approaches including explicit, implicit and direct dosimetry have been studied. To tackle the inherently complicated PDT mechanism in order to provide insights into PDT and PDT dosimetry, a theoretical one-dimensional model for aminolevulinic acid (ALA) induced protoporphyrin IX (PpIX)-PDT of human skin was developed and is presented in this thesis. The model incorporates major photophysical and photochemical reactions in PDT, and calculated temporal and spatial distributions of PDT components as well as the detectable emission signals including both sensitizer fluorescence and singlet oxygen luminescence (SOL) using typical clinical conditions. Since singlet oxygen is considered to cause PDT outcomes, the correlations of different PDT dose metrics to average reacted (¹O₂) "dose" and "dose" at different depths were examined and compared for a wide range of varied treatment conditions. The dose metrics included absolute fluorescence bleaching metric (AFBM), fractional fluorescence bleaching metric (FFBM) and cumulative singlet oxygen luminescence (CSOL), and the varied treatment conditions took into account different treatment irradiances and wavelengths, varied initial sensitizer concentration and distribution, and a wide range of optical properties of tissue. These investigations and comparisons provide information about the complicated dynamic process of PDT such as the induction of tissue hypoxia, photosensitizer photobleaching and possible PDT-induced vascular responses. It was also found that the CSOL is the most robust and could serve as a gold standard for the testing of other techniques. In addition to these theoretical studies, recent progress on the assessment of a novel, more efficient superconducting nanowire single photon detector (SNSPD) for singlet oxygen luminescence detection will be introduced and the current photomultiplier tubes (PMT) system will be briefly described as well. The author participated in the experimental assessments of the SNSPD and analyzed the results shown in this thesis.</p>