Photodynamic Therapy (PDT) of cancer involves radiating photosensitizing drugs with light in tumors, which results in generating active singlet oxygen that kills cancer cells. Photosensitizers currently used in PDT are of low quantum yield and require high energy radiation, normally laser. Therefore there is always need for more effective PDT drugs. In this project we synthesized new derivatives of phenothiazinium for potential applications in PDT. Phenothiazinium was synthesized and derivatized by linking it to side groups containing imidazole rings. These derivatives are also expected to catalyze certain hydrolytic reactions. Such ôhydrolase modelsö use molecular recognition based on ??? stacking between the phenothiazinium ring and aromatic rings of specific substrates, such as anthracene monophosphate, while imidazole groups catalyze the hydrolysis of the phosphate ester by general acid-base mechanism.

Molecular oxygen in its lowest electronically excited state plays an important roll in the field of chemistry. This excited state is often referred to as singlet oxygen and can be generated in a photosensitized process under one- or two-photon excitation of a photosensitizer. It is particularly useful in the field of photodynamic cancer therapy (PDT) where singlet oxygen formation can be used to destroy cancerous tumors. The use of two-photon activated photosensitizers possesses great potential in the field of PDT since near-IR light is used to activate the sensitizer, resulting in deeper penetration of light into biological tissue, less photobleaching of the sensitizer, and greatly improved resolution of excitation. The synthesis and photophysical characterization of new fluorene-based photosensitizers for efficient singlet oxygen production were investigated. The spectral properties for singlet oxygen production were measured at room temperature and 77 K. Two-photon absorption (2PA) cross-sections of the fluorene derivatives were measured by the open aperture Z-scan method. The quantum yields of singlet oxygen generation under one- and two-photon excitation (Φ∆ and 2PAΦ∆, respectively) were determined by the direct measurement of singlet oxygen luminescence at ≈ 1270 nm. The values of Φ∆ were independent of excitation wavelength, ranging from 0.6 - 0.9. The singlet oxygen quantum yields under two-photon excitation were 2PAΦ∆ ≈ ½Φ∆, indicating that the two processes exhibited the same mechanism of singlet oxygen production, independent of the mechanism of photon absorption.

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<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> / Doctor of Philosophy (PhD)

The peritoneal tumor is not named after the originating of cancer cells but instead contains all tumors appearing in the region of the peritoneal cavity. There are over 250,000 new cases of malignant diseases originating from organs in the peritoneal cavity annually in the USA, and most of these cases spread by intraperitoneal seeding. Cytoreductive surgery for removal and debulking of metastases in the peritoneal cavity is the primary treatment option. Complete surgical removal of the cancerous tissues, however, is difficult to achieve because positive margins are often left behind, and it is difficult to detect the small metastases in the peritoneal cavity. Methyl aminolevulinate (MAL), a protoporphyrin X (PplX) prodrug, has been clinically used for photodynamic therapy of local malignancies such as Basal Cell Carcinoma and Actinic Keratosis. Its application for cancers in the peritoneal cavity, however, has been limited by its non-specific biodistribution and adverse effects. Since nanoparticles can play an essential role as drug deliver platforms as a result of their loading capacity, sustained drug release profile, and potential targeting ability, I proposed a liposomal delivery system, Folic-modified liposome (FL). The goal of this study is to take advantage of this observation by developing a FL system of MAL for photodynamic diagnosis and therapy of cancers in the peritoneal cavity in a more specific and efficient manner. Based on the results presented, FL has the potential to improve cytoreductive surgery in the following manner: a) A hydrophilic core can encapsulate high amounts of MAL and protect it from metabolic degradation; b) FL systems loaded with MAL can enlarge the gap between PpIX accumulation in tumor cells and normal tissues. c) FL system loaded with MAL can provide photodynamic diagnosis and photodynamic therapy as complementary functions. / Pharmaceutical Sciences