Horimatsu T, Muto M, Yoda Y, Yano T, Ezoe Y, et al. (2012) Tissue Damage in the Canine Normal Esophagus by Photoactivation with Talaporfin Sodium (Laserphyrin): A Preclinical Study. PLoS ONE 7(6): e38308. doi:10.1371/journal.pone.0038308 / 京都大学 / 0048 / 新制・論文博士 / 博士(医学) / 乙第12870号 / 論医博第2086号 / 新制||医||1006(附属図書館) / 31588 / (主査)教授 羽賀 博典, 教授 坂井 義治, 教授 平岡 眞寛 / 学位規則第4条第2項該当 / Doctor of Medical Science / Kyoto University / DFAM

京都大学 / 0048 / 新制・論文博士 / 博士(医学) / 乙第13132号 / 論医博第2136号 / 新制||医||1024(附属図書館) / (主査)教授 溝脇 尚志, 教授 坂井 義治, 教授 山田 泰広 / 学位規則第4条第2項該当 / Doctor of Medical Science / Kyoto University / DFAM

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Two-photon absorbing (2PA) materials has been widely studied for their highly localized excitation and nonlinear excitation efficiency. Application of 2PA materials includes fluorescence imaging, microfabrication, 3D data storage, photodynamic therapy, etc. Many materials have good 2PA photophysical properties, among which, the fluorenyl structure and its derivatives have attracted attention with their high 2PA cross-section and high fluorescence quantum yield. Herein, several compounds with 2PA properties are discussed. All of these compounds contain one or two fluorenyl core units as part of the conjugated system. The aim of this dissertation is to discuss the application of these compounds according to their photophysical properties. In chapters 2 to 4, compounds were investigated for cell imaging and tissue imaging. In chapter 5, compounds were evaluated for photodynamic therapy effects on cancer cells. Chapters 2 and 3 detail compounds with quinolizinium and pyran as core structures, respectively. Fluorene was introduced into structures as substituents. Quinolizinium structures exhibited a large increase in fluorescence when binding with Bovine Serum Albumin (BSA). Further experiments in cell imaging demonstrated a fluorescence turn-on effect in cell membranes, indicating the possibility for these novel compounds to be promising membrane probes. Pyran structures were conjugated with arginylglycylaspartic acid peptide (RGD) to recognize integrin and introduced in cells and an animal model with tumors. Both probes showed specific targeting of tumor vasculature. Imaging reached penetration as deep as 350 µm in solid tumors and exhibited good resolution. These results suggest the RGD-conjugated pyran structure should be a good candidate probe for live tissue imaging. Chapter 4 applied a fluorene core structure conjugated with RGD as well. Application of this fluorenyl probe compound is in wound healing animal models. Fluorescence was collected from vasculature and fibroblasts up to ≈ 1600 µm within wound tissue in lesions made on the skin of mice. The resolution of images is also high enough to recognize cell types by immunohistochemical staining. This technology can be applied for reliable quantification and illustration of key biological processes taking place during tissue regeneration in the skin. Chapter 5 describes three fluorenyl core structures with photoacid generation properties. One of the structures showed excellent photo-induced toxicity. Cancer cells underwent necrotic cell death due to pH decrease in lysosomes and endosomes, suggesting a new mechanism for photodynamic therapy.

Photodynamic therapy (PDT) has been investigated over the past three decades and is currently an approved therapeutic modality for skin cancer, the treatment of superficial bladder, early lung and advanced esophageal cancers, and age-related macular degeneration in a number of countries. In PDT, the absorption of light by a chromophore generates cytotoxic species such as reactive singlet oxygen, leading to irreversible destruction of the treated tissue. The measurement of the singlet oxygen quantum yield is an important determinant used to evaluate the efficiency of new photodynamic therapy agents developed in the laboratory, to screen potential photosensitizers in aqueous media.The singlet oxygen quantum yield is a quantitative measurement of the efficiency in which photosensitizers are able to use energy, in the form of light, to convert oxygen in the ground state to the reactive species singlet oxygen useful in photodynamic therapy. Singlet oxygen quantum yields of photosensitizers differ when measured in different solvents. The majority of the existing quantum yield values found in literature for various photosensitizers are documented with the sensitizers in organic solvents though values in aqueous media are more valuable for actual applications. Determination of accurate and precise quantum yield values in aqueous solution is a much more difficult problem than in organic media. Problems in aqueous solution arise primarily from the physicochemical properties of singlet oxygen in water. Singlet oxygen has a much shorter lifetime in water than it does in organic solvents, causing challenges with respect to quantitative detection of singlet oxygen.The ensuing pages are an attempt to explore the theory and document the procedures developed to provide the accurate measurement of singlet oxygen in aqueous media. Details of this experimental method and singlet oxygen quantum yield results of new compounds relative to established photosensitizers will be presented.

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京都大学 / 新制・論文博士 / 博士(医学) / 乙第13565号 / 論医博第2292号 / 新制||医||1068(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 小林, 恭, 教授 小濱, 和貴, 教授 上杉, 志成 / 学位規則第4条第2項該当 / Doctor of Medical Science / Kyoto University / DFAM

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