Photodynamic Therapy (PDT) has become a promising cancer treatment method due to its minimal invasiveness, spatiotemporal selectivity, low systemic toxicity compared to other treatment method. The therapeutic effect of PDT is mainly coming from the explosive production of cytotoxic reactive oxygen s...
Photodynamic Therapy (PDT) has become a promising cancer treatment method due to its minimal invasiveness, spatiotemporal selectivity, low systemic toxicity compared to other treatment method. The therapeutic effect of PDT is mainly coming from the explosive production of cytotoxic reactive oxygen species (ROS) through light activation of photosensitizers (PSs) followed by increase of intracellular oxidative stress which trigger apoptosis or necrosis of target cancer cells. From this aspect, a lots of studies have mainly focused on the issue of improving ROS generation yield of PSs by modifying their structure. However, growing body of research have suggested that due to complicate nature of cancer cells, there are many obstacles that attenuate the cytotoxic effect of ROS generated by PDT. Therefore, to enhance therapeutic effect of PDT, it is of great importance to develop multi-functional PDT system that can overcome intracellular hurdles that hinder the increase of oxidative stress. In the first chapter, a multi-functional PDT system combined with inhibition of Glutathione S-transferase P1-1 (GST-p) is discussed. This system was constructed by incorporating Ethacrynic acid (GST-p inhibitor) to the BODIPY PS. Through GST-p inhibition during PDT, remarkably enhanced photo-cytotoxicity toward GST-p overexpressed cancer cells was achieved. Thorough studies revealed that remarkable photo-cytotoxicity was resulted from the decreased of Glutathione (GSH) level, GST-p activity, s-glutathionylation and detoxification process of lipid peroxide during photo-toxic event. Moreover, the synergetic effect of GST-p inhibition with PDT was also verified in vivo study. In the second chapter, a cancer/cancer stem cell targetable multi-functional PDT system combined with Cu(II) delivery is discussed. This system was constructed by incorporating Acetazolamide (CAIX inhibitor) and Cu(II) ligand to a BODIPY PS. Thorough studies revealed that incorporated Cu(II) hampered the fluorescence emission, also singlet oxygen generation of PDT system. However, this suppressed property was observed to be recovered by GSH through redox coupling reaction of Cu(II) vs GSH. In vitro studies revealed that this system exhibited superior photo-cytotoxicity to cancer cells due to prominent decrease of intracellular GSH level and increase of ROS level. Moreover, remarkable photo-cytotoxicity to CD133-positive cancer stem-like cells was observed. Furthermore, in vivo studies confirmed its superior tumor inhibition ability. In the third chapter, a cancer/mitochondria targetable single component Photodynamic/Photothermal therapy (PDT-PDT) combination system is discussed. It was constructed by incorporating Triphenylphosphonium (TPP) moiety (cancer mitochondria target unit) to the Diketopyrrolopyrrol and Metoxytriphenylamine based D-A-D type PDT-PTT agent. Photo-physical studies revealed its large photon absorbing, superior ROS generation in aqueous solution and also heat generation. Moreover, in vitro studies confirmed its remarkable photo-toxicity toward cancer cell specifically.
Photodynamic Therapy (PDT) has become a promising cancer treatment method due to its minimal invasiveness, spatiotemporal selectivity, low systemic toxicity compared to other treatment method. The therapeutic effect of PDT is mainly coming from the explosive production of cytotoxic reactive oxygen species (ROS) through light activation of photosensitizers (PSs) followed by increase of intracellular oxidative stress which trigger apoptosis or necrosis of target cancer cells. From this aspect, a lots of studies have mainly focused on the issue of improving ROS generation yield of PSs by modifying their structure. However, growing body of research have suggested that due to complicate nature of cancer cells, there are many obstacles that attenuate the cytotoxic effect of ROS generated by PDT. Therefore, to enhance therapeutic effect of PDT, it is of great importance to develop multi-functional PDT system that can overcome intracellular hurdles that hinder the increase of oxidative stress. In the first chapter, a multi-functional PDT system combined with inhibition of Glutathione S-transferase P1-1 (GST-p) is discussed. This system was constructed by incorporating Ethacrynic acid (GST-p inhibitor) to the BODIPY PS. Through GST-p inhibition during PDT, remarkably enhanced photo-cytotoxicity toward GST-p overexpressed cancer cells was achieved. Thorough studies revealed that remarkable photo-cytotoxicity was resulted from the decreased of Glutathione (GSH) level, GST-p activity, s-glutathionylation and detoxification process of lipid peroxide during photo-toxic event. Moreover, the synergetic effect of GST-p inhibition with PDT was also verified in vivo study. In the second chapter, a cancer/cancer stem cell targetable multi-functional PDT system combined with Cu(II) delivery is discussed. This system was constructed by incorporating Acetazolamide (CAIX inhibitor) and Cu(II) ligand to a BODIPY PS. Thorough studies revealed that incorporated Cu(II) hampered the fluorescence emission, also singlet oxygen generation of PDT system. However, this suppressed property was observed to be recovered by GSH through redox coupling reaction of Cu(II) vs GSH. In vitro studies revealed that this system exhibited superior photo-cytotoxicity to cancer cells due to prominent decrease of intracellular GSH level and increase of ROS level. Moreover, remarkable photo-cytotoxicity to CD133-positive cancer stem-like cells was observed. Furthermore, in vivo studies confirmed its superior tumor inhibition ability. In the third chapter, a cancer/mitochondria targetable single component Photodynamic/Photothermal therapy (PDT-PDT) combination system is discussed. It was constructed by incorporating Triphenylphosphonium (TPP) moiety (cancer mitochondria target unit) to the Diketopyrrolopyrrol and Metoxytriphenylamine based D-A-D type PDT-PTT agent. Photo-physical studies revealed its large photon absorbing, superior ROS generation in aqueous solution and also heat generation. Moreover, in vitro studies confirmed its remarkable photo-toxicity toward cancer cell specifically.
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