Design, synthesis and investigation of in vitro therapeutic effects of silicon-substituted xanthene based phototheranostic agents

Cancer remains to be major public health problem and leading cause of mortality worldwide despite extensive efforts to develop effective cancer therapeutic methods. Tumor heterogeneity, metastasis and therapy resistance are among the major problems limiting therapeutic efficacy. The combination of therapeutic action with diagnostic imaging known as theranostic action is a developing modality to address these challenges. So far photodynamic therapy (PDT) has been accepted as highly promising methods as it offers non-invasive treatment, low systemic toxicity, negligible drug resistance and immune system activation against the tumor. PDT involves the generation of cytotoxic reactive oxygen species (ROS) through the interaction of a photosensitizer (PS), light and molecular oxygen (3O2). However, there are some obstacles of PDT including limited penetration depth of incident light through tissues hindering the widespread application in clinical studies. Therefore, the development of PSs to address current challenges is in great importance. Herein, this thesis put emphasis on development of new phototheranostic agents with improved properties. In the first part, SF-I, iodinated derivative of silicon fluorescein (SF), was introduced as the first example of SF based PDT agent, which holds great promise as a small molecule-based theranostic agent. Photophysical properties and singlet oxygen generation of SF-I in aqueous solutions was evaluated and found to be promising in phototheranostic applications with red shifted absorption and high singlet oxygen quantum yield up to 45%. Cytotoxicity and fluorescent imaging potential of SF-I in vitro was evaluated in two different (MDA MB-231, HCT-116) cancer cell lines. Novel designs based on SF-I to increase selectivity towards cancer cells are easy to apply by substitution through phenolic groups in the structure. In the second part, our aim was to design an activatable phototheranostic agent. In this direction, another silicon-xanthene core Tokyo Magenta (TM) was converted into theranostic agent by modifying structure with iodine and a H2S cleavable cage group. High singlet oxygen quantum yield (34%) and fluorescence quantum yield (34%) of TM-I-H2S after activation with H2S makes it a great candidate for theranostic applications. Phototheranostic efficacy of TM-I-H2S was studied in colorectal cancer cells (HCT116) and triple-negative breast cancer (MDA MB-231). It was concluded that, TM-I-H2S can induce singlet oxygen production in cancer cells with high H2S level and allows fluorescent imaging at the same time.