Development of Cancer Cell Selective Photodynamic Therapy Agents & Bio-Chemiluminescent Probes for Tumor Imaging

Cancer is one of the major global health threats. Therapies involving conventional methods have a range of drawbacks, resulting in complicated adverse effects. Recently, alternative therapy methods have been introduced for cancer treatment. To this end, photodynamic therapy (PDT) emerged as a promising treatment modality. Many photosensitizers (PS) have been introduced as promising drug candidates for PDT action. However, selectivity towards cancer cells, without harming healthy cells appeared as one of the challenges in PDT. Herein, in the first part activatable resorufin-based photosensitizers (R1, RR-1, RB-1, and RAM) are introduced for selective PDT on cancer cell. The first agent, R1, not only marks the first resorufin based PS, but also features the first Monoamine Oxidase (MAO) activatable PDT agent. RR-1, on the other side, is the first resorufin-based activatable PDT agent, which is classified as a theranostic agent, exhibiting both imaging and therapy properties in cancer cells upon reacting with H2O2. The third agent developed in the scope of this thesis namely RB-1 illustrates the first -galactosidase responsive PS for imaging and ablation of glioblastoma cells. Dual analyte responsive PSs are known to prevent undesired photocytotoxicity on normal cells due to the presence of an additional control mechanism PS activation. In this direction, we designed a dual locked resorufin-based PS, RAM, which marks the first ever resorufin-based double aPS that can be utilized for the treatment of Aminopeptidase N and Monoamine Oxidase overexpressing liver cancer cells. Need for external light source in the excitation of fluorophores dramatically restricts the wider acceptance of conventional fluorophores in clinical practices. In this sense, alternative imaging techniques were proposed in the last few decades. Bioluminescence, which utilizes luciferin-luciferase pair, emerged as one of the bio-inspired imaging methods. It eliminates the external light source and requires a luciferase enzyme as a catalyst to form excited oxyluciferin, which emits light while relaxing to its ground state. By using the principles of bioluminescence, a novel matriptase activatable probe (A1) was proposed in the imaging of prostate cancer. Matriptase shows elevated expression in prostate cancer and plays as one of the important biomarkers in the imaging applications. Enzyme dependence of luciferin-based imaging brings difficulties during in-vivo experiments, especially in the case of inefficient luciferase transfection. For this purpose, the last part of the thesis focuses on the development of novel chemiluminescent probes, an imaging method based on a chemical reaction, which does not require any additional catalyst for activation. New generation chemiluminescent probes are -elongated, phenoxy 1,2-dioxetanes, which possesses enhanced solubility and brighter emission in aqueous solutions. The phenolic group in the core structure is suitable for insertion of caging (masking) groups that are triggerable with the analyte of interest in the production of chemiluminescence signal. Although many activatable chemiluminescent probes have been developed so far, organelle targeted activatable ones are not reported yet in the literature. In this direction, first ever example of a mitochondria targeted and leucine aminopeptidase (LAP) activatable phenoxy-1,2-dioxetane based chemiluminescent probe (MCL) was synthesized and discussed. LAP is an important metallopeptidase cleaving N-terminal leucine from peptides and takes crucial roles in invasion, proliferation of tumor cells. MCL offers the first ever organelle imaging of cancer cells based on chemiluminescence mechanism.