Development of small molecule-based probes for cancer cell selective imaging and phototherapy

Clinical practice still requires better understanding of diseases along with the development of advanced tools that facilitate monitoring, screening and treatment. The activity-based approach is a smart strategy that leverages biomarker selectivity and activity to monitor and treat various diseases with high precision and accuracy. The main purpose of this thesis was to develop strong imaging platforms and therapeutics and subsequently apply them in cancer-focused studies. Fluorescence imaging is an established and continuously evolving imaging modality applied widely in cancer imaging. In this direction, an acetylcholinesterase (AChE) activatable fluorescent platform (TCFPB-AChE) with a smart molecular design approach was developed in the first section. TCFPB-AChE remained in its silent form and produced a fluorescence output upon interacting with AChE. Using this activity-based turn on response, TCFPB-AChE monitored AChE activity in U87 glioblastoma cells, Alzheimer's disease mice brain tissues, and living mice brains. In the second section, H2S-activatable PDT agents were developed for the treatment of neuroblastomas. The first PDT agent RHS, was developed using a heavy atom incorporated resorufin scaffold. Selective activation of RHS by H2S resulted in red-shifted emission, as the photocytotoxic Res-I scaffold was released for efficient PDT. RHS displayed a singlet oxygen quantum yield of 0.42, and was used for cancer-selective PDT action. Although PDT agents can generate abundant singlet oxygen, their therapeutic efficacy is limited by the hypoxic nature of the tumor microenvironment. To address this issue, HEHM was developed to produce type I radicals and sustain ROS generation even in hypoxic tissues. Accordingly, HEHM generated superoxide radical anions and hydroxyl radicals in SH-SY5Y neuroblastoma cells and exerted its photocytotoxic effects under both normoxic and hypoxicconditions. Chemiluminescent materials, particularly extended Schaap's 1,2-dioxetanes, have recently emerged as powerful imaging tools in cancer biology. Since external irradiation is not required, chemiluminescence achieves notably lower detection limits compared to fluorescence. Leveraging this characteristic, a highly selective α-L-Fucosidase (AFU) activatable chemiluminescent platform (α-Fuc) was fabricated in the third section. α-Fuc marks the first example of AFU-specific chemiluminescent scaffold. α-Fuc was employed to monitor AFU activity in HepG2 liver cancer cells, tumor models and a human serum sample.