Modulation of the Luminescence Properties and Photocytotoxic Activity of Transition Metal Complexes through Dissociative Bioorthogonal Reactions for Diagnostic and Therapeutic Applications

The project investigates the modulation of the luminescence properties and photocytotoxic activity of inorganic and organometallic transition metal complexes with dissociative bioorthogonal reactivity for diagnostic and therapeutic applications. For nearly two decades, bioorthogonal chemistry has allowed investigations of biological processes and molecules in their native environments, leading to a diverse range of novel applications in life sciences. While bioorthogonal chemistry has traditionally focused on biocompatible ligation reactions between two reaction partners under physiological conditions, there is a rapidly emerging interest in dissociative bioorthogonal reactions, or “click-to-release” reactions, where specific bonds are cleaved as a consequence of a bioorthogonal trigger. Bioorthogonal cleavage reactions have been successfully applied to study the functions of small molecules and proteins through an uncaging process, design innovative reaction-based sensing and imaging reagents, and release payloads in a highly specific and controlled manner. Due to their interesting photophysical and singlet oxygen photosensitization behavior, excellent membrane permeability, and controllable cellular uptake properties, luminescent transition metal complexes continue to attract enormous interest in biosensing, bioimaging, and phototherapeutic applications. We envisage that combining the intriguing photophysical and photosensitization properties of transition metal complexes and the specificity associated with bioorthogonal reactions will yield a generation of innovative activatable biological reagents. In this project, we will modify transition metal complexes with dissociative bioorthogonal groups that possess efficient emission quenching capability, with an emphasis on modulating the luminescence properties and singlet oxygen photosensitization activity of the complexes. The cleavage transformation of the bioorthogonal units will not only render the complexes to exhibit phosphorescence turn-on, but also activate the photosensitization properties of the complexes, which will afford interesting phosphorogenic probes for controlled activation of photocytotoxicity, biomolecular sensing and imaging, and investigations of protein activity and functions. Although the click-to-release strategy has been applied in different areas, we are confident that an exploration of photofunctional inorganic and organometallic probes with dissociative bioorthogonal reactivity will substantially widen the scope of bioorthogonal chemistry and further strengthen its impact in biological applications, which will be of broad interest to the chemical biology, biochemistry, and cell biology communities. This project will generate results that showcase the unique properties and roles of luminescent transition metal complexes for the development of biological reagents, which will substantially contribute to the basic understanding of biological processes in live cells and living systems, and provide exciting opportunities for a diverse range of diagnostic and therapeutic applications.