Molecular Probes for Biomembrane Recognition

The biological membrane is made up of primarily polar lipids and integral membrane proteins. Polar lipids are a broad class of amphiphilic biomolecules that serve diverse biological roles encompassing energy storage, cell compartmentalization, and cell signaling. The first part of the dissertation is an introduction to the structures of polar lipids and their self-assembly properties followed by a summary of biological strategies for polar lipid recognition. The final section of the first chapter is an introduction to synthetic receptors for polar lipids. The next two chapters focus on research towards new probes for anionic phospholipids such as phosphatidylserine (PS) using synthetic zinc(II)-bis(dipicolylamine) (Zn2BDPA) coordination complexes. PS targeting is relevant to cell death since PS is exposed on the surface of dead and dying cells. Zn2BDPA coordination complexes are known to selectively recognize PS-rich membranes and act as cell death molecular imaging agents. However, there is a need to improve in vivo imaging performance by selectively increasing target affinity and decreasing off-target accumulation. The first study (Chapter 2) focuses on the synthesis and screening of a small library of modified Zn2BDPA complexes constructed through the oxime ligation to better understand the structural requirements for membrane PS recognition. The second study (Chapter 3) compares the cell death targeting ability of two new phenoxide-bridged Zn2BDPA deep-red fluorescent probes in cells and two animal models of cell death. An [111]In-labelled radiotracer version of the monovalent probe also exhibited selective cell death targeting with the most favorable in vivo biodistribution profile yet reported for a Zn2BDPA complex. Thus, the monovalent phenoxide-bridged Zn2BDPA scaffold is a promising candidate for further development as a cell death imaging agent in living subjects. In chapters 4 and 5, the focus moves from developing affinity ligands for anionic lipid recognition to developing molecular design principles for liposomal pH nanosensors (Chapter 5) and new analytical strategies for anion detection using indicator displacement assays (Chapter 6).