DESIGN, SYNTHESIS, AND STUDY OF ZINC-RESPONSIVE LIPID SWITCHES FOR TRIGGERED RELEASE OF LIPOSOMAL CONTENT

Smart drug delivery platforms such as designer liposomes can be used to enhance medicinal properties by enabling control over the time and location of therapeutic cargo release. This can be achieved by designing liposomes that respond to different stimuli by releasing encapsulated contents. Specifically, this work focuses on the synthesis of ion recognition lipid switches. These lipids are designed such that their physical properties are altered upon chelation of a given metal ion, in this case Zn²⁺, becoming membrane destabilizing upon molecular recognition. This contributes to the current state of passively controlled release, where pathophysiological conditions associated with a diseased site are used to control spatiotemporal release of therapeutic cargo. The use of molecular recognition events to effect conformational change and thus cargo release is a newly emerging field of research. Here, a panel of zinc recognition lipids based on known zinc chelating moieties including trispicoylamine (TPA) and N,N,N′,N′-Tetrakis(2-pyridylmethyl) ethylenediamine (TPEN) were synthesized and their release potential analyzed. With incorporation into a liposome platform, these lipids can be used to enhance the selectivity of release at diseased cells exhibiting elevated zinc concentrations including ischemic tissues, neurodegenerative diseases, and certain cancer types.^3-8