The goal of this proposal is to develop a general modular approach to photolabile amphiphiles, suitable for preparation of liposomes that (i) can entrap a biological effecter, such as a pharmaceutical, and (ii) can release their content upon irradiation. Furthermore, we aim to design such a delivery system, for which the photorelease is conditional, i.e. before the system becomes light-sensitive, a triggering event has to occur to """"""""arm"""""""" the system. The PI has developed methodology, based on photoinduced carbon-carbon bond fragmentation in hydroxy- (or amino) alkyl dithiane and trithiane derivatives, which offers a ready access to various molecular and macromolecular systems capable of photochemical """"""""disassembly"""""""". This basic photochemical methodology will be further optimized to suit the goals of this research. Our general approach, which is based on externally sensitized systems, is inherently suitable for these applications. This is because the potentially photocleavable dithiane-based amphiphiles are not light sensitive per se, but can be made light sensitive when an external stimulus is applied, for example, a molecular recognition event brings a sensitizer/initiator closer to the dithiane-carbonyl photolabile """"""""latch"""""""". ? ? An integral part of this project will be to synthesize photolabile lipids tethered to polyethylene glycol polymeric chains for stealth liposome fabrication. Such liposomes will be able to shed their polymeric coat upon irradiation, thus dramatically changing their stability. ? ? The fundamentals of these type delivery vesicles will be demonstrated on a model system, whereby a fluorescent molecular probe will be delivered to a living cell using RGD-integrin recognition as a model targeting mechanism. We will demonstrate docking of the vesicles to the cell wall and internalization of the probe molecules upon irradiation. These studies will lay the groundwork for design and development of targeted stealth liposomes that can be used in various molecular biology applications to deliver biological effecters to living cells and internalize them upon irradiation (a kind of photoinduced endocytosis). Ultimately, these studies will pave way for development of photolabile targeted liposomes for drug delivery. ? ?
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