Smart hydrophilic/ hydrophobic switches for targeted membrane delivery

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The cell membrane acts as a barrier that regulates the movement of molecules into and out of our cells. The lipid bilayer that makes up the membrane contains a hydrophobic interior, and as such polar, hydrophilic molecules such as ions and some drug molecules cannot cross this barrier unaided. This means that new drug targets need to be hydrophobic enough to enter cells and tissues by crossing the cell membrane, but also hydrophilic enough to dissolve in the blood in order to be carried by the circulation to the intended site of action. Achieving this balance is a significant challenge in drug design. Nearly 90% of molecules in the discovery pipeline are poorly water-soluble, and drug candidates with poor solubility carry a higher risk of failure.The challenge of balancing hydrophilicity and hydrophobicity is particularly difficult when designing therapeutics to localise and function inside a cell membrane. Examples of potential drug targets that function in this environment include small molecule ion carriers. Ion carriers could be used as channel replacement therapies for diseases such as Cystic Fibrosis, a life-shortening genetic disorder that impairs the function of naturally occurring ion channels. However, in order to function inside a lipid bilayer (rather than just passing through), the ion carriers need be extremely hydrophobic. As a result they are rarely water soluble, and hence their delivery into cells and tissues is extremely challenging. This limits their potential application as treatments for disease.To address this problem, we propose to develop small molecules that can reversibly switch between hydrophilic and hydrophobic on the application of a triggering stimulus (light or heat). These switches will be designed as "tags" that can be easily appended to small therapeutic and imaging agents. This will enable us to control the hydrophilic-to-hydrophobic balance of the appended molecules in real time by applying triggering stimuli, and allow us to deliver hydrophobic cargoes into lipid bilayers where they can function. We will firstly demonstrate that we can deliver appended hydrophobic cargoes into simple models of cell membranes, which will help us to optimise the molecular design of the "tags" and gain precise control of their switching capabilities. We will then perform experiments in real cells to demonstrate the delivery and function of the hydrophobic cargoes into cell membranes in response to stimuli. Overcoming the problem of delivering these hydrophobic molecules to cells will pave the way for their development as viable drug candidates in the future. Additionally, the "tags" will also become valuable tools in the development of new and existing pharmaceuticals and diagnostic agents, as well as agrochemicals and fragrances, in which understanding and controlling the distribution of chemicals in physiological and ecological systems is crucial.