Smart hydrophilic/ hydrophobic switches for targeted membrane delivery

细胞膜起到了屏障的作用，调节分子进出细胞的运动。构成膜的脂质双层包含一个疏水的内部，因此，亲水性分子，如离子和一些药物分子，不能在没有帮助的情况下越过这一屏障。这意味着新的药物靶点需要具有足够的疏水性，以便通过穿过细胞膜进入细胞和组织，但也需要足够的亲水性，以便溶解在血液中，以便被循环携带到预定的作用部位。在药物设计中，实现这一平衡是一个重大挑战。在发现管道中，近90%的分子水溶性差，溶解性差的候选药物失败的风险更高。在设计治疗药物以定位和发挥细胞膜内的功能时，平衡亲水性和疏水性的挑战尤其困难。在这种环境中发挥作用的潜在药物靶点的例子包括小分子离子载体。离子载体可用于治疗囊性纤维化等疾病的通道替代疗法，囊性纤维化是一种缩短寿命的遗传性疾病，会损害自然产生的离子通道的功能。然而，为了在脂质双层内发挥作用(而不是仅仅通过)，离子载体需要非常疏水。因此，它们很少是水溶性的，因此它们在细胞和组织中的传递极具挑战性。这限制了它们作为疾病治疗的潜在应用。为了解决这个问题，我们建议开发小分子，这些小分子可以在触发刺激(光或热)的作用下在亲水和疏水之间进行可逆切换。这些开关将被设计成“标签”，可以很容易地添加到小型治疗和成像试剂上。这将使我们能够通过施加触发刺激来实时控制附加分子的亲水到疏水的平衡，并允许我们将疏水货物运送到脂类双层中，在那里它们可以发挥作用。我们将首先展示我们可以将添加的疏水货物输送到简单的细胞膜模型中，这将帮助我们优化“标签”的分子设计，并获得对其开关能力的精确控制。然后，我们将在真实细胞中进行实验，以演示疏水货物在刺激下进入细胞膜的传递和功能。解决将这些疏水分子输送到细胞的问题将为它们未来成为可行的候选药物铺平道路。此外，“标签”还将成为开发新的和现有的药物和诊断剂以及农用化学品和香料的宝贵工具，其中了解和控制化学品在生理和生态系统中的分布至关重要。

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.