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Smart hydrophilic/ hydrophobic switches for targeted membrane delivery

用于靶向膜输送的智能亲水/疏水开关

基本信息

批准号：
EP/T025735/1
负责人：
Cally Haynes
金额：
$ 49.86万
依托单位：
University College London
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2021
资助国家：
英国
起止时间：
2021 至无数据
项目状态：
未结题

来源：
https://gtr.ukri.org/projects?ref=EP%2FT025735%2F1
关键词：
Smart hydrophilic hydrophobic switches targeted

项目摘要

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.

细胞膜作为一个屏障，调节分子进出我们的细胞。构成膜的脂质双层含有疏水内部，因此极性亲水分子如离子和一些药物分子不能单独穿过该屏障。这意味着新的药物靶点需要足够疏水，以通过穿过细胞膜进入细胞和组织，但也需要足够亲水，以溶解在血液中，以便通过循环携带到预期的作用部位。实现这种平衡是药物设计中的一个重大挑战。近90%的药物分子水溶性差，而溶解性差的候选药物失败的风险更高。当设计出定位于细胞膜内并在细胞膜内发挥作用的治疗药物时，平衡亲水性和疏水性的挑战尤其困难。在这种环境中起作用的潜在药物靶标的实例包括小分子离子载体。离子载体可以用作疾病的通道替代疗法，例如囊性纤维化，这是一种缩短寿命的遗传性疾病，会损害天然存在的离子通道的功能。然而，为了在脂质双层内发挥作用（而不仅仅是通过），离子载体需要具有极强的疏水性。因此，它们很少是水溶性的，因此将它们递送到细胞和组织中极具挑战性。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，我们建议开发能够在触发刺激（光或热）的应用下在亲水性和疏水性之间可逆切换的小分子。这些开关将被设计为“标签”，可以很容易地附加到小的治疗和成像剂。这将使我们能够通过施加触发刺激来真实的控制附加分子的疏水-疏水平衡，并使我们能够将疏水货物递送到它们可以发挥作用的脂质双层中。我们将首先证明，我们可以将附加的疏水货物输送到简单的细胞膜模型中，这将有助于我们优化“标签”的分子设计，并精确控制它们的开关能力。然后，我们将在真实的细胞中进行实验，以证明疏水性货物响应刺激进入细胞膜的递送和功能。克服将这些疏水分子递送到细胞的问题将为它们在未来作为可行的候选药物的发展铺平道路。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。