A combined experimental and computational approach for the rational synthesis of rotaxanes as 'smart' drug delivery systems

合理合成轮烷作为“智能”药物输送系统的实验和计算相结合的方法

• 批准号: 2896287
• 金额: --
• 依托单位: Imperial College London
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2896287
• 关键词: combined; experimental; computational; approach; rational

The efficacy of many drugs can be limited by undesirable properties such as poor aqueous solubility, low bioavailability, and "off-target" interactions in the body. To combat these deficiencies, various drug carriers have been investigated to enhance the pharmacological profile of therapeutic agents. In particular, there is growing interest in systems that have high degree of spatiotemporal control for the release of the drug to a specific target. However, such systems are scarce due to synthetic challenges and difficulties in applying them in vivo. We have recently developed a novel approach to control the interactions of a drug with its biomolecular targets as well as for its controllable delivery to cancer cells using external stimuli (Angew. Chem. Int. Ed. 2021, 60, 10928). This has been achieved by 'caging' the drug in a rotaxane - a type of interlocked molecule. This project will build on our initial results to develop a systematic approach for the modular caging of different drugs into rotaxanes. In the new assemblies, we will incorporate drug molecules that can target different biomolecules (e.g. DNA, RNA or proteins) as well as 'triggers' to control the delivery of the drugs to specific cells (e.g. cancer cells). To achieve these aims, the project will involve synthesis of sophisticated rotaxanes, testing the 'uncaging' mechanisms to target the desired biomolecules/cells and application of data-driven and computer modelling approaches for the rational design of the new systems.

许多药物的功效可能受到不良性质的限制，例如水溶性差、生物利用度低和体内“脱靶”相互作用。为了克服这些缺陷，已经研究了各种药物载体以增强治疗剂的药理学特性。特别地，对具有高度时空控制以将药物释放到特定靶标的系统的兴趣日益增加。然而，这种系统是稀缺的，由于合成的挑战和困难，在体内应用它们。我们最近开发了一种新的方法来控制药物与其生物分子靶标的相互作用以及使用外部刺激将其可控地递送至癌细胞（Angew.国际化学版2021，60，10928）。这是通过将药物“笼”在轮烷中实现的-轮烷是一种互锁分子。这个项目将建立在我们的初步结果，以开发一个系统的方法，模块笼不同的药物到轮烷。在新的组件中，我们将结合可以靶向不同生物分子（例如DNA，RNA或蛋白质）的药物分子以及“触发器”，以控制药物向特定细胞（例如癌细胞）的递送。为了实现这些目标，该项目将涉及合成复杂的轮烷，测试“释放”机制以靶向所需的生物分子/细胞，以及应用数据驱动和计算机建模方法来合理设计新系统。