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

许多药物的功效可能受到不良性质的限制，如水溶性差、生物利用度低和在体内的“脱靶”相互作用。为了克服这些缺陷，研究人员研究了各种药物载体，以增强治疗剂的药理学特征。特别是，对药物释放到特定靶标具有高度时空控制的系统越来越感兴趣。然而，由于合成方面的挑战和在体内应用的困难，这种系统是稀缺的。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点的相互作用，以及使用外部刺激将其可控地递送到癌细胞中。化学。Int。编辑。2021,60,10928)。这是通过将药物“笼化”在轮烷（一种互锁分子）中实现的。该项目将以我们的初步结果为基础，开发一种系统的方法，将不同的药物模块化笼化到轮烷中。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）的药物分子以及控制药物向特定细胞（例如癌细胞）递送的“触发器”。为了实现这些目标，该项目将涉及复杂轮烷的合成，测试“解锁”机制以瞄准所需的生物分子/细胞，并应用数据驱动和计算机建模方法来合理设计新系统。

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.