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

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.