Supramolecular chemistry involves systems held together by non-covalent interactions. These systems hold promise in the design of drug delivery systems targeting cancer. Our goal is to use the supramolecular chemistry of rotaxanes as a scaffold for building multi-modality imaging agents. To this end, we report the synthesis and characterisation of functionalised, cancer targeting radiotracers.

A cooperative capture approach was used to develop radiolabelled, mechanically interlocked molecules (rotaxanes). Our attention focused on a ‘click’ chemistry reaction involving triazole formation by catalysis using CB[6] and β-CD. An efficient preorganisation between the azide and alkyne derivatives, CB[6] and β-CD via hydrogen bonds, facilitated a rapid synthesis of rotaxanes functionalised with metal ion complexes, fluorophores and cancer-specific ligands. The monofunctionalisation of β-CD also expand the versatility of the construct. To demonstrate the flexibility of our design, we synthesised various radioactive rotaxanes in a one-pot strategy. Thus, ⁶⁸Ga-desferrioxamine or ⁶⁸Ga-NODAGA complexes, fluorescein and Lys-NHC(O)NH-Glu inhibitors were used as stoppers on the axels of the rotaxanes or as functional features on the β-CD macrocycle. Reactions to make multi-functional rotaxanes were complete in less than one minute at 70 °C in biologically compatible media. All constructs were characterised by multinuclear NMR, high-resolution electrospray ionisation mass spectrometry and high-performance liquid chromatography. Radiolabelling reactions gave ⁶⁸Ga-rotaxanes in high radiochemical yield and purity. To the best of our knowledge, this work represents the first use of supramolecular chemistry to access cancer-specific radiotracers for multi-modality imaging. Biological studies including cellular uptake and binding assays, and PET imaging in mouse models of human cancer, are underway.

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