Supramolecular rotaxane-based imaging agents targeting cancer biomarkers

Mechanically interlocked molecules present opportunities to construct therapeutic drugs and diagnostic imaging agents but harnessing supramolecular chemistry to make biologically active molecules in water is a challenge. Here, we describe a rotaxane-based approach in the synthesis of radiolabelled proteins and peptides for molecular imaging of cancer-specific biomarkers in vivo. Host-guest chemistry with mono-functionalised beta-cyclodextrin, combined with curcurbit[6]uril catalysed cooperative capture synthesis, produced radioactive gallium-68 or zirconium-89-labelled metallo[4]rotaxanes. Simultaneous, one-pot radiolabelling and photochemical conjugation to monoclonal antibodies produced a viable radiotracer that was evaluated in vivo for quantitative positron emission tomography (PET) imaging of cancer biomarker expression. The rotaxane architecture can be easily tuned to accommodate different radioactive metal ion complexes, other proteins and peptide-based drugs, and fluorophores for optical detection. This technology provides a future platform to explore the use of mechanical bonding to optimise drug delivery, control metabolism and excretion profiles, and enhance the efficacy of tumour specific agents.