Sarah Newton

Doctoral Researcher 
Physical Sciences of Imaging in the Biomedical Sciences CDT

Project completed in 2016.

Thesis project - "Optimisation of a new class of MRI contrast agent"

Supervisors:
Dr Anna Peacock, School of Chemistry
Dr Melanie Britton, School of Chemistry
Dr Iain Styles, School of Computer Science 

The Peacock Group have previously reported that Gd(III) coiled coils can display promising relaxivity, and that introduction of the Gd(III) binding site towards the N-terminus, Gd(MB1-1)3, yielded the highest relaxivity complex.

This design was adopted for subsequent optimisation, firstly to evaluate if the dependence of relaxivity on molecular rotation, could be exploited to further modulate the MRI efficiency of the Gd(III) complex. Peptides with four, five and six heptads were investigated. It was found that the longest coiled coil has only a small impact on folding and stability in the apo and lanthanide forms. The shortest peptide remains poorly folded on the addition of Gd(III), despite this, all three peptides have the same inner sphere water coordination, coordination chemistry and the relaxivity of the two longer peptides display the same potential as an MRI contrast agent.

In order to further optimise the coiled coil, secondary sphere and outer sphere water coordination and dynamics were investigated through the design and characterisation of five new peptides. It was found that a water channel located within the coiled coil allows secondary sphere to come within close proximity, with the potential to increase relaxivity.

Finally, the physiological potential of the coiled coils was investigated for use in biological systems. As the peptides have differing positions of the Ln(III) binding site and different amount of inner sphere water coordination, it was first of interest to investigate how these changes would affect the potential for transmetalation. Subsequently cell lines were treated with Gd(MB1-1)3 at MRI relevant concentrations in order to assess the toxicity of the metallo complex. It was found that transmetalation occurs in each peptide to different extents and that cell death occurs at high concentrations of the metallo peptide.