(Poster) 10^th World Molecular Imaging Conference, Philadelphia, Pennsylvania, USA. 16^th of September, 2017.

Background:  Multidrug resistance in chemotherapy is a considerable challenge to overcome in the treatment of metastatic cancers. Monitoring this resistance with a non-invasive imaging technique would allow clinicians to readily alter the treatment plan to allow for a higher survival rate and potentially preventing metastasis due to chemotherapeutic resistance.  Magnetic Resonance Imaging (MRI) possesses the spatial resolution necessary to assess the presence of a solid tumour mass, but lacks the specificity to assess the biochemical behaviour of the tumour.  One such biomarker, glutathione, is a tripeptide that has been well-documented to be released in higher concentrations in pre-metastatic and drug resistant tumours¹.  While ¹H MRI allows for assessment of tissue types, ¹⁹F-MRI offers a unique diagnostic platform with minimal endogenous background signal in vivo and increased sensitivity. A nanoprobe capable of imaging a biological process, particularly in response to treatment, is therefore a valuable tool to monitor the progression and efficacy of chemotherapy on a biochemical level.

Hypothesis:  Assessment of glutathione levels in multidrug resistant cancer cell lines can be non-invasively assessed using a chemically responsive probe by taking advantage of the specificity of contrast enhanced ¹⁹F-MRI.

Aims:  The initial aim of this project was to prepare and assess the viability of a ¹⁹F switchable probe utilising the paramagnetic relaxation enhancement effect (PRE) by gadolinium (Gd³⁺) on the ¹⁹F nuclei.   The second aim was to analyse the responsiveness of a previously reported hyperbranched polymeric nanocarrier², modified with an biologically responsive linker, to changing concentrations of glutathione in both standard solutions and in different cellular environments.

Results & Summary:  Two ¹⁹F enriched polymers were prepared with fixed DOTA chelators at different structural positions to assess the optimal proximity and composition for the greatest PRE response.   Both T1 and T2 relaxation times, as well as ¹H- and ¹⁹F-MR images confirmed that the adjacent pairing of the ¹⁹F source and Gd³⁺ yielded the best switchable response.  A ¹⁹F enriched nanprobe bound with a tumour-microenvironment responsive DOTA[Gd³⁺] switch is therefore expected to exhibit a concentration dependent ¹⁹F T2-weighted MR image, allowing for the analysis of the biological response to a treatment and assessment of the progression of the disease.  The reported nanoprobe and method holds the potential to add significant diagnostic information in the assessment and treatment of metastatic cancer by utilising existing imaging modalities.

References:

1. Calvert, P., Yao, K.-S., Hamilton, T. C. & O’Dwyer, P. J. Clinical studies of reversal of drug resistance based on glutathione. Chemico-biological interactions 111, 213–224 (1998).
2. Rolfe, B. et al. Multimodal polymer nanoparticles with combined 19F magnetic resonance and optical detection for tunable, targeted, multimodal imaging in vivo. Journal of the American Chemical Society 136, 2413