(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

(Poster) 10^th World Molecular Imaging Conference, Philadelphia, Pennsylvania, USA. 12^th of September, 2017.

Background:  Nanomedicines have been shown to have great potential for the diagnosis and treatment of a variety of cancers, but their utility towards brain cancers has been limited due to the difficulty in penetrating the blood-brain barrier (BBB). Testing of these nanomedicines requires preclinical studies, but typically rely on orthotopic glioma models which disrupt the BBB in the process and are not indicative of human glioma. In order to create a preclinical method to assess nanomedicines which can be translated for use in the treatment of human brain cancer, we have utilised a mouse model with endogenous glioma formation. ¹   Current clinical diagnosis of glioma makes use of dynamic contrast enhanced (DCE) magnetic resonance imaging (MRI), with positron emission tomography (PET) becoming more commonly used for validation as well. In order to improve the efficacy of nanomedicines in the treatment of brain cancer, establishment of a clinically translatable, preclinical technique for the analysis and refinement of nanomedicines is of significant need.

Hypothesis:  By using PET-MR to measure tumor volume, BBB integrity and the crossing of nanomedicines, a relationship between tumor progression and particle size can be made for the benchmarking and improvement of nanomedicines for the diagnosis and treatment of glioma.

Aims:  To create a suitable molecular imaging protocol using PET-MRI to measure the progression of glioma and then assess whether or not a nanomedicine could cross the BBB at each stage, validating with both live imaging and post-mortem analysis.

Results & Summary:  A series of pre- and post-contrast enhanced MRI were used at various time points across the development of the glioma to measure the volume of the tumor and a DCE-MRI sequence was run to analyze the leakiness of the BBB. [¹⁸F]-fluoro-dopamine (¹⁸FDOPA), an established radiotracer for glioma detection, was co-injected at time points where the tumor was known to be visible with MRI to validate the presence and volume of the tumor. A precise region of interest (ROI) for the tumor was made from the contrast enhanced MR image utilizing a random walker algorithm, and was validated with a similar technique off the ¹⁸F-PET image. Leakiness of the BBB was assessed by measuring the uptake of Gadovist® at multiple time points for the tumour and fitting an equation to give a two-parameter measure for the maximum extent and rate of leakiness. A ⁶⁴Cu labelled, antibody targeted nanomedicine was then injected at key time points, allowed to circulate for 18-24 hours, and the uptake into the tumor was measured. The nanomedicines were observed only to cross at time points in the late terminal stage of the cancer, but not at earlier stages.  The work presented herein serves as a proof-of-concept that can be used to test a variety of nanomedicines of different shape, size, and charge to allow the further development of BBB permeable nanomedicines.

References:
(1)       Chow, L.; Endersby, R.; Zhu, X.; Rankin, S.; Qu, C.; Zhang, J.; Broniscer, A.; Ellison, D.; Baker, S. Cancer Cell 2011, 19, 305–316.

(Poster) Nano Frontiers Symposium – Columbia, Missouri, USA.

An overview of the major research projects at the International Institute of Nano & Molecular Medicine was given.

(Poster) Nano Frontiers Symposium – Columbia, Missouri, USA.

An overview of targeted polyhedral borane scaffolds was shown.