(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.