Gene-based Contrast for MRI

Several BIRC scientists are collaborating to develop reporter gene expression for MRI. This imaging modality relies on tissue and cellular contrast agents that perturb the local magnetic field, providing a signal that can be spatially and temporally related to the subject. While superparamagnetic iron oxide (SPIO) nanoparticles are effective contrast agents, tracking cells using these synthetic particles is limited by their dilution during cell division, degradation by the cell, and lack of inherent biological activity. To address these shortcomings, the genetic activity of magnetotactic bacteria, which form membrane-enclosed iron biominerals, termed magnetosomes are being studied. Magnetosomes are similar to SPIO in size, composition of the iron oxide (magnetite) and magnetic properties. To induce the formation of magnetosome-like particles in mammalian cells, MagA, a putative iron transporter from M. magneticum sp. AMB-1, has been overexpressed in several cell types, including cancer and stem cell models. To date, all cells expressing MagA respond to extracellular iron supplementation by increasing cellular iron content. This property leads to an effective increase in MR contrast and has been used to monitor the growth of tumours from transplanted MagA-expressing cells.

Thus, through genetic engineering, magnetic characteristics are imparted to cells, creating a tracking system suitable for long-term, repetitive imaging of cellular function, including migration, mitosis, differentiation and cell death. Molecular imaging with MRI using magnetosome gene expression in eukaryotic cells has been patent protected and advanced from provisional filing to national phase in both Canada and the USA. In 2011, a European patent was awarded in Germany, France and the U.K. and in 2014 a second related provisional was filed. In addition, global interest in MagA expression has resulted in negotiation of six Material and Information Transfer and Use Agreements. Through BIRC collaborations, examination of MagA expression in cancer cells has been expanded to the measurement of MRI relaxation rates to characterize the molecular signature of this form of gene-based contrast (Sengupta et al, 2014, Frontiers in Microbiol 5, 29).

Repetitive 3T MRI of MagA expression versus the parental control tumour. Representative images are from a mouse receiving 10 million tumour cells subcutaneously: MagA-expressing (L), parental (R). The animal is oriented back down and head toward the viewer; arrows point to tumours. For perspective, the first row gives the full view of the mouse body in axial cross section, at day 20 post-injection. The middle and last rows show a magnified view of MagA-expressing or control tumours, respectively, over time. Several regions of signal loss (arrowheads) were observed in MagA-expressing and parental tumours at all time points. In this representative mouse, no void was detected in the parental tumour at day 2 post-injection.

To gain further insights into iron-specific MR detection methods, BIRC scientists are also examining the fundamental NMR signal in MagA-expressing cells. This complements developments in other imaging modalities and reporter gene expression systems. Using hybrid imaging with PET/MRI permits simultaneous cell tracking with two different reporter genes and two different imaging methods, combining the best in sensitivity (nuclear) and resolution (MR). This work is directly applicable to development of MagA expression in a cardiac model of progenitor cell transplantation and will complement studies using cells radiolabelled with 111-Indium for SPECT.

Funding of this molecular imaging research is a partnership between private business, governmental and institutional sectors. In the clinical setting, there is an immediate need for tracking cell therapy, such as stem cells implanted to regenerate function in a failing organ. In preclinical research, cell tracking can be used to monitor the growth of metastatic cells and to evaluate the efficacy of anti-cancer therapies. Commercialization opportunities are anticipated in the future for magnetosome gene expression vectors that permit reporter gene expression for MRI.

Investigators
Savita Dhanvantari, PhD, Molecular Imaging
Paula Foster, PhD, MRI
Neil Gelman, PhD, MRI
Donna Goldhawk, PhD, Molecular Imaging
Lisa Hoffman, PhD, Molecular Imaging
Jim Koropatnick, PhD, Molecular Oncology
Michael Kovacs, PhD, PET Radiochemistry
Ting-Yim Lee, PhD, PET/CT
Frank Prato, PhD, Bioelectromagnetics
Robert Stodilka, PhD, Hybrid Imaging
Terry Thompson, PhD, MRI
Gerry Wisenberg, MD, Cardiac Imaging

Collaborators
Claude Lemaire, PhD, MRI (U of Waterloo)