This proposal is in response to PA-06-371 for an In vivo cancer imaging exploratory/developmental grant (R21). The objective is to explore the potential of magnetite (produced by magnetotactic bacteria) in magnetic resonance imaging (MRI) for diagnosing cancer and tracking cancer metastasis. The proposed work is relevant to public health as it seeks to improve cancer imaging, early cancer detection, and monitoring cancer treatment. It is in accord with the mission of the Cancer Imaging Program of the National Cancer Institute, and is fully responsive to PA-06-371, as it """"""""focuse(s) on in vivo cancer imaging for detection, diagnosis, and monitoring of response to therapy"""""""". Magnetotactic bacteria will be used to target tumors;their magnetite can provide a positive MRI contrast, which, compared to negative contrast, is superior for anatomical studies. Furthermore, unlike the current efforts to target MRI contrast agents to tumors, replication of the delivery agent (i.e., the magnetotactic bacteria) in tumors will not dilute the contrasting agent.
Aim 1 will investigate the colonization of orthotopic and metastatic mouse tumors by magnetotactic bacteria, using both MRI and bioluminescence imaging (BLI);to accomplish the latter, the bacteria will be modified to express bacterial luciferase. This dual probe modality will make the tracking of the bacteria highly reliable. MRI will be performed using a dedicated small-animal 7T scanner, and BLI using the IVIS system. It is important that the magnetotatic bacteria generate magnetite as they divide in tumors so as to prevent the dilution of the contrast agent. To investigate this propensity, magnetotactic bacteria grown without iron will be used to target tumors, permitting determination of whether magnetite formation is possible within the tumors. As these bacteria possess potent iron uptake systems, and the tumor environment can be expected to be iron-rich, it is hypothesized that this is possible and will be explored using the dual tracking strategy as above. Since positive MRI contrast is superior, Aim 2 will compare two positive contrast MRI techniques with magnetotactic bacteria: off-resonance excitation, with spatial- spectral radio frequency pulses;and susceptibility-induced gradient mapping. The ability of these techniques to quantify magnetotactic bacteria will be evaluated both in vitro and in vivo. A bacterial system may pose hazards in the clinic. Therefore, Aim 3 will develop a mammalian cell system to deliver magnetite to tumors. Cytokine induced killer (CIK) cells, which can target and kill tumor cells, will be used. The gene(s) required for magnetite production will be transduced into the CIK cells using a lentiviral system. Iron uptake and magnetite formation will be compared in vitro and in vivo by positive- contrast MRI. The results are expected to show that magnetite-encoding genes serve as a powerful reporter system for tracking cancer and can be delivered to tumors through bacteria or CIK cells.
The proposed work will develop a novel sensitive and safe method for early detection of cancer, cancer metastasis, and treatment evaluation. Since all these aspects are critical to fight cancer, these studies address an important public health issue. In the long run, the approach described can also have other health related benefits.
| Benoit, Michael R; Mayer, Dirk; Barak, Yoram et al. (2009) Visualizing implanted tumors in mice with magnetic resonance imaging using magnetotactic bacteria. Clin Cancer Res 15:5170-7 |
