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Living Factories for Imaging

Nobody could have guessed that magneto-tactic bacteria could be used as MRI contrast agents, yet scientists from CEA-Institute Joliot and CEA-BIAM did it.

Published on 14 February 2017

MRI is an especially fertile field of exploration for molecular imaging; e.g., visualizing biomarkers that are specific to a certain pathology. At NeuroSpin, within CEA-I2BM, researchers are developing processes to identify brain tumors. They focus their research on molecular indicators for neoangiogenesis, a tactic by which a tumor may surround itself with newly grown blood vessels to feed its growth. "The inner walls of these blood vessels are covered with receptors called integrins", said Sébastien Mériaux, researcher at CEA-Institute Joliot. "Our goal is to use molecules that combine the capacity to bind to integrins with that of locally modifying the magnetic resonance signal. We therefore expect to make brain tumor vessels visible in MRIs." Gadolinium and iron are atoms that locally modify the MRI signal. Thus, they can be used to reveal biomarkers and create what are called functionalized contrast agents. "These atoms are encapsulated in matrices to make them bio-compatible and non-toxic", Mériaux said. Despite being the most common indicators currently used in clinical examinations, some gadolinium chelates present severe toxicity risks for the patient.

In Cadarache, 800 km south of NeuroSpin, other scientists from the DRF work with magneto-tactic bacteria. The team led by David Pignol, at CEA-BIAM, is particularly interested in these organisms which produce magnetosomes, kinds of natural compasses allowing the bacteria to orient themselves in their environment. How does this relate to MRI? "The nanomagnets produced by these bacteria are surrounded by a biological membrane and are soluble in aqueous media… just like a contrast agent with an iron core!" said Mériaux. Then, the researchers decided together to genetically modify these bacteria for them to produce magnetosomes exposing, on their surface, a fluorescent protein and an integrin-identifying peptide. "We have thereby created an integrated factory that produces functionalized MRI contrast agents", the scientists said enthusiastically. The last step simply consists of cultivating these bacteria, destroying them, and harvesting the genetically modified magnetosomes by means of a magnet.

The in vitro tests show that these biological agents are three times more contrasting than standard contrast agents. Studies in a mouse model have also demonstrated that functionalized magnetosomes have the capacity of targeting integrins in vivo, and allowed for the visualization of tumor blood vessels via MRI. The scientists entrusted the team led by Laurent Bellanger, at CEA-Institute Joliot, to carry out toxicity studies. This same team has also developed an antibody capable of identifying the membrane of the magnetosomes and visualizing them by fluorescence microscopy.

As these agents are easy to produce and achieve good contrasting power, they could make it possible to identify tumors in humans with a high level of accuracy and to monitor their evolution over the course of the treatment. The researchers are also considering a therapeutic approach. "Iron has the particularity of accumulating in tumor cells", Mériaux said. "We could imagine developing a treatment by magnetic hyperthermia, which would destroy the tumor cells by heating".

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