Magnetic nanoprobes for molecular imaging
Probes could help detect cancer earlier
By adding a bit of manganese to iron oxide nanoparticles and processing the two substances together with the right recipe, researchers from Yonsei University in Seoul, Korea, have developed nanoprobes with enhanced MRI sensitivity. When conjugated with the proper antibodies, these magnetism-engineered iron oxide nanoprobes detected cancer markers better than probes available and successfully imaged small tumors implanted in a mouse.
By adding manganese, Korean researchers engineered a better nanoparticle for magnetic resonance imaging (MRI). When conjugated with a cancer-targeting antibody, these magnetism-engineered iron oxide (MEIO) nanoparticles highlighted a 50-mg tumor — a smaller cancer than could be detected before. Courtesy of Jinwoo Cheon, Yonsei University.
Chemistry professor Jinwoo Cheon, a member of the team and division head of the Yonsei Nanomedical National Core Research Center, noted that the new technology could significantly improve detection rate at early cancer stages.
The researchers started by optimizing the size of iron oxide nanoparticle probes, which are already used by other researchers. By carefully controlling nanoparticle size, they were able to boost the magnetic resonance contrast effect and achieve a fourfold increase in sensitivity for detecting in vitro cancer cells. However, the MR signal was still too weak.
Next they considered the magnetic spin structure of the iron oxide nanoparticles, which have three iron and four oxygen atoms. They decided to replace one of the iron atoms in that structure, Fe2+, with a metallic dopant of a similar valence of 2+. They therefore added small amounts of manganese, cobalt and nickel to the iron oxide.
Of the various compounds added, manganese offered the best results because of the locations it occupied in the molecular crystalline lattice and because of its magnetic spin. Because the added manganese upped the magnetic susceptibility, it increased the MR signal the most. The improvement in the signal over straight iron was 25 percent.
To control the nanoparticles’ size, composition, crystallinity and magnetism, the researchers fabricated the nanoparticles under high temperature in an organic medium rather than at the conventional low temperature with the water phase-based manufacturing method. For example, testing showed that the optimum diameter for the manganese magnenetism-engineered iron oxide particles was 12 nm, and the researchers achieved a less than eight percent standard deviation in the size distribution. The effort to improve magnetism allowed them to get some nice MRI results.
As for why this approach hasn’t been tried before, Cheon pointed out that iron oxide nanoparticles may have been assumed to be the best choice because they are commonly used. “Another possible reason could be a lack of efficient magnetic nanoparticle synthetic protocols to precisely tune the materials properties and a poor understanding of nanoscale magnetism and MR contrast effects of nanoparticles,” he said.
With the nanoparticles fabricated, the researchers tested them for in vitro cancer detection, conjugating them with the antibody Herceptin to target a marker expressed in breast and ovarian cancers. They first determined that the nanoparticles, alone or conjugated, were not toxic, at least up to a test concentration of 200 μg/ml.
As detailed in the January Nature Medicine, the scientists measured the MR response of a variety of cell lines with different levels of the marker expression. They found that the engineered nanoparticles conjugated with antibodies easily detected a very low expression level, whereas the standard magnetism-engineered iron oxide nanoparticles required a line with roughly three times the relative marker expression. The MR contrast agent-cross-linked iron oxide detected only relatively high levels of expression, picking up on cell lines with ~2300 times as great an expression level as those detected by manganese magnetism-engineered iron oxide.
Cheon noted that before these tests, the researchers were sure that the manganese magnetism-engineered iron oxide nanoparticles would show enhanced MR contrast effects. At the same time, they didn’t know how much better the nanoparticles would be with regard to spotting cancer and were caught somewhat off guard by the results. “When we performed the in vitro cancer cell detection studies, we were surprised at their highly enhanced detection sensitivity that can detect minimal cancer marker expression,” he said.
Finally, the researchers implanted small cancers about 50 mg in size in a mouse for an in vivo test. They injected 200 μl of a manganese magnetism-engineered iron oxide-Herceptin solution into the mouse. An MR image they took a few hours later clearly showed the tumor site, with a signal relaxivity value change of 34 percent after two hours at the tumor tissue. In comparison, an injection of cross-linked iron oxide-Herceptin showed a change of either nothing or less than five percent at the tumor site.
The results with the engineered nanoparticles are better than those previously possible, but Cheon noted that more progress is needed. The ultimate goal is to detect submillimeter-sized cancers with a mass of less than a milligram. That sensitivity will require developing nanoparticles with an even higher MR signal, and the group is working on that. They’re also looking into safety issues that will have to be addressed before the nanoparticles go into widespread use.
Ultimately, the researchers are working toward a next-generation nanoparticle that will offer multiple detection modes such as optical and MR imaging and that possibly will have smart therapeutic capabilities and functions such as self-navigation.
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