Fluorescence resonance energy transfer, or FRET, is widely applied in biology research. In this phenomenon, energy is transferred from a donor chromophore in an excited state to an acceptor chromophore. The magnitude of the energy transfer depends on the distance between the donor and the acceptor, which enables FRET to be exploited as a 'ruler' to measure nanoscale distances. Because it is an optical technique, however, the application of FRET in living organisms is quite limited. A recently reported sensing mechanism akin to FRET but based on the measurement of a magnetic resonance imaging (MRI) signal may open up multiple novel in vivo applications.

This new approach, called magnetic resonance tuning, or MRET, was developed by Jinwoo Cheon of Yonsei University in Korea, along with his colleagues. MRET refers to the interaction that takes place between a paramagnetic enhancer compound (such as gadolinium–DOTA) and a superparamagnetic quencher nanoparticle (such as a zinc–iron oxide nanoparticle). Like FRET, MRET is distance dependent: the strength of the T1 MRI signal depends on the separation between the enhancer and the quencher. Beyond a critical separation distance, the enhancer's electron spin fluctuation accelerates the relaxation of protons in water, thus producing a strong T1 MRI signal. However, as the enhancer and quencher move closer together, the spin fluctuation slows, and the T1 MRI signal weakens, eventually turning off below the critical separation distance. Therefore, MRET, like FRET, can also serve as a nanoscale ruler.

Cheon's group carried out several experiments to showcase potential applications of MRET. They looked at three types of molecular interactions: cleavage, binding and folding. They detected the cleavage of a peptide or sulfonate bond linking enhancer and quencher by a protease or an oxidant, respectively. They monitored the hybridization reaction between complementary DNA strands, as well as the copper-mediated click chemistry reaction between alkyne-functionalized enhancer and azide-functionalized quencher. And they detected the folding of oligonucleotides upon a change in pH or the addition of a metal.

Magnetic resonance tuning (MRET) monitors the cleavage of a peptide by MMP-2, a cancer biomarker. Credit: Reprinted with permission from Choi et al. (2017).

They also performed studies in cancer cell lines with an MRET probe designed to sense the activity of the cancer biomarker matrix metalloprotease 2 (MMP-2). The activity levels they measured in cell lines correlated well with commercial kit results. Finally, they sensed MMP-2 activity in mice with xenograft tumors and observed a strong T1 MRI signal at the tumor site, and a lack of signal in animals treated with an MMP-2 inhibitor.

Cheon believes that MRET will be useful for many different sensing applications. “Thanks to the deep penetrating propensity of magnetic fields, MRET can be a valuable tool to explore a wide range of biological events, such as enzymolysis, pH variation, and protein–protein interactions, especially at complex tissue and whole-body levels,” he says. Of course, many challenges will have to be overcome before MRET can be broadly used in vivo. The probes are rapidly cleared by the mononuclear phagocyte system; Cheon thinks that modifying the nanoparticle surface by applying a 'stealth' coating could help the probe evade the immune system and improve circulation time. Targeting the probes to specific locations in vivo is also a challenge; exploring different delivery vehicles may address this issue. “We hope that our research can provide a stepping stone for other researchers who are developing smart MRI nanoprobes for monitoring a wide range of biological events,” says Cheon.