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Science Highlight: March 2, 2015

Organic, Non-toxic Sensor Allows Dual MRI and Fluorescent Imaging

Offers broad potential for medical diagnostics, tracking response to therapy

NIBIB-funded researchers have developed a dual-imaging molecular sensor using an organic polymer that allows both magnetic resonance imaging (MRI) and near-infrared fluorescence imaging of tissues in the body. Dual imaging from the single nano-particle can facilitate delineating one tissue from another without moving the patient, which is essential for determining the exact position of diseased and healthy tissue such as during cancer surgery. The modular polymer design offers the potential to improve medical diagnostics and provide real-time monitoring of treatments such as targeted cancer therapy.

diagram of polymer sensor in the oxidized and reduced state

The branched-bottlebrush polymer behaves differently in different conditions in the body. On the left, the green dots are nitroxide molecules in their native state that provide the MRI signal and inhibit fluorescence. On the right, ascorbate (vitamin C) creates what is known as a reduced state; the yellow star represents the Fluorophore, which actively emits fluorescence, while the reduced nitroxides give no MRI signal. Source: Jeremiah Johnson, MIT.

 

A novel organic modular sensor

The modular polymer design, described as a “branched-bottlebrush” allows the researchers to mix and match the various components of the molecule to target specific tissues and vary the intensity of the MRI or fluorescent signal. This versatility opens the possibility for a range of potential uses as molecules with different functions, such as enhancing imaging signals, delivering drugs to target tissues, or sensing levels of various metabolites, can be efficiently attached to the modular polymer.

One specific area of interest is in cancer treatment and monitoring, says senior author Jeremiah Johnson, assistant professor of chemistry at MIT. “These sensors could be designed to deliver drugs to a tumor and also send back valuable information about the state of the tumor and the effect of the targeted drug treatment.” Dr. Johnson explains another novel and biologically important aspect of this new probe: “Until now, sensors to enhance MRI contained metals, which can be toxic and limit their use in certain patients, such as those with kidney disease. Our use of molecules called nitroxides instead of metals makes this sensor available to more patients. In addition, the sensor can be in a patient longer without concerns about metal toxicity."

mouse with yellow fluorescence in liver

Fluorescence is strong in the liver of a live mouse where there are high levels of vitamin C. In the heart, with no vitamin C, the fluorescent signal is inhibited. In the kidney, minimal levels of vitamin C result in minimal fluorescence. Source: Jeremiah Johnson, MIT.

How it works

To demonstrate the utility of their approach, the team of chemists synthesized a branched-bottlebrush polymer that contains nitroxides, which provide an MRI signal, and molecules called fluorophores, which provide fluorescence. Their experimental system takes advantage of the fact that vitamin C, which is in high concentrations in mouse liver, creates what is known as a reduced state, which inhibits MRI and enhances fluorescence. Conversely, in the blood, which does not have a significant concentration of vitamin C, the nitroxides in the molecule are in their native state, which enhances the MRI signal and inhibits fluorescence.

MRI of mouse kidney and aorta

MRI of mouse organs and blood vessels. No MRI signal is seen on the left before injection of the branched-bottlebrush polymer sensor. On the right, following injection of the sensor, the aorta (labeled “blood”) and the large blood vessels of the kidney are visible by MRI. In the liver, no MRI signal is produced because the vitamin C in the liver creates a reduced environment, which inhibits MRI. The colored bar at the top indicates the range from oxidized areas of the tissue (red) to reduced areas (yellow).Source: Jeremiah Johnson, MIT.

When introduced into the mouse circulation, the polymer that reached the liver and the high concentration of vitamin C resulted in a high fluorescent signal while the MRI signal was greatly reduced. In contrast, in the blood of the aorta and major blood vessels of the kidneys, where there is little vitamin C, the MRI signal was high while the fluorescence was minimal.

 

A versatile molecular platform

The molecule that was built and successfully tested in this experiment demonstrates the versatility of the modular polymer design to create molecules with the desired functions. Johnson elaborates about the potential uses of the approach: “What’s exciting about this system is that we can mix and match and add what we need in order to change the function of the nano-particle sensor. For example, we are now creating versions carrying different drugs and fluorescent sensors that allow us to determine whether the drug reaches the correct target organ. The critical thing is that there are no metals in this polymer, so we can design molecules that can stay in the body for longer periods of time and perform multiple functions, without the build-up of metal toxicity.”

The work was supported by multiple grants from the National Institute of Biomedical Imaging and Bioengineering (NIBIB), awards EB008484, and EB018529. The work is reported in the November 18 issue of Nature Communications.1

 

1. Redox-responsive branched-bottlebrush polymers for in vivo MRI and fluorescence imaging. Sowers MA, McCombs JR, Wang Y, Paletta JT, Morton SW, Dreaden EC, Boska MD, Ottaviani MF, Hammond PT, Rajca A, Johnson JA. Nat Commun. 2014 Nov 18;5:5460

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NIBIB’s mission is to improve health by leading the development and accelerating the application of biomedical technologies. The Institute is committed to integrating the physical and engineering sciences with the life sciences to advance basic research and medical care. NIBIB supports emerging technology research and development within its internal laboratories and through grants, collaborations, and training. More information is available at www.nibib.nih.gov

Health Terms: 
Cancer,
Diagnostic,
Nanotechnology