Biodegradable phosphoester polymers for greener MRI color

Polymer scientists from the University of Twente have developed a new phosphorus-based polymer that they say could help heteronuclear MRI end its reliance on fluoropolymers.

“As a scientist, you’re always an idealist and want to make the world a little bit better,” said Olga Koshkina, who co-led the project with PhD student Timo Rheinberger.

Koshkina said it’s the first phosphorus-based material compatible with fast MRI imaging.

Rheinberger presented the work on Sunday in a talk at ACS Fall 2023 in the Division of Colloid and Surface Chemistry. The group also published a paper on the project last month in Nature Communications (DOI: 10.1038/s41467-023-40089-0).

Fluorine MRI is handy for adding contrast to functional imaging of inflammation and tumors, tracking cells, drug delivery, and more. But current imaging agents are based on nondegradable perfluorinated polymers. Koshkina wanted to figure out a more sustainable alternative.

She and her coauthors decided to look into phosphorus MRI contrast agents as a greener option because the only naturally-occurring stable isotope of the element, ³¹P, is both spin-active and highly biocompatible. Phosphate esters make up the backbones of many important biomolecules, including DNA, RNA, and ATP.

But the same thing that gives phosphorus a biocompatibility advantage also makes it difficult to use for MRI: all of those phosphorus-containing biomolecules create a lot of background noise. And the element has lower sensitivity to begin with: its magnetic resonance signal is less than 10% as strong as that from hydrogen or fluorine. While some on the team doubted it would be possible to use phosphorus for imaging, Koshkina said, others were sure that they had the polymer chemistry know-how to make it work. “It’s a super cool toolbox to provide solutions to problems,” said Rheinberger.

The researchers used several chemical tricks to make phosphorus-based polymers that would stand out from the background signal. They chose phosphonate monomers with side chains that would give them an MRI signature distinct from phosphate-based biomolecules. Stringing two different monomers together into gradient copolymers provided a way to adjust the polymers’ magnetic relaxation time and ability to self-assemble into phosphorus-rich nanoparticles that would stay in the body long enough for useful imaging. Ultimately, the researchers were able to match the lowest detectable concentration of fluoropolymers with their phosphorus-based polymer.

They tested their new imaging agent’s capabilities by injecting it into tobacco hornworm (Manduca sexta) caterpillars. It showed up bright and clear against the background and persisted in the hemolymph (invertebrate equivalent of blood) for over 24 h, a promising sign that it could work for targeting imaging. The researchers also found degradation products in the caterpillars’ feces after injecting the polymer particles into the gut, proving that the polymers naturally break down.

In addition to their imaging ability, the polymer particles also show promise for drug delivery. The researchers loaded the nanoparticles with proteolysis-targeting chimeras (PROTACs) and successfully used them to deliver the hydrophobic drugs to kill cancer cells in vitro.

Francesca Baldelli Bombelli, who studies nanomaterials for MRI at the Polytechnic University of Milan said she thinks Koshkina and colleagues were “very smart to propose this approach, and also brave” to take on the challenge of making phosphorus MRI workable. She said she’s eager to see further development of phosphorus-based tracers and imaging methods.

Rheinberger and Koshkina said their next steps are to continue fine-tuning the polymer design to try and achieve even better MRI signal and nanoparticle-forming properties. They’re also looking into forming a start-up to commercialize their phosphorus polymers so that more people with expertise in imaging and drug delivery can study them. “We cannot do all the research ourselves,” Rheinberger said.