Using a nanogel as a drug taxi

Researchers throughout the world are looking for methods that allow to deliver drugs specifically to the site of a disease while reducing the side effects. Gregor Fuhrmann is also pursuing this goal: At the Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), he is investigating extracellular vesicles in combination with nanoparticles and nanogels in order to develop new therapeutic approaches.

When a patient swallows a tablet, the drug in the tablet gets into the blood and is distributed throughout the body even if the substance is needed in a small place only. For this reason, researchers throughout the world are looking for methods that allow them to deliver drugs specifically to the site of a disease in order to be able to reduce the side effects. Gregor Fuhrmann of the Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) also pursues this kind of approach: He uses tiny membrane vesicles, which are naturally released by cells, to transport drugs. Body cells and bacteria alike utilise these so-called extracellular vesicles for communication with each other: They exchange various signaling molecules by means of these vesicles – and Fuhrmann aims to extend this to drugs.

He recently combined his vesicles with another drug transport approach: He embedded them in hydrogels. These aqueous, gel-like structures are also being tested as medical transporters which, loaded with a drug, are transported to the desired site in the body to release their freight. "One current drawback of these gels is that they exert their effect immediately and for a short period of time only. The vesicles can be utilised for a longer period of time, but it has not been possible to keep them permanently in one place – as they become diluted in the body," Fuhrmann says.

"We wanted to combine the two approaches in order to eliminate their shortcomings."

Gregor Fuhrmann, Leader of the Junior Research Group Biogenic Nanotherapeutics

And it worked: In cooperation with a research team from the London Imperial College, Fuhrmann isolated vesicles from mesenchymal stem cells, loaded an enzyme – β-glucuronidase – into them and embedded them in a hydrogel of the size of a 1-cent coin. Then he tested these gels in a cell model for inflammatory reactions: Immune cells in culture – activated macrophages – received first a gel coin and then an anti-inflammatory agent that was coupled to a sugar. The enzyme contained in the vesicles cleaved off the sugar and released the drug. For comparison, Fuhrmann also tested gels loaded with synthetically produced transport vesicles – so-called liposomes – as well as gels loaded with free enzyme.

"We used certain markers to show that the inflammatory reaction was reduced in these approaches," Gregor Fuhrmann says. "It was even possible to use the gels with encapsulated enzymes repeatedly since their activity persisted significantly longer than that of the gels with free enzyme." Stem cell vesicles possess a crucial advantage as compared to liposomes: They exert an anti-inflammatory effect even in the absence of enzyme, as has been shown in control experiments. "Hydrogels with these vesicles can therefore be developed as drugs against skin infections or inflamed wounds," Fuhrmann says.

Did you know?

Gregor Fuhrmann is awardee of the Galenus Technology Prize for his work about extracellular vesicles for the development of new therapeutic approaches. [more]

The fact that even the empty vesicles reduce inflammation might be related to their origin: Stem cells use the vesicles to communicate with immune cells and might have a beneficial effect on these cells. Accordingly, the vesicles may be responsible for at least some of the success of stem cell therapies, as has been presumed for some time in this research field.

In further control experiments, the scientists used dye-converting enzymes and metal ions as freight. This allowed them to compare the enzyme activity between vesicles, liposomes and gels with free enzyme. Moreover, metal ions can be detected by electron microscopy: The vesicles were indeed stably embedded in the gels. The results have been published in Advanced Materials, which selected the publication for its "Back Cover".

Original publication:

Gregor Fuhrmann, Rona Chandrawati, Paresh A. Parmar, Timothy J. Keane, Stephanie A. Maynard, Sergio Bertazzo, and Molly M. Stevens: Engineering Extracellular Vesicles with the Tools of Enzyme Prodrug Therapy. Advanced Materials 2018, 1706616, Wiley-VCH Verlag GmbH & Co. KGaA. DOI: 10.1002/adma.201706616

Author: Andreas Fischer

Published: April 2018

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Gregor Fuhrmann – Nano-researcher, but well-earthed

Gregor Fuhrmann wants to use tiny membrane vesicles to transport active substances to where they are needed in the body.

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