Promising replacement for polyethylene glycols developed

Researchers at Johannes Gutenberg University Mainz (JGU) have discovered a highly promising replacement for polyethylene glycols (PEGs), which are considered almost indispensable in the pharmaceutical and medical fields.

The new substance class, called rPEG, offers all the advantages of PEGs while avoiding their drawbacks. It also has the potential to evade adverse reactions of the immune system and its antibodies, which PEGs has gradually lost over the years.

PEGs are all-rounders in the chemical and pharmaceutical industries, considering the many ways they are used. These water-soluble polymers are present in shower gels and toothpastes, washing powders and rechargeable lithium-ion batteries, baking mixes and functional clothing. They were even used to preserve the recovered wreck of the legendary Vasa, a royal Swedish warship that sank on its maiden voyage in the 17th century.

PEGs can be employed in so many different applications because of their excellent tolerability, their solubility in water and their chemical stability, not to mention the fact that they are cheap to produce. As noted by JGU’s Professor Holger Frey, “polyethylene glycols have become almost irreplaceable” since their discovery in the 1930s.

PEGs play a particularly important role in pharmaceutical and medical applications. By means of a process called ‘PEGylation’, active drug substances and proteins are linked to PEG, thus concealing them from the immune system and promoting their solubility in water. Once equipped with this ‘cloak of invisibility’, active drug molecules — such as mRNA vaccines — are protected against premature degradation by endogenous enzymes and can avoid recognition by the immune system. PEGylation has thus turned out to be a very practical way of administering medications safely and effectively, according to Frey.

However, it has become increasingly apparent in recent years that the immune system has developed the ability to detect PEGs, and the majority of the Western industrialised population already has antibodies to the polymer. The good news is, PEGs are the starting point of an innovative new concept developed by Frey’s team at JGU.

“We combined the basic building block of PEG, ie, ethylene oxide, with a structurally related molecule known as glycidyl methyl ether (GME),” explained postdoctoral researcher Dr Rebecca Matthes. “The resultant materials are no longer recognised by anti-PEG antibodies because the chains now possess little, randomly distributed branches at the chains. In effect, what we have done is sew together a new cloak of invisibility.”

Matthes created the novel combination working in collaboration with Frey and Dr Philip Dreier, but the team’s success was not guaranteed from the start. With currently available technologies, it should not have been possible to undertake the controlled polymerisation of GME — in other words, to link the individual components of GME together to form a chain of molecules. Matthes and Dreier managed this by initially synthesising highly pure GME components using an optimised synthesis protocol.

The new polymer was designated ‘rPEG’ — with the ‘r’ referring to the random distribution of the two components along the chain. It has properties similar to PEG in that it is water-soluble and well tolerated by the human body. At the same time, it does not form crystals but has a viscous consistency rather like honey.

“We have been able to capitalise on the outstanding properties of PEGs while also eliminating the problems that PEGs otherwise confronted us with,” Frey said.

With the first rPEG polymer having been generated by Frey’s research group in late 2020, the team has been engaged in two parallel endeavours in the years since. On the one hand, they have carefully analysed the chemical aspects and scientific implications. On the other hand, they have built a global network for testing various possible applications.

“We intend to create a platform technology based on these rPEGs that will open up an extensive range of possible applications,” Frey said.

“We already have a wealth of ideas for using the new rPEG class in the future, starting with medicine through pharmaceutical applications to the materials sciences,” Matthes added.

In terms of medical applications, the researchers are concentrating on mRNA-based therapeutic agents to be used in the treatment of chronic diseases. In view of the corresponding long-term treatment regimens required, as for example in cancer therapy, it is essential to prevent undesired immune reactions to the drugs used.

In early 2024, Evonik Industries and JGU announced they would be collaborating on the commercialisation of rPEGs. Evonik Industries is a specialist chemical firm based in Germany and plans to use and market rPEGs for its platform of specialised lipids.

In the meantime, Frey said the JGU team “welcomes new suggestions and ideas from science and application communities”.

Image caption: The rPEG polymers are synthesised in this reactor in an inert gas atmosphere. Image credit: Philip Dreier.