Anyone with a chronic illness such as diabetes or kidney disease needs a daily injection of insulin or erythropoietin (EPO), respectively. This can be inconvenient and every injection brings the risk of infection. It is a great handicap, especially for children.

Researchers from various disciplines at ETH Zurich have now developed a new procedure that should replace the daily injection. The solution is a gel-like substance that patients now need to inject as a depot medicine only every 2 to 4 weeks. After that, instead of daily injections, they can take a tablet of a clinically permitted substance that releases the active ingredient, e.g. insulin, from this depot in a targeted, controlled way.

Mixture of synthetic and natural product

The gel consists of tiny, thin polymer threads one ten thousandth of a millimetre long onto which the protein, gyrase, is attached. Gyrase originates from the intestinal bacterium Escherichia coli. When the antibiotic, coumermycin, is added to this mixture, the gyrases join together in pairs. With the gyrases acting as an adhesive, this turns the threads into a tangle known as a hydrogel, which encloses the active substance. The gel has a consistency similar to blancmange. The antibiotic, Novobiocin, in turn releases the gyrase bonds, thus liquefying the gel once again. This releases the embedded active ingredient, which is free to do its work in the body.

The researchers have already tested the method successfully with human cells in a cell culture. They did this by embedding into the gel a growth factor that was released from the lumps of gel in proportion to the amount of Novobiocin added and that stimulated increased growth in the cells.

The dose determines the release

Wilfried Weber, Group Leader at the Department of Biosystems Science and Engineering (D-BSSE) of ETH Zurich in Basel, stresses that, “The amounts of the medicine that are released can be determined precisely via the dose of the antibiotic.” For example, a diabetic could swallow a pill before a meal to liberate the required dose of insulin into the body from the medicine store.

Weber says that Novobiocin has very few side-effects. However, because he cannot exclude the possibility that bacteria may become resistant to it, the scientists now want to develop other gels that can be dissolved without this antibiotic. The researcher gives assurance that the polymer threads, on the other hand, are harmless. “Polymers of the kind we use have already been tested in various animal models and in humans, and they are excreted through the kidneys.” He says many therapeutic proteins such as interferon alpha or EPO are coupled to similar polymers as a standard procedure. Weber says this has not caused any problems in therapeutic use; on the contrary, it has yielded an improvement instead. In addition, the polymer shields the protein from attacks by the immune system.

A Lego brick approach from Synthetic Biology

The scientists led by Wilfried Weber found the building blocks for this gel by using a starting point in Synthetic Biology. In this subject area, biologists build new living systems based on system components that have been accurately characterised, rather than, for example, analysing how cells function. According to Weber, “We use modules whose way of functioning we understand precisely, like taking pieces from a box of Lego, and we build new biological systems.”

The novel gel is only a prototype, but the patent application has already been filed. In the next few months, the ETH Zurich researchers want to test the prototypes on diabetic rats, for example. This will bring the interdisciplinary team of biotechnologists, polymer chemists and materials scientists, supported by the Gebert Rüf Foundation, one step nearer to its goal: to be able to offer chronically ill patients an alternative to the daily injection in a few years’ time.

Literature reference:

Ehrbar M, Schoenmakers R, Christen EH, Fussenegger M & Weber W: Drug-sensing hydrogels for the inducible release of biopharmaceuticals. Nature Materials advance online publication 10^th August 2008, doi:10.1038/nmat2250