Radioactive substances fight cancer in a mini-laboratory

Radioactivity can save lives. If neither chemotherapy, surgery nor external radiation can help against a tumour, modern medicine uses so-called radiopharmaceuticals. These radioactive drugs not only lyse cancer cells, they also enable targeted radiation from the inside, which destroys the tumour. However, before such substances can be used in humans, extensive animal experiments are still required during their development. A joint project between the Fraunhofer Institute for Material and Beam Technology IWS in Dresden and the Helmholtz Centre Dresden-Rossendorf (HZDR) is currently researching an alternative method. This is based on artificial organ structures and tumours in chip format.

According to information from the Federal Ministry of Food and Agriculture, a total of 1.86 million vertebrates and cephalopods were used for research purposes in Germany in 2021. Although this is two per cent less than in the previous year, it is still a very large number. Mice, fish and rats are the most commonly used animals in German laboratories. „Many research tasks can currently only be solved with the help of such animal experiments“, explains Dr Wiebke Sihver from the Radionuclide Diagnostics Department at the Institute of Radiopharmaceutical Cancer Research at the HZDR. It is therefore extremely important to look for alternative methods. „In addition, animal models often lack important references to the human organism.“

In their work, Wiebke Sihver and her HZDR colleagues are working on the development and application of radiolabelled substances for cancer diagnostics and, in particular, cancer therapy. These radioligands are equipped with a radioactive nuclide (radionuclide) and bind to a target molecule, in the case of cancer to specific target structures of the tumour. This means that the radiopharmaceutical acts directly on the tumour. Surrounding healthy tissue is spared. When developing radiopharmaceuticals, they have to be tested in animal models such as mice and rats following in vitro characterisation. Several years ago, Wiebke Sihver was already looking for a replacement for the many animal experiments in radiopharmaceutical research. Her research into alternative systems quickly led her to the Fraunhofer IWS. For several years, a team there has been researching microphysiological systems that use cultivated human mini-organoids to mimic the functioning of the human organism – thanks to the use of human cells, for example, closer to the human tumour than animal experiments could. It was the starting point for a new idea.

Development with great potential

Researchers at the Fraunhofer IWS have been working on mini-laboratories for over ten years. With these microphysiological systems in the format of a box of tablets, organ functions or even disease processes can be simulated with the help of cell cultures. Valves and channels simulate the vascular system and a small pump simulates the heartbeat. The chips are made from plastic films layered on top of each other. Blood vessels and chambers are cut into these using a laser. The users later create cell cultures in special modules, which can survive for up to a month in the microfluidic systems. Meanwhile, blood circulates in the miniature laboratory in the form of a nutrient medium that supplies the cells with oxygen and nutrients. Just a few years ago, it was only possible to visualise two organs in this setting. Today, four can be simulated simultaneously on these innovative multi-organ chips.

When the HZDR team turned to the Fraunhofer IWS, the experts there very quickly recognised the potential for a new application. Reduce the number of animal experiments

The aim of the joint research work is to place 3D tumour models on a chip, which will subsequently simplify the testing of radiopharmaceuticals and make it cheaper. The first challenge was therefore to produce a three-dimensional cell aggregate from a two-dimensional cell culture – a sphäroid that can imitate tumour tissue. „This allows us to integrate the characteristics of the micro-tumour into our system“, explains development engineer Stephan Behrens from the Fraunhofer IWS. In the future, this representation on the chip will become increasingly detailed, for example through the use of patient-specific cells or to determine newly discovered, characteristic proteins on different tumour cell types that can be detected radiopharmacologically.

The first tests carried out by Wiebke Sihver and her team with the multi-organ chips have already shown positive results. They initially used known substances whose properties can be easily observed on the chip. „We saw that the binding to the tumour spheroids already works“, she explains. The plan is to also visualise a kidney model and a liver organoid on the chips. The kidneys in particular are considered to be dose-limiting and therefore play an important role in radiopharmaceutical research. In colloquial terms, this means that if the radioligand gets stuck, this can lead to damage in the kidneys, but also in the liver cells," explains the scientist. Testing such substances using cell cultures on a chip is therefore a promising alternative. If the tests in the project continue to be positive, it should also be possible to test unknown radioligands in the systems in the future. „This saves a large number of animal experiments“, says Sihver. Even if animal testing cannot yet be completely avoided with their research, the researchers are working on reducing their number.

Florian Schmieder sees many advantages for patients in the future as a result of the new development. We could transfer patient-specific cells onto a chip and thus simulate how a cancer develops.

In this way, customised therapies would be possible. „Cancer also forms tumour-specific antigens that cannot be reproduced in animal models.“ This should also work on the chips.

The close collaboration between the two research institutes is an impressive example of the added value of the DRESDEN-concept scientific alliance, in which 36 partners have joined forces to promote Dresden as a research location and to create and utilise synergies in research and teaching as well as infrastructure and administration.

Press release from 09.01.2023