Smart keys for cancer therapy: research team develops new system for imaging and treating tumours

In principle, we can think of it as the functionality of a smart key that we use to control our car. We use so-called radionuclides, i.e. unstable atomic nuclei that spontaneously emit ionising radiation as they decay. We use a diagnostic radionuclide to detect the tumour. The targeted internal irradiation near the diseased tissue then uses another, therapeutically effective radionuclide“, says Dr Manja Kubeil from the Institute of Radiopharmaceutical Cancer Research at the HZDR, describing her theranostic approach.

Her team in the Radionuclide Diagnostics Department is developing precisely such substances to detect and destroy tumours. The researchers use coordinated pairs of radionuclides that can be used both for imaging and for the treatment of tumours on the same target molecule due to their decay characteristics.

The respective radionuclide is stably bound in a so-called chelator and linked to a biomolecule via a type of chemical bridge. „The word chelator is borrowed from Latin, its root associates a clasping by crab claws. We prefer the image of a molecular cage that firmly encloses the radionuclide so that it cannot spread uncontrollably throughout the body. The target-seeking biomolecule, in turn, must fit exactly to the docking sites on the cancer cells, just like a key to a lock. The radionuclide then accumulates on the tumour tissue and only develops its destructive effect there, according to the plan," says Kubeil.

Stable bonds at practical temperatures
Lutetium-177, for example, is well suited as an electron-emitting beta emitter for the treatment of various tumours and as a gamma ray source for imaging. Actinium-225, an alpha emitter that can be used for efficient treatment, is even more effective in destroying tumours and is also very tightly bound by the chelator. Both radionuclides do not occur naturally on earth and are obtained artificially using suitable methods.

Alpha emitters emit particles consisting of two protons and two neutrons. They are used in cancer therapy because their range in the tissue is very short and yet their high energy makes them very effective at attacking and killing cancer cells. The half-life of seven and ten days in the case of lutetium-177 and actinium-225 is ideal for this: it is long enough to enable effective treatment.

New chelator with advantages
To date, there is only one chelating agent on the market that binds both radionuclides equally well: DOTA. The most frequently used chelator in nuclear medicine is known for its very stable metal complexes. However, DOTA has the major disadvantage that complete binding of theranostic radionuclides can only be achieved at temperatures above 80 degrees Celsius, which is very high by biochemical standards. „When working with protein derivatives, these temperatures are clearly too high. Because if these are even above 40 degrees Celsius, denaturation sets in: they are destroyed. Our new chelator system works reliably even at these lower temperatures," says Kubeil.

In addition, it exhibits faster radiolabelling than existing chelators under milder conditions. Another advantage is that the new system binds efficiently to various bioconjugates. This means that the choice of docking sites on diseased tissue is also greater. The chelator developed could therefore form the basis for new modular and personalised pharmaceutical systems that can be targeted to different areas for imaging and therapy by simply exchanging the chemical substructures.

Publication:
P. Cieslik, M. Kubeil, K. Zarschler, M. Ullrich, F. Brandt, K. Anger, H. Wadepohl, K. Kopka, M. Bachmann, J. Pietzsch, H. Stephan, P. Comba, Toward Personalised Medicine: One Chelator for Imaging and Therapy with Lutetium-177 and Actinium-225, Journal of the American Chemical Society, 2022 (https://doi.org/10.1021/jacs.2c08438)

Source: Helmholtz-Zentrum Dresden-Rossendorf from 26.05.2023