Munich, Apr 07, 2020
Ions are important signal substances for cells: Among other things, they activate signaling cascades, regulate enzyme activity and pH. A sudden ion overdose often leads to programmed cell death. So far, it has been difficult to investigate such an influence of certain ions on the cell because the complex control mechanisms of the cell prevent manipulation of the ion concentration. Scientists led by Hanna Engelke and Evelyn Plötz from the Faculty of Chemistry and Pharmacy at LMU now for the first time have, with the help of nanoparticles, been able to release iron ions in the cell in such a way that there is a sudden overdose. This triggers a special type of cell death that primarily affects cells of the immune system. As the scientists report in the journal Advanced Materials, this effect holds great potential for the development of new therapies, since it could kill tumor cells and at the same time trigger an immune response against cancer.
The structure of the nanoparticles is crucial for success: they are organometallic framework compounds in which iron is complexed with oxygen. “Ultimately, these are structurally small hexagons that are connected via organic linker molecules,” Ploetz says. “You can compare that to scaffolding. The nanoparticle has relatively large pores through which potential reactants can penetrate.” The nanoparticles are surrounded on the outside by a lipid shell, which enables them to dock onto the cell membrane and penetrate into the cell.
In the cell, the nanoparticles are passed on to certain cell organelles, the lysosomes, where they decompose. "We have now been able to show that the rate of decomposition depends on the pH outside the cell," says Ploetz. "If the pH is comparatively low, this happens quickly and there is a sudden release of many iron ions." The scientists suspect that this effect is due to the fact that a molecule that is important for the degradation of the nanoparticle - cysteine - at low extracellular pH Values in excess.
"It was particularly surprising for us that the iron release from the nanoparticles does not induce ferroptosis, as one might assume, but a so-called pyroptosis," says Ploetz. In pyroptosis, e.g. cells of the innate immune system are activated and there is a highly inflammatory process in which the affected cell dies.
According to the scientists, the nanoparticles could have great therapeutic potential, especially for tumor therapy. “The extracellular milieu of tumor cells is more acidic than that of other cells. It is therefore possible that the pH dependency of iron release could be used in a targeted manner: the nanoparticles could attack the primary tumor directly and the induced pyroptosis activates the immune system, ”says Ploetz. "But the nanoparticles also offer perfect conditions for other applications, such as basic research, because of their controllability through the pH."
Advanced Materials 2020