Scientists around the world are studying how cancer drugs can more effectively reach the tumors they target. One possibility is to use engineered bacteria as “ferries” to transport drugs through the blood to tumors. Researchers at ETH Zurich have now succeeded in controlling certain bacteria so that they can effectively cross the wall of blood vessels and infiltrate tumor tissue.
Led by Simone Schürle, Professor of Reactive Biomedical Systems, the ETH Zurich researchers chose to work with naturally magnetic bacteria because of the iron oxide particles they contain. These bacteria of the genus Magnetospirilla react to magnetic fields and can be controlled by magnets outside the body.
Exploit temporary gaps
In cell cultures and in mice, Schürle and his team have now shown that a rotating magnetic field applied at the level of the tumor improves the ability of bacteria to cross the vascular wall near the cancerous growth. At the level of the vascular wall, the rotating magnetic field propels the bacteria forward in a circular motion.
To better understand the mechanism of crossing the vascular wall, a detailed examination is necessary: the wall of the blood vessels consists of a layer of cells and serves as a barrier between the blood circulation and the tumor tissue, which is impregnated with many small blood vessels. Narrow spaces between these cells allow certain molecules to pass through the vascular wall. The size of these intercellular spaces is regulated by the cells of the vessel wall, and they may be temporarily wide enough to even allow bacteria to cross the vessel wall.
Strong propulsion and high probability
Using experiments and computer simulations, researchers at ETH Zurich were able to show that propelling bacteria using a rotating magnetic field is effective for three reasons. First, propulsion via a rotating magnetic field is ten times more powerful than propulsion via a static magnetic field. The latter only fixes the direction and the bacteria must move on their own.
The second and most critical reason is that the bacteria driven by the rotating magnetic field are constantly in motion, moving along the vascular wall. This makes them more likely to encounter the spaces that briefly open between cells of the vascular wall compared to other types of propulsion, in which the movement of the bacteria is less exploratory. And third, unlike other methods, the bacteria do not need to be tracked by imaging. Once the magnetic field is positioned over the tumor, it does not need to be readjusted.
“Cargo” accumulates in the tumor tissue
“We also use the natural, autonomous locomotion of bacteria,” says Schürle. “Once the bacteria have passed through the blood vessel wall and are in the tumor, they can independently migrate deep into its interior.” For this reason, scientists use propulsion via the external magnetic field for only one hour, long enough for the bacteria to efficiently cross the vascular wall and reach the tumor.
These bacteria could carry cancer drugs in the future. In their cell culture studies, the ETH Zurich researchers simulated this application by attaching liposomes (nanospheres of fatty substances) to bacteria. They marked these liposomes with a fluorescent dye, which enabled them to demonstrate in the Petri dish that the bacteria had indeed delivered its “cargo” inside the cancerous tissue, where it accumulated. In a future medical application, the liposomes would be filled with a drug.
Bacterial cancer therapy
Using bacteria as ferryboats for drugs is one of two ways bacteria can help fight cancer. The other approach is more than a century old and is currently undergoing a revival: using the natural propensity of certain species of bacteria to damage tumor cells. This may involve several mechanisms. In any case, we know that the bacteria stimulate certain cells of the immune system, which then eliminate the tumor.
Many research projects are currently investigating the effectiveness of E. coli bacteria against tumors. Today, it is possible to modify bacteria by synthetic biology to optimize their therapeutic effect, reduce side effects and make them safer.
Make non-magnetic bacteria magnetic
Yet, to utilize the inherent properties of bacteria in the treatment of cancer, the question of how these bacteria can effectively reach the tumor remains. While it is possible to inject the bacteria directly into tumors near the surface of the body, this is not possible for tumors deep inside the body. This is where Professor Schürle’s microrobotic control comes in. “We believe we can use our engineering approach to increase the effectiveness of bacterial cancer therapy,” she says.
E. coli used in cancer studies is not magnetic and therefore cannot be propelled and controlled by a magnetic field. In general, magnetic reactivity is a very rare phenomenon in bacteria. Magnetospirilla is one of the few genera of bacteria that possess this property.
Schürle therefore wants to make E. coli magnetic bacteria too. This could one day make it possible to use a magnetic field to control clinically used therapeutic bacteria that have no natural magnetism.
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Material provided by ETH Zurich. Original ecrit by Fabio Bergamin. Note: Content may be edited for style and length.