Researchers at ETH Zurich want to use magnetic bacteria to fight cancerous tumors. They have now found a way for the microorganisms to penetrate the blood vessel wall and then colonize a tumour.
Scientists around the world are researching how cancer drugs can most efficiently reach tumors where they are supposed to take effect. One possibility is to use modified bacteria as ferries that transport the drugs through the bloodstream to the tumors. Researchers at ETH Zurich have now succeeded in controlling certain bacteria in such a way that they can efficiently penetrate the blood vessel wall and enter the tumor tissue.
The researchers led by Simone Schürle, Professor of Reactive Biomedical Systems, used bacteria that are naturally magnetic because they contain iron oxide particles as model bacteria. These bacteria of the genus Magnetospirillum react to magnetic fields and can be controlled from outside the body using magnets.
Schürle and her team have now shown in cell culture and in mice that a rotating magnetic field directed at the tumor is particularly suitable for the bacteria to penetrate the blood vessel wall near the tumor. At the vessel wall, the rotating magnetic field drives the bacteria to perform a forward rotational movement.
In order to better understand the penetration of the vessel wall, it is necessary to take a detailed look at it: The blood vessel wall is the barrier between the bloodstream and the tumor tissue, which is crisscrossed by many fine blood vessels. It consists of a layer of cells. Certain molecules from the bloodstream can slip through the narrow spaces between the cells and thus pass through the vessel wall. The size of the intercellular space is regulated by the vessel wall cells. Temporarily, the cells can also open the gap so wide that other cells (and therefore also bacteria) can pass through the vessel wall.
There are three reasons why driving the bacteria via a rotating magnetic field is effective, as the ETH researchers were able to show with experiments and computer simulations. Firstly, this type of propulsion is particularly strong, so that the bacteria can squeeze through the narrow spaces between cells particularly well. The drive via a rotating magnetic field is ten times stronger than a drive via a static magnetic field, which only determines the direction and in which the bacteria have to move under their own power.
Secondly, the bacteria propelled by the rotating field are constantly in motion; they dance along the blood vessel wall. As a result, the probability of them encountering a briefly opening gap between the vessel wall cells is higher than with the other types of propulsion, in which the bacteria move less dynamically. And thirdly, unlike other methods, the bacteria do not need to be tracked via imaging for guidance. Once the magnetic field is aligned with the tumor, passing bacteria are captured by the magnetic field.
"We also use the natural and autonomous movement of the bacteria," explains ETH Professor Schürle. "Once the bacteria have passed through the blood vessel wall and are inside the tumor, they can autonomously penetrate deep into it." The scientists therefore only use the drive via the external magnetic field for one hour so that the bacteria can efficiently overcome the vessel wall and reach the tumor.
In future, such bacteria could be loaded with cancer drugs. As part of their cell culture studies, the ETH researchers simulated this using liposomes (nanobubbles made of fat-like substances), which they attached to the bacteria. These liposomes were filled with a fluorescent dye. In this way, the scientists were able to prove in the Petri dish that the bacteria had actually delivered their cargo to the inside of cancer tissue, where it accumulated. In a future medical application, a drug would be used instead of the dye.
The approach pursued here of using bacteria as ferries for active substances is only one of two possibilities for using bacteria in cancer medicine. In science, another approach that is over a hundred years old is currently experiencing a revival: bacteria of certain species can damage tumors. It is possible that several mechanisms of action are involved. In any case, it is known that the bacteria stimulate certain cells of the immune system, which then act against the tumor.
There are currently several research projects investigating the effectiveness of Escherichia coli bacteria against tumors. It is now possible to modify the bacteria using synthetic biology in order to optimize their therapeutic effect, reduce side effects and increase safety.
But even if one wants to use the inherent properties of bacteria in cancer therapy, the question arises as to how these bacteria efficiently reach a tumor. In the case of cancerous tumors close to the body surface, it is possible to inject the bacteria into the tumor. For those deep inside the body, this becomes difficult. This is where ETH Professor Schürle's microrobotics come into play. "We think that we can increase the effectiveness of bacterial cancer therapy with our engineering approach," she says.
The Escherichia coli bacteria used in the cancer studies are not magnetic and therefore cannot be driven and controlled by a magnetic field. Magnetism is a very rare phenomenon among bacteria. Magnetospirillum is one of the few bacterial genera that have this property.
Schürle would therefore also like to make Escherichia coli bacteria magnetic. This could one day make it possible to control medically effective bacteria without natural magnetism via a magnetic field.
Source: ETH Zurich; Original publication: Gwisai, T.; Mirkhani, N.; Christiansen, M.G.; Nguyen, T.T.; Ling, V.; Schuerle, S.: Magnetic torque-driven living microrobots for increased tumor infiltration, Science Robotics October 26, 2022, doi: 10.1126/scirobotics.abo0665[https://doi.org/10.1126/scirobotics.abo0665]
