Scientists have explored the use of bacteria for cancer treatment for more than a century, with some strains progressing onto clinical trials. More recently, the idea has emerged of using modified bacteria as “ferries” to carry anti-cancer drugs through the bloodstream to the tumours.
Translation of this technique to the clinic requires an effective way to manipulate the drug-carrying bacteria such that they can effectively cross the blood vessel wall and infiltrate tumour tissue. With this aim, Simone Schürle and colleagues at ETH Zurich are investigating the use of magnetic bacteria controlled by external magnetic fields. In particular, they have shown that a uniform rotating magnetic field (RMF) can increase tumour infiltration by these “living microrobots”.
Magnetic fields are ideal for medical use due to their established clinical safety. To date, however, strategies to control magnetic therapeutic agents often relied on static field gradients to draw them towards target sites. This approach requires active position feedback and is also unsuitable for deep-seated tumours, as magnetic field gradients rapidly diminish with increasing distance from their source. In contrast, uniform RMFs can be generated at clinically relevant scales, can control bacterial microrobots in deep tumours and do not require any positional tracking.
To test their approach in vitro, Schürle and her team investigated Magnetospirillum magneticum bacteria, which are naturally magnetic due to the iron oxide particles that they contain. The researchers combined these magnetic bacteria with fluorescently labelled liposomes (which could act as the drug carrier in future medical applications) and used an RMF to guide them across a monolayer of human microvascular endothelial cells, representing the vascular wall in a blood vessel.
Bacteria exposed to RMF for one hour exhibited 4.6-fold higher permeation across the barrier compared with those exposed to a directional magnetic field or unactuated controls. To understand the mechanisms driving this enhanced translocation, the team employed a computational model in COMSOL Multiphysics.
The simulation showed that while a static magnetic field merely guides the direction of the bacteria (which have to move under their own power), an RMF generates torque in the bacteria that propels them forward along a surface in a circular motion. Importantly, as the bacteria are constantly in torque-driven motion along the blood vessel wall, they are more likely to encounter the narrow gaps that briefly open between cells in the wall and traverse the barrier.
Next, the team examined the transport of fluorescently labelled magnetic bacteria into a three-dimensional tumour spheroid. Confocal imaging revealed that after 24 and 120 h, fluorescence signals in RMF-exposed spheroids to were 9.9- and 21.3-fold higher, respectively, than signals in unactuated controls, with the highest intensity in the centre of the spheroid.
Finally, the researchers evaluated their actuation strategy in vivo in tumour-bearing mice. They injected bacteria into the animals’ tail veins and subjected the anaesthetized mice to an RMF for 1 h. One day after treatment, they observed a high concentration of bacteria in the tumours, with consistently higher fluorescence intensity in tumours exposed to RMF than in controls. Bacteria accumulated preferentially in the tumour rather than in the major organs, except for the liver, where full clearance was expected by day six.
Laser manipulation turns white blood cells into medicinal microrobots
Schürle and colleagues conclude that the magnetic bacteria–liposome platform, combined with RMF actuation, is a versatile biohybrid system that could improve targeting and colonization of therapeutic bacteria in tumours. “By merging the benefits of bacteria-mediated therapy with a scalable magnetic torque-driven control strategy, our approach enables effective, targeted delivery of living microrobots for improved cancer treatment,” they write.
The research is described in Science Robotics.
