Researchers are equipping bacteria with artificial components in order to control them better and achieve an additional therapeutic effect in the destruction of tumor cells.
A team of scientists at the Max Planck Institute for Intelligent Systems, which conducts research at the interface between the fields of robotics and biology, equipped E. coli bacteria with artificial components in a research project in order to construct biohybrid microrobots [1].
First, the team from the Department of Physical Intelligence attached several spherical nanoliposomes to each bacterium (Fig. 1). In their outer ring, these transport components enclose a material (ICG, green particles) that causes the nanoliposome to melt when illuminated with near-infrared light. They encapsulated water-soluble chemotherapeutic drug molecules (DOX) in the core.
Iron oxide particles as a drive
The second component that the researchers attached to the bacterium are magnetic nanoparticles. When the highly mobile and agile bacteria are exposed to a magnetic field, the tiny iron oxide particles act as an additional drive. It is also easier to control the swimming of the bacteria - an improved design should such microrobots one day be steered through a body.
The threads that bind the liposomes and magnetic particles to the bacteria consist of a streptavidin-biotin complex. This was developed several years ago and was of great benefit in the construction of the biohybrid microrobots, as the compound is very stable and difficult to break.
Bacteria are fast and versatile swimmers that can maneuver through a wide variety of materials - from liquids to very viscous tissue. But that's not all: they also have very fine sensors. Bacteria are attracted to low oxygen levels or high acidity - both of which occur around tumor tissue. Scientists call the treatment of cancer by injecting bacteria in the immediate vicinity of the altered tissue bacteria-mediated tumor therapy. When injected into a vein, the microorganisms flow to the tumor and colonize it. This triggers an immune response in the patient and the immune system now turns against the cancer. The therapeutic approach of fighting cancer with bacteria is more than 100 years old.
In recent decades, scientists have been looking for ways to increase the superpowers of these microorganisms even further. They have equipped the bacteria with additional components to support them in their fight. However, adding artificial building blocks is no easy task. There are complex chemical reactions involved, and density matters: what percentage of a bacterial solution is loaded with particles? A thin mixture does not achieve much. The Stuttgart team has now set the bar pretty high. They have succeeded in equipping 86 out of 100 bacteria with both liposomes and magnetic particles.
Fig. 2: Schematic representation of bacteria-based biohybrid microrobots that are magnetically guided through fibrous environments. The biohybrid microrobots can then release their drug load when irradiated with near-infrared light. Akolpoglu et al, Sci. Adv. 8, eabo6163 (2022)In a research paper, the scientists showed how they were able to control such a high-density solution through various courses from the outside. First, the microrobots passed through an L-shaped narrow channel with two bulges at each end, each containing a tumor spheroid (a lump of tumor cells). The scientists then guided the microrobots through even narrower pathways resembling tiny blood vessels. They also placed a magnet on one side and showed how they could precisely steer the drug-loaded microrobots towards the tumor spheroids. Third, going one step further, the team steered the microrobots through three variants of a viscous collagen gel (which resembles tumor tissue): The viscosity ranged from soft to medium to stiff. The stiffer the collagen and the denser the network of protein strands, the more difficult it was for the bacteria to find a way through the tightly woven matrix (Fig. 2). However, the team was able to show that bacteria surrounded by a magnetic field are able to reach the other end of the gel. Thanks to the magnetic environment, the bacteria loaded with magnetic nanoparticles receive an additional boost. With a constant orientation of the magnetic field, the bacteria made their way through the fibers.
As soon as the microrobots have accumulated at the desired location (the tumor tissue), a near-infrared laser generates beams of up to 55 degrees. The heat triggers a melting process of the liposome and a release of the enclosed medication. A low pH value or an acidic environment also cause the nanoliposomes to break open. In this way, the drugs are automatically released in the vicinity of a tumor.
"Imagine if we were to inject such bacteria-based microrobots into the body of a cancer patient. Using a magnet, we could direct the particles precisely towards the tumor. As soon as enough microrobots surround the tumor, we aim a laser at the tissue and trigger the drug release. Not only is the immune system activated; the drugs also help to destroy the tumor," says Birgül Akolpoglu, PhD student in the Department of Physical Intelligence at the MPI for Intelligent Systems. The study was published in Science Advances on July 15, 2022 [2].
"This on-the-spot drug delivery would be minimally invasive for the patient, painless, non-toxic and the drugs would take effect where they are needed instead of throughout the body," adds Alapan.
"Bacteria-based biohybrid microrobots with medical functions could one day effectively fight cancer. It is a new therapeutic approach that may not be too far in the future," says Prof. Dr. Metin Sitti, who heads the department and is the last author of the study. "The impact of medical microrobots in finding and destroying tumor cells could be significant. Our work is a great example of basic research that benefits society."
Literature
[1] Source: Max Planck Institute for Intelligent Systems
[2] M. B. Akolpoglu et al: Magnetically steerable bacterial microrobots moving in 3D biological matrices for stimuliresponsive cargo delivery, Sci. Adv., vol. 8, no. 28, p. eabo6163, Jul. 2022, doi: 10.1126/sciadv.abo6163
