Bacterial-based biohybrid microrobots on a mission to fight cancer someday
Stuttgart – A team of scientists in the Department of Physical Intelligence at the Max Planck Institute for Intelligent Systems has combined robotics with biology by equipping E. coli bacteria with artificial components to build a biohybrid microrobot. First, as can be seen in Figure 1, the team attached several nanoliposomes to each bacterium. In its outer ring, this spherical carrier encloses a material (ICG, green particle) that melts when illuminated by near infrared light. Further to the center, within the aqueous core, liposomes encapsulate water-soluble chemotherapeutic drug (DOX) molecules.
The second component the researchers attached to the bacteria were magnetic nanoparticles. When exposed to a magnetic field, the iron oxide particles serve as a boost over these already highly motile microorganisms. In this way, it is easier to control the bacterial pool – a design refined towards in vivo applications. Meanwhile, the binding strap of liposomes and magnetic particles in bacteria is a highly stable and unbreakable complex of streptavidin and biotin, which was developed several years earlier (https://www.nature.com/articles/s41598-018-28102-9) and useful when building micro-biohybrid robots.
E. coli bacteria are fast and versatile swimmers that can navigate through materials ranging from liquids to highly viscous tissues. But that’s not all, they also have very advanced sensing capabilities. Bacteria are attracted to chemical gradients such as low oxygen levels or high acidity – both of which are common near tumor tissue. Treating cancer by injecting nearby bacteria is known as bacteria-mediated tumor therapy. Microorganisms flow to where the tumor is, grow there and in this way activate the patient’s immune system. Bacterial-mediated tumor therapy has been a therapeutic approach for more than a century.
Over the past few decades, scientists have been looking for ways to further enhance the superpowers of these microorganisms. They equip bacteria with extra components to help fight the battle. However, adding artificial components is not an easy task. Complex chemical reactions are at play, and the degree of density of the particles loaded onto the bacteria is important to avoid dilution. The team at Stuttgart have now raised the bar quite high. They managed to equip 86 out of 100 bacteria with liposomes and magnetic particles.
The scientists demonstrated how they managed to direct such high-density solutions through different pathways externally. First, through a narrow L-shaped channel with two compartments at each end, with one tumor spheroid each. Second, a narrower arrangement that resembles a small blood vessel. They added an extra permanent magnet to one side and demonstrated how they precisely controlled the drug-filled microrobot toward the spheroidal tumor. And third – going one step further – the team guided the microrobot through a thick collagen gel (resembling tumor tissue) with three levels of stiffness and porosity, ranging from soft to medium to stiff. The stiffer the collagen, the tighter the protein network, the harder it is for bacteria to find their way through the matrix (Figure 2). The team showed that once they added a magnetic field, the bacteria managed to navigate all the way to the other end of the gel because the bacteria had a higher strength. Due to the constant alignment, bacteria find their way through the fibers.
Once the microrobot has accumulated at the desired point (spheroid tumor), the near-infrared laser generates a beam with a temperature of up to 55 degrees Celsius, triggering the liposome melting process and closed drug release. A low pH level or an acidic environment also causes the nanoliposomes to open – hence the drug is released near the tumor automatically.
“Imagine we would inject such bacteria-based microrobots into the bodies of cancer patients. With magnets, we can precisely direct the particles towards the tumor. Once the microrobots have sufficiently surrounded the tumor, we aim the laser at the tissue and thereby trigger the release of the drug. Now, not only is the immune system triggered to wake up, but additional drugs also help destroy tumors,” says Birgül Akolpoglu, Ph.D. student in the Department of Physical Intelligence at MPI-IS. He is the first author of a publication entitled “Magnetic controllable bacterial microrobots that move in a 3D biological matrix for stimulus-responsive cargo delivery” led by a former postdoctoral researcher in the Department of Physical Intelligence, Dr. Yunus Alapan. It was published in Science Advances on July 15, 2022.
“This on-site delivery will be minimally invasive to the patient, painless, minimally toxic and the drugs will develop their effects where needed and not in the rest of the body,” Alapan added.
“Bacteria-based biohybrid microrobots with medical functions could one day fight cancer more effectively. This is a new therapeutic approach that is not too far from the way we treat cancer today,” said Prof. Dr. Metin Sitti, who heads the Department of Physical Intelligence and is the last author of the publication. “The therapeutic effect of medical microrobots in finding and destroying tumor cells can be enormous. Our work is a great example of basic research aimed at benefiting our society.”
____
Figure 1: Bacterial biohybrid carrying nanoliposomes (200 nm) and magnetic nanoparticles (100 nm). The nanoliposomes were loaded with the chemotherapeutic DOX and the photothermal agent ICG, and both loads were conjugated to E. coli bacteria (2 to 3 m long) via biotin-streptavidin interaction. Akolpoglu et al., Sci. Adv. 8, eabo6163 (2022).
Figure 2: Schematic showing a bacterial biohybrid microrobot magnetically guided through a fibrous environment. Bacterial biohybrids can shed their charge on NIR irradiation. Akolpoglu et al., Sci. Adv. 8, eabo6163 (2022).
#Bacterialbased #biohybrid #microrobots #mission #fight #cancer
Comments
Post a Comment