M.Microscopic swimming robots are currently being developed that can navigate the body to perform medical tasks such as providing targeted cancer therapies or surgery. In a study published March 24 in Science roboticsScientists made magnetically controlled microrobots based on neutrophils, a type of white blood cell. In mice, these so-called neutrobots penetrated the blood-brain barrier (BBB) to deliver drugs to brain cancer cells.
“This is a very cool idea,” says Liangfang Zhang, a nano-engineer and bio-engineer at the University of California at San Diego who was not involved in the study. “I would say this paper is still an early proof of concept study, but I think the overall concept is new. It’s interesting because it rethinks how to send cargo to the brain. “
A major hurdle in treating neurological disorders is getting drugs beyond the BBB, a highly selective barrier that prevents most substances from being absorbed into the brain. However, certain white blood cells are given special access to treat infection and inflammation, making them good Trojans to get drugs after this blockage. In previous studies, researchers loaded brain cancer drugs into neutrophils and macrophages, which have a natural ability to detect cancer as they swim towards higher concentrations of inflammatory chemicals released by diseased tissue.
However, previous iterations of drug-eluting immune cells have failed to fully treat mouse brain tumors, likely in part due to slow migration to the disease site. To improve speed and control, researchers have equipped microrobots based on sperm, bacteria or red blood cells with magnetic material to guide them externally with magnetic fields, says Zhiguang Wu, bio-engineer at the Harbin Institute of Technology in China and co-author of the new one Study.
To treat glioma, a type of brain tumor, in mice, Wu and colleagues developed neutrophil-based microrobots – neutrobots – that could be controlled with a magnetic field. First, the team made nanoparticles from a gel in which magnetic iron oxide beads and the widely used cancer drug paclitaxel were embedded. Next, the nanoparticles were encased E. coli Bacterial membrane. Disguised as harmful bacteria, the nanoparticles were much more easily engulfed by mouse neutrophils in vitro than mere nanoparticles. The bacterial coat also prevented drugs from leaking prematurely and made the particles less toxic to the neutrophils, the researchers found.
A transmission electron microscope image of a single neutrobot. The yellow arrow indicates a cluster of nanoparticles that contain iron oxide and paclitaxel, each enclosed by one E. coli Membrane. The scale is 2 μm.
The team tested the navigational and drug delivery capabilities of the Neutrobots in vitro. Under the control of a rotating magnetic field, the neutrobots reached a speed of 16.4 µm per second, about 50 times faster than the speed of natural neutrophils. By monitoring the neutrobots through a microscope, the researchers were able to instruct them to move in complex orientations on an artificial substrate.
To evaluate the inflammation-seeking ability of the neutrobots, the researchers placed them in a gel with a concentration gradient of an inflammatory factor. The neutrobots migrated to higher concentrations of the chemical at a rate comparable to natural neutrophils. And in a BBB model, neutrobots invaded mouse cells grown on a membrane to gain access to glioma cells and released their drug payload when exposed to inflammatory signals.
Finally, the researchers tested whether the bots could treat brain tumors in mice. First, they injected glioma cells into the brain of mice. After 10 days, they performed surgery on some mice to remove part of the tumor and increase the inflammatory signals that attracted neutrophils. The researchers injected neutrobots into the tails of each of the mice, and in a subset of mice they used a rotating magnetic field to direct the neutrobots toward the brain. Using magnetic resonance imaging (MRI), the team found that mice treated with both surgery and the magnetic field had more neutrobots accumulated around gliomas than mice that were not exposed to the magnetic field either did not undergo surgery or did not none received. The double-treated mice also survived longer – evidence that the two interventions were complementary. Transmission electron microscopy confirmed that neutrobots penetrated the BBB and invaded glioma tissue.
All mice treated with Neutrobot survived longer than animals treated with only one injection of saline or paclitaxel, indicating that neutrobots can still deliver drugs through the BBB in response to a weak inflammatory signal or a strong inflammatory signal without a magnetic drive.
According to Zhang, the individual components of the study – the use of immune cells as drug carriers, magnetically controlled nanoparticles and bacterial membranes as cloaks – are not new. “But they integrated these common individual components together and assembled them into a new system,” he says. “They [developed] a very unique functionality – that is, remote control of neutrophils. ”
Mariana Medina-Sánchez, a bio-engineer at the Leibniz Institute for Solid State and Materials Research Dresden in Germany, who did not contribute to the research, says the study is valuable because it demonstrates effective treatment of tumors in vivo, a goal of many researchers in the field. “[The study] is complete, systematic and there is strong evidence that what they developed works, ”she says.
Knowing the amount of drug you are loading per microrobot can help you control the drug dose by swarming these microrobots in a controlled manner.
—Mariana Medina-Sánchez, Leibniz Institute for Solid State and Materials Research Dresden
However, before microrobots can be used to treat cancer in humans, there are still a number of challenges to overcome. One of them is improving the percentage of micro-robots that make it to the tumor. “They had about eleven percent accumulation of these neutrophil-based microrobots at the disease site [in vivo]. So what happens to the others? “says Medina-Sánchez. Microrobots could build up in other organs or regions of the body, and the long-term side effects are unknown, she says.” However, this happens for any type of microrobot, not just for this specific job. This is a challenge for all [overcome]. ”
Once the microrobots arrive at the disease site, another hurdle is making sure they are delivering enough of the drug. “You need to increase the overall drug payload inside and also control the premature drug release,” says Zhang. “It takes time for the neutrophil to reach its destination. You don’t want them to dump all of the payload before they reach the destination. ”
Since a single microrobot cannot carry enough drugs to treat a disease, the researchers are also trying to understand how they move as swarms – similar to the collective movements of groups of ants, fish, or birds. “If you know the amount of drug you load per microrobot, you can control the drug dose by swarming these microrobots in a controlled manner,” says Medina-Sánchez. “So that’s one of the challenges: How to transport several [microrobots] in a controlled manner and deliver them to a destination. “Wu and his colleagues found that neutrobots formed four-headed chains in vitro, and these swarms swam about five times faster than individual bots. According to Medina-Sánchez, other microrobot researchers are aiming for swarms of hundreds, thousands, or even millions. “It depends on the destination and the location,” she says. “You may only need a few or millions of them.”
It is not clear how the neutrobots swarmed in mice, as current imaging techniques are not good enough to track single or small chains of microrobots in real time with a sufficiently high resolution in vivo – another challenge for the precise navigation of these tiny drug couriers in humans.
H. Zhang et al., “Dual-Responsive Biohybrid Neutrobots for Active Target Delivery”, Sci Robot, doi: 10.1126 / scirobotics.aaz9519, 2021.