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From a young age, we are taught to protect ourselves from germs. From scrubbing our teeth to washing our hands, the hygienic routines we learned as kids help us steer clear of harmful single-celled organisms. And for good reason – research suggests bacterial infection is a significant risk factor for developing cancer. More surprising, however, are the studies suggesting we can repurpose bacteria to treat cancer, with scientists enlisting harmless bacteria to secrete anti-cancer toxins, compete with cancer cells for nutrients, and stimulate the immune system.
Expanding upon this idea, a group from MIT has investigated how bacteria may be used to enhance the delivery of therapeutic nanoparticles to tumors. Nanoparticles are molecules that are even smaller than cells. They can be used as delivery vehicles that encapsulate a drug and transport it to tumors while leaving healthy tissues unharmed. In one facet, nanoparticles serve to protect a drug molecule so it is not removed or destroyed by the body before it can do its job. They can also be constructed with specific size and surface properties to enhance their accumulation at the tumor site or enhance their ability to release drug contents at the appropriate time. Despite these potential advantages, delivering an effective dose of therapeutic nanoparticles to tumors remains a challenge. The tissues surrounding a tumor, known as the tumor microenvironment (TME), contain a complex system of blood vessels to supply the nutrients and oxygen tumors rely on for rapid growth. This creates high fluid pressure in the tumor, consequently blocking the diffusion of the drug from the blood vessels to the tumor.
This study sought to overcome this barrier to diffusion by using a kind of bacteria called magnetotactic bacteria (MTB), which are able to respond to magnetic fields. MTB sense magnetic poles through special lipid-covered chains of iron oxide and use appendages called flagella to align their bodies with the magnetic field. When a rotating magnetic field is applied, the bacteria start rotating with it, continuously attempting to align with the field. Remarkably, when a large group of MTB are all spinning in this manner, they interact with each other and move forward as a layer. This movement creates a net flow in a given direction, which the authors hypothesized could help push nanoparticles through the pressure differential blocking their diffusion and into cancerous tissue.
The team first set out to test how well MTB exposed to rotating magnetic fields (RMFs) would produce a net flow in fluid. To do this, they added a large amount of MTB to a fluorescent nanoparticle solution, applied the RMFs, and analyzed the flow directionality and velocity. Next, the team investigated whether MTB could drive nanoparticles into collagen, which mimics the density and strength of cancerous tissue. In this experiment, they combined the fluorescent nanoparticles and MTB in a small channel and measured the accumulation of fluorescence at five selected areas. Notably, when RMFs were applied there was a 3-fold increase in nanoparticle accumulation in the collagen. The nanoparticles also penetrated deeper into the collagen.
These results suggest that the net flow produced by MTBs can increase the rate of nanoparticle accumulation in tissue. While this is a good start, the most clinically impactful goal is to increase the total amount of nanoparticles reaching the tumor site over a long period of time. In any diffusion process, whereby a molecule passes from one side of a membrane to the other, there is an equilibrium point. It follows that after a certain amount of nanoparticle transport from the blood vessel to cancerous tissue, the equilibrium point will be reached and there will be no further increase in the amount of nanoparticles crossing the barrier. The final phase of this study investigated if MTB stimulation could produce a diffusion saturation point higher than the normal equilibrium point for nanoparticle transport into collagen. Increasing this diffusion saturation point would lead to more nanoparticles coming in contact with cancerous cells and potentially a greater therapeutic effect. Fluorescent nanoparticles with MTB were run in the channel apparatus for a full 60 minutes without RMFs. As expected, the nanoparticle accumulation plateaued after a period of time. The channel was then run for another 60 minutes with RMFs. Encouragingly, the RMFs immediately stimulated an uptick in nanoparticle transport into the collagen and allowed for more than double the nanoparticle transport over the 60 minute period.
Overall, this study demonstrates magnetotactic bacteria were capable of creating a flow that stimulates a greater number of nanoparticles diffusing into collagen, greater depth of nanoparticle penetration into collagen, and an elevated threshold before nanoparticle diffusion into collagen maxes out.
While treating patients with magnetotactic bacteria may sound unconventional, the authors maintain that their discovery has clinical potential. In practice, MTB could be injected along with the nanoparticles while RMFs applied over the tumor region spin the MTB and guide nanoparticles into the diseased tissue. Once injected, the bacteria would continue to multiply, further increasing the number of nanoparticles being delivered into the tumor. Notably, because this strategy relies on the magnetic properties of the bacteria and not the nanoparticles themselves, the authors emphasize that their strategy is compatible with many different types of therapeutic nanoparticles.
It is commonly said, “the enemy of my enemy is my friend.” In this theme, researchers are continuing to explore the potential of bacteria as an unlikely tool in improving nanoparticle-based chemotherapy. Because when it comes to the fight against cancer, we need all the friends we can get.
Edited by Emily Costa
Schuerle S, Soleimany AP, Yeh T, et al. Synthetic and living micropropellers for convection-enhanced nanoparticle transport. Science Advances. 2019;5(4). doi:10.1126/SCIADV.AAV4803/SUPPL_FILE/AAV4803_SM.PDF
Fernandes C, Suares D, Yergeri MC. Tumor Microenvironment Targeted Nanotherapy. Frontiers in Pharmacology. 2018;9:1230. doi:10.3389/FPHAR.2018.01230/BIBTEX
Figure created with BioRender.