E. coli bacteria
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Researchers from the Physical Intelligence Department at the Max Planck Institute for Intelligent Systems in Stuttgart, Germany, have created bacterial microbots they hope will one day deliver anti-cancer drugs directly to tumors.

The Escherichia coli bacteria are loaded with magnetic nanoparticles that can be used to control target localization and nanoliposomes that carry chemotherapeutic molecules.

“Wild-type bacteria were found to contain certain anti-cancer properties more than a century ago, with pioneering work by Dr. William Coley, and this has been the foundation of what we today call bacteria-mediated tumor therapy,” explained Birgul Akolpoglu, a Ph.D. student at the Max Planck Institute for Intelligent Systems and first author of the study, which was published in Science Advances last week.

She added: “Since then, genetically engineered bacteria have also been researched for cancer therapy due to their specific targeting of tumor regions and activation of anti-tumor immune response in the host body.”

Creating “biohybrids” of bacteria and nanoparticles can boost these natural anti-tumor capabilities by improving tumor localization and accumulation, localizing chemotherapy, and enhancing immune compatibility.

Akolpoglu and team developed their biohybrid microbots using a strain of E. coli that expresses biotin on its surface and therefore allows the binding of avidin-coated magnetic nanoparticles through an avidin–biotin interaction, which is the strongest known non-covalent bond between a protein and ligand.

The spherical-shaped nanoliposomes they developed have two layers; an outer lipid bilayer that contains indocyanine green (ICG), a material that melts when exposed to near infrared light, and an inner aqueous core which encapsulates the hydrophilic form of doxorubicin, doxorubicin hydrochloride.

The nanoliposomes also have biotin on their surface, so the researchers treated the E. coli surface with an avidin solution, then added the nanoliposomes to create a triple bridge bond of biotin-avidin-biotin that binds the nanoliposomes to the bacteria.

“This method does not harm the cell nor does it damage the particles or liposomes and the reaction is carried out in physiological conditions of neutral pH and [regular] body temperature,” Akolpoglu remarked.

The investigators tested the microbots in series of in vitro experiments and were able to show that the bacteria maintained their original swimming velocity after the artificial units were added.

Using magnets, the microbots were successfully steered towards 3-dimensional (3D) tumor spheroids through microchannels designed to mimic small blood vessels and through 3D collagen gels resembling tumor tissue.

When the microbots reached the tumor spheroids, which were created with colon cancer cells, they were heated with near infrared laser rays triggering a melting process of the liposome and release of the enclosed drugs.

Fluorescence microscopy confirmed the uptake of doxorubicin by the tumor cells following irradiation. The researchers also noted that some samples showed doxorubicin uptake without the near-infrared trigger, which they say could be attributed to simple diffusion or a lower pH in the tumor microenvironment.

Akolpoglu said that the team has now started testing the microbots in vivo and “are very excited to push the scientific boundaries of what is currently possible with these tiny swimmers and their use in clinical applications.”

However, before the microbots can be transferred for human use a number of challenges still need to be overcome.

“We must develop strategies to navigate and control these microrobots inside the host body with high precision, taking body fluid flows, and viscous and fibrous microenvironments found in tissues into account. We must also make sure that patient safety is guaranteed, and that these microrobots can be operated within a body for the long term, even in the face of potential immunological reactions,” Akolpoglu noted.

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