Targeted Medicine: Using Bacteria as Navigators

Badwater Basin in Death Valley, California

Recently, a new strain of bacteria was isolated from brackish water at the Badwater Basin in Death Valley National Park in California and characterized as a novel species of magnetotactic bacteria (1), a type of bacterium that synthesizes nanocrystals of magnetite (Fe3O4) and greigite (FeS4). These bacteria orient themselves and navigate along geomagnetic fields using intracellular, membrane-bound magnetic nanocrystals, collectively named the magnetosome.

[Yawn] Another bacterial strain in a world where bacteria are one of the most abundant life forms. Ho hum, right? Not so fast! Wait until you see what these bacteria—or more specifically, the magnetosomes—can do. Magnetotactic bacteria might provide us with a great new tool to target delivery of chemotherapeutic drugs, recombinant proteins and medically relevant antibodies, ligands and nucleic acids to treat a wide range of diseases.

As part of their research on magnetotactic bacteria, Lefèvre et al. collected water and sediment samples from the Badwater Basin and analyzed bacterial 16S rRNA gene sequences to create a phylogenetic tree of large rod-shaped magnetite- and greigite-producing bacteria. They then narrowed their focus to a new strain of bacterium, named BW-1, and determined that BW-1 belongs to a previously unknown group of sulfate-reducing bacteria. Under high-sulfide culture conditions (>0.3mM sulfide), most BW-1 magnetosomes contained greigite, but under low-sulfide conditions, most magnetosomes were comprised of magnetite. Genetic analysis revealed that BW-1 has two separate clusters of magnetosome (mam) genes, one of which is most closely related to mam genes of Desulfovibrio magneticus, a magnetotactic bacterium that produces magnetite, and another that is most closely related to those of the greigite-producing Candidatus Magnetoglobus multicellularis. This raises the possibility that two different sets of genes are responsible for magnetite and greigite production and that these gene clusters could be differentially regulated, resulting in different ratios of magnetite and greigite nanocrystals in the cell.

Still yawning? Well, consider that bacterial magnetosomes could become one of the hottest new biomedical tools in site-directed drug delivery (reviewed in reference 2). By targeting delivery of therapeutic agents to the site of disease, doctors can increase the local concentration, making the agent more effective, without increasing the systemic concentration and thus the risk of side effects and general toxicity. Scientists are investigating the use of bacterial magnetosomes as vehicles to direct an agent to a specific site within the body simply by applying a magnetic field. These nanocrystals can target delivery of proteins, radioactive isotopes and chemotherapeutic drugs in live organisms, as well as DNA or RNA delivery for gene therapy or RNA interference studies.

For example, in studies with BALB/c mice that had solid tumors derived from H22 cells, treating the mice with the anticancer drug doxorubicin, doxorubicin-magnetosome conjugates or unconjugated magnetosomes resulted in 78.6%, 86.8% and 4.3% tumor suppression rates and 80%, 20% and 0% mortality, respectively (3). Thus, the doxorubicin-magnetosome treatment was just as effective as doxorubicin alone but had much lower mortality.

Scientists can take treatment one step further. With the proper cross-linking capabilities, bacterial magnetosomes can become multifunctional, allowing scientists to deliver multiple therapeutic agents simultaneously. Magnetosomes can be conjugated to anticancer drugs and radioactive isotopes or radioisotope-labeled antibodies, then injected and magnetically directed to a tumor, thus attacking cancer cells via two different mechanisms.

Discovery and characterization of magnetotactic bacteria are exciting because these deceptively simple organisms are better at synthesizing magnetic nanocrystals than scientists. BW-1 is particularly exciting because this strain offers scientists a way to characterize magnetosomes with magnetite’s lesser known cousin greigite. Bacterial nanocrystals have many advantages over nanocrystals synthesized in a lab, including narrow size distribution (25–55nm), uniform morphology, high purity and the presence of a membrane, which is composed of lipids and proteins and has plenty of primary amino groups that can be used to covalently link to a drug of interest. Once purified and sterilized, bacterial magnetosomes are surprisingly nontoxic, with slight acute toxicity, immunotoxicity and cytotoxicity. Rats injected with bacterial magnetosomes (40mg/kg body weight) showed no significant differences in routine blood exam results, liver and kidney function and levels of lymph cell stimulation compared to control rats.

Will bacterial magnetosomes make an appearance in your doctor’s office any time soon? Unlikely. Scientific studies are still being conducted to identify potential problems and make sure that these tiny drug delivery tools are safe. However, preliminary results are promising.

Isn’t science cool?

References

  1. Lefevre, C. et al. (2011). A cultured greigite-producing magnetotactic bacterium in a novel group of sulfate-reducing bacteria. Science, 334, 1720–3. PubMed ID: 22194580
  2. Sun, J. et al. (2011) Bacterial magnetosome: A novel biogenetic magnetic targeted drug carrier with potential multifunctions. J. Nanomater. doi:10.1155/2011/469031
  3. Sun, J.B. et al. (2007) In vitro and in vivo antitumor effects of doxorubicin loaded with bacterial magnetosomes (DBMs) on H22 cells: The magnetic bio-nanoparticles as drug carriers. Cancer Letters 258, 109–17.
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Terri Sundquist

Terri has worked as a Scientific Communications Specialist at Promega Corporation for more than 13 years, and prior to that, spent more than 5 years solving problems and answering questions as a Promega Technical Services Scientist. She graduated with B.S. degrees in Chemistry and Biology at the University of Wisconsin—River Falls, then earned her M.S. in Molecular Biology from the Mayo Graduate School in Rochester Minnesota.

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