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Microbot Drug Delivery

Microbot Drug Delivery. Which model organism? Mark Fang, Stanford iGEM. Microbots: Overview.

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Microbot Drug Delivery

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  1. Microbot Drug Delivery Which model organism? Mark Fang, Stanford iGEM

  2. Microbots: Overview Microbot drug delivery involves attaching drugs to the exterior of microscopic biological chasses, such as bacteria and viruses, so that when the chasses are phagocytosed by their target cells they bring inside with them the drugs. Choosing the chassis is thus an important design parameter, since the chassis will be responsible for which cells are targetted and how it will travel to those cells. In order to get the chassis to localize to the desired targets, we will need to make several considerations:

  3. Selecting a chassis The chassis that will transport the drug should be: • Highly specific • Immune response • Genetically well characterized • Pathogenically well characterized

  4. Two broad chassis classes: Bacteria Viruses SEM micrograph of Escherichia coli Bactofection vs. Virofection Vesicular Somatitis Virus

  5. Highly Specific As with all drug delivery methods, the more specific, the fewer the side effects. The chassis can be engineered to be specific: • Quorum sensing • Hypoxia • Inducible control The chassis can also be naturally specific: • Listeria monocytogenes • Vesicular somatitis virus rp34a

  6. Immune response The patient’s immune response can be a hindrance or a mechanism for inducing localization of the chassis. Macrophage engulfing bacteria. The chassis will need to avoid being engulfed by immune cells to prevent incidentally compromising the immune system.

  7. Genetically/structurally well characterized Bacteria: many strains have entire genome sequenced. Ex. E. coli has been used extensively in genetic engineering. Virus: more difficult to engineer. Virus may also be too small – for example, lambda phages can only hold genomes between 75 and 105% the size of the normal genome.

  8. Non-pathogenic: The virulence of certain bacteria species can be attenuated through knock out mutants. The rate and extent of bacterial expansion can also be controlled. Pathogenically well characterized

  9. Advantages vs. Disadvantages Viruses: • More difficult to engineer • May be too small • Can cause undesirable mutations during integration of viral genome into host genome • Can be naturally specific Bacteria: • Easier to manipulate, virulence shown to be pliable, some are also naturally localized in body

  10. Choosing a chassis Listeria monocytogenes – with the view of targeted drug delivery to cancer cells: • Has been show to localize to tumor cells and metastases • Has been engineered to exhibit attenuated virulence • Expansion can be controlled • Riboswitches naturally extant in certain Listeria species

  11. Testing the chassis • HeLa cancer cells – can conduct in vitro test for general invasion of human cancer cells • Human glioma cells - to establish possibility for chassis to invade brain cancer cells. Further tests in animals may show whether the chassis is able to penetrate the blood brain barrier. • For a listing of 60 human cancer cell lines: http://dtp.nci.nih.gov/docs/misc/common_files/cell_list.html

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