Transcript Microbot Drug Delivery

Microbot Drug Delivery
Which model organism?
Mark Fang, Stanford iGEM
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:
Selecting a chassis
The chassis that will transport the drug should be:
 Highly specific
 Immune response
 Genetically well characterized
 Pathogenically well characterized
Bactofection vs. Virofection
Two broad chassis classes:
 Bacteria
 Viruses
Vesicular Somatitis Virus
SEM micrograph of Escherichia coli
Highly Specific
As with all drug delivery methods, the more specific, the fewer
the side effects.
The chassis can be engineered to be specific:
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Quorum sensing
Hypoxia
Inducible control
The chassis can also be naturally specific:
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Listeria monocytogenes
Vesicular somatitis virus rp34a
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.
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.
Pathogenically well characterized
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.
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
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
Testing the chassis
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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/c
ell_list.html