32 THE SCIENTIST | the-scientist.com
release the drug over time. In that sense, basic forms of nanorobots
are already in clinical use.
Scientists can manipulate the shape, size, and composition
of nanoparticles to improve tumor targeting, and newer systems
employ strategies that specifically recognize cancer cells. Still, precise
navigation to tumor sites remains a holy grail of nanorobot research
and development. A 2016 meta-analysis assessing the efficiency of
nanodelivery vehicles tested in animal studies in the previous 10 years
revealed that a median of fewer than 1 percent of the injected nano-
vehicles actually reached the tumor site, and that this could be only
marginally improved with active targeting mechanisms, such as sur-
face decoration with specific antibodies or peptides for tumor-specific
receptor binding.^1
How can we make these nanobots better at steering themselves to
tumor sites? Wireless energy transmission remains a huge challenge,
and batteries are not yet efficient at the nanometer scale. Research-
ers have used external forces such as ultrasound or magnetic fields to
promote the homing of nanomedicines to tumor tissues, but the fluid
dynamics of the circulatory system work against nanoshuttles, whose
surface-to-volume ratio is 1 billion times that of objects on the scale
of meters. This causes surface and drag forces to become more domi-
nant: to the nanoparticle, it might feel like moving through honey
when navigating the aqueous environment of the vasculature.
But as it so often does, nature might just have a solution:
bacteria. The microscopic organisms swim autonomously through
fluids, driven by molecular motors that spin their cilia or flagella in a
corkscrew-like fashion—a very effective propulsion mechanism at
this scale that has inspired many nanoroboticists that try to mimic
this functionality. Researchers have fabricated helical, magnetic
swimmers that can be spun forward by a rotating magnetic field,
for example.^2 But bacteria, especially in the context of treating
cancer, are more than just role models for efficient swimming; some
are actually themselves therapeutic. In addition, microbes can sense
biochemical cues and adjust their trajectories accordingly, similar to
the envisioned on-board computation.
The idea of using bacteria to treat cancer is not ne w. One of
the earliest reports on bacteria as a cancer therapy comes from the
immunotherapy pioneer William Coley, who in the late 19th century
recognized that some cancer patients also suffering from skin
infections were more likely to get better. He began injecting bacterial
toxins, heat-inactivated microbes, or even live cultures of
Streptococcus bacteria into his patients with inoperable bone
and soft-tissue cancers, often leading to remissions. It was a bold
approach, given the risk of uncontrollable infections from these
bacterial formulations before the widespread availability of anti-
biotics. Largely because of that danger, and the promise of the
nascent concepts of radiation and chemotherapy, the clinical use of
bacteria as therapeutic agents for cancer went undeveloped. Today,
this revolutionary idea has been experiencing a renaissance.
Thanks to the convergence of fields from biology and chem-
istry to materials science, engineering, and computer sciences,
new avenues for the development of bacterial therapies for
cancer are opening up. The toolkits made available thanks toreduced costs of both sequencing and synthesis of DNA, along
with synthetic-biology approaches for custom genetic design of
bacterial-like behaviors, are paving the way for the emerging
fields of micro- and nanorobotics.Bacteria with anti-cancer payloads
Bacillus Calmette-Guérin (BCG), an attenuated bacterium typically
used as a vaccine strain for tuberculosis, has been repurposed for
the last several decades to locally treat bladder cancer. The concept
behind this approach, similar to that postulated by Coley, is that the
administration of bacteria stimulates the patient’s immune system
to fight off the cancer.
Even better, though unbeknownst to Coley, many bacteria
(though, for unknown reasons, not BCG) also have the potential to
selectively grow within solid tumors, in the bladder and elsewhere;
reduced immune surveillance in the tumor’s hypoxic and acidic
environment provides anaerobic bacteria with a safe haven to grow
and thrive. While inside tumors, some bacteria produce toxins and
compete with cancer cells for nutrients. Ultimately, the accumula-
tion of bacteria within the tumor induces immune-cell infiltration,
which can then lead to anti-cancer responses. Still, despite hav-
ing tested many naturally occurring and laboratory-made bacterial
strains in animal models of cancer, and having conducted human
trials testing bacteria to treat cancer, researchers have observed
little efficacy beyond the benefits that continue to be seen in blad-
der cancer patients.As a result, the field has shifted to genetically engineering
bacteria to serve as ferries for recombinant payloads. The selec-
tive targeting and subsequent growth of bacteria in tumors, along
with local delivery of therapeutics facilitated by the microbes them-
selves, could minimize the collateral damage to healthy cells that
is common with systemic cancer therapies. Several groups have
engineered bacteria to produce a wide variety of cargo, including
anticancer toxins, cytokines, and apoptosis-inducing factors. The
production of potentially toxic therapeutic cargo necessitates fur-
ther control over the bacteria, in case they land in locations they
shouldn’t. Thus, researchers are now moving toward engineering
next-generation bacterial systems to sense a physiological cue and
respond by producing a therapeutic at the local disease site.
To aid in this goal, over the last two decades the field of syn-
thetic biology has developed a repertoire of genetic circuits
to control microbial behaviors. These circuits consist of pos-Precise navigation to tumor sites
remains a holy grail of nanorobot
research and development.