YSM Issue 90.1

FOCUS
biomedical engineering
Eyes on the prize, you jump into a river, furiously swimming for the shoreline.
Yet, the second you reach for it, the current pulls you away. This is the
challenge cancer drugs face in the human body: rapid clearance from the
treatment site. The protection and safe delivery of these drugs as they travel
to their target region are important factors in the drug’s success.
In order to combat this problem of rapid
clearance, a group of Yale researchers
has been studying therapeutic drug delivery
through the use of sticky biodegradable
nanoparticles. This technique targets tumors
more efficiently by releasing drugs directly
into the cancerous regions. The Yale study
found that bioadhesive nanoparticles were
capable of remaining in the tumor regions for
long periods of time, demonstrating the potential
for drug delivery through nanoparticles
to fight cancer.
Promising potential
Surgery and chemotherapy are common
treatments for aggressive tumors arising from
the ovary and uterus. Unfortunately, many
patients undergoing these therapies redevelop
tumors or, in the case of chemotherapy,
see their tumors become resistant to the
treatment. For a little over the past decade,
nanoparticles have emerged as a delivery
system for agents such as drugs, targeting a
larger portion of the drug to the tumor and
causing less severe side effects. Nanoparticles
can be engineered to enclose these drugs,
protecting them on their way to the target site
in the body.
Nanoparticle size plays an important role in
the drug’s ability to stay in the region of the
tumor. Too large a particle results in the drug’s
accumulation in the lower abdomen, while
too small of a particle results in a greater
chance of abdominal fluid clearing the drug
out of the system. With successful control
of nanoparticle size, however, nanoparticles
have the potential to allow for safer and more
effective cancer treatment.
A sticky finding
Mark Saltzman, a professor at the Yale
School of Engineering and Applied Science,
is working to harness the potential
of nanoparticles. His team developed
nanoparticles with an outer coating of a
polymer known as hyperbranched polyglycerol
(HPG). HPG nanoparticles are like
branched trees, where each branch is terminated
in water-loving groups that make the
particles water-soluble. This specific HPG
outer coating has proven to be more effective
than even the most highly regarded
particle coating, possessing higher stability,
lower risk of absorption in the body by proteins,
and longer circulation in blood.
Experimenting with nanoparticles of
different sizes, the team found nanoparticles
measuring around 100 nanometers to
be most effective in distributing throughout
the body cavity and dispensing their
encapsulated drug to the target site. The
longer the time in the body, the longer the
nanoparticles will release the therapeutic
drugs into the tumors.
Initially, Saltzman and his laboratory
team worked with non-sticky nanoparticles
that would circulate around the body
for extended periods of time and eventually
accumulate in the tumor. However, Yang
Deng, a postdoctoral associate working in
the laboratory, had an interesting finding.
With organic chemistry techniques, he was
able to make the nanoparticles that stick to
protein-coated surfaces. This was done by
using sodium periodate to transform the
outer coating of the particles, generating
aldehyde groups which are able to form
bonds with other proteins.
Once the team discovered these sticky
particles, the race was on to find suitable
applications. The team was able to invent
a new kind of sunblock that lasted longer
on the skin, taking advantage of how the
nanoparticles could stick to the skin’s top
layer. However, the researchers also realized
they could apply these sticky nanoparticles
to areas such as cancer treatment. This is
where Alessandro Santin came in.
Alessandro Santin, a professor at the Yale
School of Medicine, treats patients with gynecological
tumors with origins in the uterus
and ovaries. In some cases, the tumor
spreads out of the reproductive tract and
into the abdomen, where it would grow in
PHOTOGRAPHY BY GEORGE ISKANDER
►A member of the Saltzman lab prepares
reagents for her experiment. The Saltzman
lab has pioneered the use of nanoparticles
for drug delivery.
little clusters of cells that stick to the membrane
surfaces of the abdomen.
Saltzman believed his sticky nanoparticles
were relevant to Santin’s work for
a variety of reasons. “If they’re sticky,
we thought they would stick to the same
membranes that the cancer cells stick to
and they should get all over the abdomen,
and eventually stick to the same surfaces
tumor cells stick to,” Saltzman said.
Saltzman and his team hypothesized that
the sticky nanoparticles they had created
could be applied to deliver drugs to tumors.
16 Yale Scientific Magazine December 2016 www.yalescientific.org