Nanotechnology offers powerful new
possibilities for targeted cancer therapies, but the design challenges are
many. Northwestern
University scientists now
are the first to develop a simple but specialized nanoparticle that can deliver
a drug directly to a cancer cell’s nucleus—an important feature for effective
treatment.
They also are the first to directly image
at nanoscale dimensions how nanoparticles interact with a cancer cell’s
nucleus.
“Our drug-loaded gold nanostars are tiny
hitchhikers,” said Teri W. Odom, who led the study of human cervical and
ovarian cancer cells. “They are attracted to a protein on the cancer cell’s
surface that conveniently shuttles the nanostars to the cell’s nucleus. Then,
on the nucleus’ doorstep, the nanostars release the drug, which continues into
the nucleus to do its work.”
Odom is the Board of Lady Managers of the
Columbian Exposition Professor of Chemistry in the Weinberg College of Arts and
Sciences and a professor of materials science and engineering in the McCormick
School of Engineering and Applied Science.
Using electron microscopy, Odom and her
team found their drug-loaded nanoparticles dramatically change the shape of the
cancer cell nucleus. What begins as a nice, smooth ellipsoid becomes an uneven
shape with deep folds. They also discovered that this change in shape after
drug release was connected to cells dying and the cell population becoming less
viable—both positive outcomes when dealing with cancer cells.
The results are published in ACS Nano.
Since this initial research, the
researchers have gone on to study effects of the drug-loaded gold nanostars on
12 other human cancer cell lines. The effect was much the same. “All cancer
cells seem to respond similarly,” Odom said. “This suggests that the shuttling
capabilities of the nucleolin protein for functionalized nanoparticles could be
a general strategy for nuclear-targeted drug delivery.”
The nanoparticle is simple and cleverly
designed. It is made of gold and shaped much like a star, with five to 10
points. (A nanostar is approximately 25 nm wide.) The large surface area allows
the researchers to load a high concentration of drug molecules onto the
nanostar. Less drug would be needed than current therapeutic approaches using
free molecules because the drug is stabilized on the surface of the
nanoparticle.
The drug used in the study is a
single-stranded DNA aptamer called AS1411. Approximately 1,000 of these strands
are attached to each nanostar’s surface.
The DNA aptamer serves two functions: it is
attracted to and binds to nucleolin, a protein overexpressed in cancer cells
and found on the cell surface (as well as within the cell). And when released
from the nanostar, the DNA aptamer also acts as the drug itself.
Bound to the nucleolin, the drug-loaded
gold nanostars take advantage of the protein’s role as a shuttle within the
cell and hitchhike their way to the cell nucleus. The researchers then direct
ultrafast pulses of light—similar to that used in LASIK surgery—at the cells.
The pulsed light cleaves the bond attachments between the gold surface and the
thiolated DNA aptamers, which then can enter the nucleus.
In addition to allowing a large amount of
drug to be loaded, the nanostar’s shape also helps concentrate the light at the
points, facilitating drug release in those areas. Drug release from
nanoparticles is a difficult problem, Odom said, but with the gold nanostars
the release occurs easily.
That the gold nanostar can deliver the drug
without needing to pass through the nuclear membrane means the nanoparticle is
not required to be a certain size, offering design flexibility. Also, the
nanostars are made using a biocompatible synthesis, which is unusual for
nanoparticles.
Odom envisions the drug-delivery method,
once optimized, could be particularly useful in cases where tumors are fairly
close to the skin’s surface, such as skin and some breast cancers. (The light
source would be external to the body.) Surgeons removing cancerous tumors also
might find the gold nanostars useful for eradicating any stray cancer cells in
surrounding tissue.
