PHILADELPHIA -- Research studies, based at the University of Pennsylvania,
demonstrate that biodegradable nano-particles containing two potent cancer-fighting
drugs are effective in killing human breast tumors. The unique properties
of the hollow shell nano-particles, known as polymersomes, allow them to deliver
two distinct drugs, paclitaxel, the leading cancer drug known by brand names
such as Taxol, and doxorubicin directly to tumors implanted in mice. Their
findings, presented online in the journal Molecular Pharamaceutics, illustrate
the broad clinical potential of polymersomes.
"The system provides a number of advantages over
other Trojan horse-style drug delivery system, and
should prove a useful tool in fighting a number of
diseases," said Dennis Discher, a professor in Penn's
School of Engineering and Applied Science and a member
of Penn newly established Institute for Translational
Medicine and Therapeutics. "Here we show that
drug-delivering polymersomes will break down in the
acidic environment of the cancer cells, allowing
us to target these drugs within tumor cells."
One key feature of molecular mechanism involves
putting pores in the cancer cell membranes and has
been simulated with supercomputers by Michael F.
Klein and Goundla Srinivas of Penn's Department of
Chemistry. While cell membranes and liposomes (vesicles
often used for drug-delivery) are created from a
double layer of fatty molecules called phospholipids,
a polymersome is comprised of two layers of synthetic
polymers. The individual polymers are degradable
and considerably larger than individual phospholipids
but have many of the same chemical features. This
results in a structure that looks like a very small
cell or virus.
Discher and his colleagues take advantage of the
polymersome properties to ferry their drug combination
to the tumor. The large polymers making up
the shell allow paclitaxel, which is water-insoluble,
to embed within the shell. Doxorubicin, which
is water-soluble, stays within the interior of the
polymersome until it degrades. According to
the researchers, the polymersome and drug combination
is self-assembling the structure spontaneously forms
when all of the components are suitably mixed together.
"Recent studies have shown that cocktails of paclitaxel
and doxorubicin lead to better tumor regression than
either drug alone, but there hasn't been any carrier
system that can carry both drugs as efficiently to
a tumor," said Fariyal Ahmed, the lead author, former
doctoral student in bioengineering,and now a fellow
at Harvard Medical School. "Polymersomes get
around those limitations
Discher developed polymersomes with Penn bioengineer
Daniel Hammer in the 1990s. The Discher lab
is further studying the drug- and gene-delivery capabilities
of polymersomes, tailoring their shapes, sizes, loading
and degradability to each application. Discher
theorizes that polymersomes could be made capable
of traveling to places in the body that are difficult
for most drug-carrier systems to access.
This research was supported by grants from the National
Institutes of Health, the National Science Foundation-Materials
Research Science and Engineering Center and the Nanotechnology
Institute.
Co-authors on these findings include Aaron Brannan
and Frank Bates of the University of Minnesota and
Refika Pakunlu and Tamara Minko of Rutgers University.
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