News
New Polymer Shows Promise for Drug Delivery
Biodegradable polyketals have advantages for intracellular delivery and sustained release
Atlanta (March 28, 2006) — A newly developed family of biodegradable polymers has shown potential for use in intracellular delivery and sustained release of therapeutic drugs to the acidic environments of tumors, inflammatory tissues and intracellular vesicles that hold foreign matter.
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These polymers have several advantages over existing biodegradable polymers,
researchers said. Among them, the polymers – called polyketals – are
biodegradable into Food and Drug Administration-approved compounds. Synthesis
is a simple and easily customized process. Degradation of the polymer does
not produce inflammation-causing acid, but instead generates membrane-permeable
products that allow all of the polymer’s byproducts to diffuse outside
the cell. That means byproducts shouldn’t accumulate in a patient’s
tissue and cause inflammation.
“We’ve known for 20 to 30 years that when cells take
up particles, they move them to a part of the cell with a low pH—about 5.0,” said
Niren Murthy, an assistant professor in the Wallace H. Coulter Department of
Biomedical Engineering at the Georgia Institute of Technology and Emory University. “Researchers
have been able to successfully exploit this process in cell culture and in
animal models, but have done so using materials that generated acid degradation
products and that hydrolyzed too slowly for chronic use. Thus, there has been
very little clinical activity in this area.”
However, polyketal nanoparticles use the cell’s acid to hydrolyze into
hydrophilic compounds that can release encapsulated therapeutics at an accelerated
rate in the acidic environments to which they are targeted, Murthy explained.
Also, unlike polyester-based biomaterials, polyketal nanoparticles do not generate
acid when they degrade. Researchers don’t know yet whether polyketals
will be less inflammatory than current polymers used for drug delivery, but
expect to evaluate this response within the next year.
Murthy presented information on the development and potential applications
of polyketals March 27 at the 231st American Chemical Society National
Meeting in Atlanta. His collaborators are Emory University immunologist Bali
Pulendran, University of Rochester physician Robert Pierce, and Georgia Tech
graduate students Michael Heffernan and Stephen Yang. Their research—under
way for the past two and a half years—is funded by the National Institutes
of Health and the National Science Foundation.
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Development of the polymer was a surprisingly straightforward process, Murthy
said. “There is a reaction that is well known in synthetic organic chemistry
called the acetal exchange reaction,” he explained. “We can change
this reaction a little bit and use it to make these polymers. It’s normally
a reaction used to protect alcohols, but when you make it react with a molecule
with two alcohols, it makes this polymer.”
Because this chemical process is a simple one, it is feasible for production
of the polymer on an industrial scale, potentially making it widely available,
Murthy said.
“We have a lot of flexibility in terms of the types of alcohols we incorporate
into the polymer,” he added. “We can tailor the polymer’s
hydrolysis rates and mechanical properties, which would broaden its medical
applications. For example, in some cases you want drug delivery faster than
others. With acute liver failure, you want drug release in one to two days,
whereas with arthritis, you want release over one to two months.”
In addition to its simple synthesis, another advantage of polyketals is their
degradation process, which generates membrane-permeable products, Murthy said.
“The problem with using polyesters as drug delivery vehicles is that
most of the illnesses being treated are chronic diseases requiring weekly injections,
yet polyesters take months to degrade,” he noted. “Polyketals hydrolyze
in a week, diffuse out of the cell and are then excreted outside of the cell.”
Researchers hope to test polyketals in clinical trials within five years if
animal model studies show potential. To date, Pierce has done some testing
in mice to treat acute liver failure. He injected polyketal nanoparticles in
mice, and the polyketals delivered them to the animals’ livers. But researchers
don’t know yet whether their system can deliver treatment in vivo. The
answer to that question is about a year away, Murthy added.
Potential applications of polyketals include the delivery of anti-oxidants
to treat acute liver failure in people who have suffered an alcohol or acetaminophen
overdose. In these patients, the liver stops functioning because macrophage
cells in the liver create reactive oxygen species. One of the treatments is
the delivery of superoxide dismutase, an enzyme that essentially detoxifies
superoxide.
Other applications include the use of polyketals in any type of protein-based
vaccine, Murthy said, adding that researchers have not yet pursued this possibility.
Yet another application is protein delivery for a wide range of therapeutics,
including insulin delivery for Type 1 diabetics – alleviating the
need for multiple injections.
In mid-2005, Georgia Tech, Emory and the University of Rochester filed two
provisional patent applications on the polyketal drug delivery system. Murthy
noted that a Japanese patent filed in 2001 described the same polymerization
process, but used it to make photo resists, rather than a drug delivery system.
Researchers have discussed the start up of a biomedical company based on this
technology, but first they must have some compelling data from animal studies.
If they pursue commercialization, the process could potentially be done within
Emtech Bio, an early-stage biosciences business incubator operated by Emory
University and Georgia Tech.
Research News & Publications Office
Georgia Institute of Technology
75 Fifth Street, N.W., Suite 100
Atlanta, Georgia 30308 USA
Media Relations Contacts: Jane Sanders (404-894-2214); E-mail:
(jane.sanders@edi.gatech.edu) or John Toon (404-894-6986); E-mail: (jtoon@gatech.edu)
Technical Contacts:
1. Niren Murthy, Georgia Tech (404-385-5145); E-mail: (niren.murthy@bme.gatech.edu)
2. Bali Pulendran, Emory University (404-727-8945); E-mail: (bali.pulendran@emory.edu)
3. Robert Pierce, University of Rochester (585-275-1874); E-mail: (robert_pierce@urmc.rochester.edu
Writer: Jane Sanders
Related Links
Wallace Coulter Department
of Biomedical Engineering
http://www.bme.gatech.edu/#
Niren
Murthy
http://www.bme.gatech.edu/facultystaff/faculty_record.php?id=58