Researchers from Brigham and Women’s Hospital have developed a potentially new way to treat arthritis. Here their new gel (red, with yellow rectangles representing encapsulated medicine) is injected into an arthritic joint. There enzymes (black image) associated with arthritis break down the biodegradable gel, releasing the medicine. Credit: Courtesy: Praveen Vemula, Karp lab, BWH |
Some
25 million people in the United States alone suffer from rheumatoid
arthritis or its cousin osteoarthritis, diseases characterized by often
debilitating pain in the joints. Now researchers at Brigham and Women’s
Hospital (BWH) report an injectable gel that could spell the future for
treating these diseases and others.
Among
its advantages, the gel could allow the targeted release of medicine at
an affected joint, and could dispense that medicine on demand in
response to enzymes associated with arthritic flare-ups.
“We
think that this platform could be useful for multiple medical
applications including the localized treatment of cancer, ocular
disease, and cardiovascular disease,” said Jeffrey Karp, leader of the
research and co-director of the Center for Regenerative Therapeutics at
BWH.
Karp
will present the findings April 15 at the annual meeting of the Society
for Biomaterials (SFB) as part of winning the coveted SFB Young
Investigator Award for this work. The work was also reported by Karp and
colleagues in the May 2011 issue of the Journal of Biomedical Materials Research (JBMR): Part A, and is currently available on the journal’s website.
Local delivery
Arthritis
is a good example of a disease that attacks specific parts of the body.
Conventional treatments for it, however, largely involve drugs taken
orally. Not only do these take a while (often weeks) to exert their
effects, they can have additional side effects. That is because the drug
is dispersed throughout the body, not just at the affected joint.
Further, high concentrations of the drug are necessary to deliver enough
to the affected joint, which runs the risk of toxicity.
“There
are many instances where we would like to deliver drugs to a specific
location, but it’s very challenging to do so without encountering major
barriers,” says Karp, who also holds appointments through Harvard
Medical School (HMS), Harvard Stem Cell Institute (HSCI), and the
Harvard-MIT Division of Health Sciences and Technology (HST).
For
example, you could inject a drug into the target area, but it won’t
last long–only minutes to hours–because it is removed by the body’s
highly efficient lymphatic system. What about implantable drug-delivery
devices? Most of these are composed of stiff materials that in a dynamic
environment like a joint can rub and cause inflammation on their own.
Further, most of these devices release medicine continuously–even when
it’s not needed. Arthritis, for example, occurs in cycles characterized
by flare-ups then remission.
Toward the Holy Grail
“The
Holy Grail of drug delivery is an autonomous system that [meters] the
amount of drug released in response to a biological stimulus, ensuring
that the drug is released only when needed at a therapeutically relevant
concentration,” Karp and colleagues write in JBMR. His coauthors are
Praveen Kumar Vemula, Nathaniel Campbell, and Abdullah Syed of BWH, HMS
and HSCI; Eric Boilard (now at Université Laval), Melaku Muluneh, and
David Weitz of Harvard University; and David Lee of BWH, currently at
Novartis. Karp notes the key involvement of Lee, a doctor who is
“treating patients with the problem we’re trying to solve.”
From left to right are Praveen Kumar Vemula of BWH and Jeffrey Karp, co?director of the Center for Regenerative Therapeutics at BWH. Credit: Brigham and Women’s Hospital, photographer, Donna Coveney |
The
researchers tackled the problem by first determining the key criteria
for a successful locally administered arthritis treatment. In addition
to having the ability to release drug on demand, for example, the
delivery vehicle should be injectable through a small needle and allow
high concentrations of the drug. The team ultimately determined that an
injectable gel seemed most promising.
Next
step: what would the gel be made of? To cut the time involved in
bringing a new technology to market, the team focused only on materials
already designated by the Food and Drug Administration as being
generally recognized as safe (GRAS) for use in humans.
Ultimately,
they discovered a GRAS material that could be coaxed into
self-assembling into a drug-containing gel. “The beauty of self-assembly
is that whatever exists in solution during the assembly process–in
this case, a drug–becomes entrapped,” says Vemula, first author of the
paper, who also has an appointment at HST.
They
further expected that the same material would disassemble, releasing
its drug payload, when exposed to the enzymes present during
inflammations like those associated with arthritis.
Promising results
A
series of experiments confirmed this. For example, the team created a
gel containing a dye as a stand-in for a drug, then exposed it to
enzymes associated with arthritis. The drug was released. Further, the
addition of agents that inhibited the enzymes stopped the release,
indicating that the gel “can release encapsulated agents in an on-demand
manner,” the researchers write. Although the team has yet to test this
in humans, they did find that dye was also released in response to
synovial fluid taken from arthritic human joints.
Among
other promising results, the researchers found that gel injected into
the healthy joints of mice remained stable for at least two months.
Further, the gel withstood wear and tear representative of conditions in
a moving joint.
Additional
tests in mice are underway. The technique has yet to be demonstrated in
humans, but the researchers write that it “should have broad
implications for the localized treatment of many…diseases” caused by the
enzymatic destruction of tissues.
The
researchers have applied for a patent on the work, which was sponsored
by the Center for Integration of Medicine and Innovative Technology
(CIMIT) through the U.S. Army and by the Harvard Catalyst Program.
