ANN ARBOR, Mich. – University of Michigan scientists have created the nanotechnology
equivalent of a Trojan horse to smuggle a powerful chemotherapeutic drug inside
tumor cells – increasing the drug's cancer-killing activity and reducing its
toxic side effects.
Previous studies in cell cultures have suggested
that attaching anticancer drugs to nanoparticles
for targeted delivery to tumor cells could increase
the therapeutic response. Now, U-M scientists have
shown that this nanotechnology-based treatment is
effective in living animals.
"This is the first study to demonstrate a nanoparticle-targeted
drug actually leaving the bloodstream, being concentrated
in cancer cells, and having a biological effect on
the animal's tumor," says James R. Baker Jr., M.D.,
the Ruth Dow Doan Professor of Biologic Nanotechnology
at the University of Michigan, who directed the study.
"We're very optimistic that nanotechnology can markedly
improve cancer therapy," says Baker, who directs
the Michigan Nanotechnology Institute for Medicine
and the Biological Sciences. "Targeting drugs directly
to cancer cells reduces the amount that gets to normal
cells, increases the drug's anti-cancer effect and
reduces its toxicity. By improving the therapeutic
index of cancer drugs, we hope to turn cancer into
a chronic, manageable disease."
Results of the study will be published in the June
15, 2005, issue of Cancer Research.
The drug delivery vehicle used by U-M scientists
is a manmade polymer molecule called a dendrimer.
Less than five nanometers in diameter, these dendrimers
are small enough to slip through tiny openings in
cell membranes. One nanometer equals one-billionth
of a meter, which means it would take 100,000 nanometers
lined up side-by-side to equal the diameter of a
Dendrimers have a tree-like structure with many
branches where scientists can attach a variety of
molecules, including drugs. In experiments reported
in Cancer Research, U-M scientists attached methotrexate,
a powerful anticancer drug, to branches of the dendrimer.
On other branches, they attached fluorescent imaging
agents and their secret ingredient – a vitamin called
Folic acid, or folate, is an important vitamin required
for the healthy functioning of all cells. But cancer
cells, in particular, seem to need more than average
amounts. To soak up as much folate as possible, some
cancer cells display more docking sites called folate
receptors on their cell membranes. By taking advantage
of a cancer cell's appetite for folate, U-M scientists
are able to prevent the cells from developing resistance
to chemotherapeutic drugs.
"It's like a Trojan horse," Baker explains. "Folate
molecules on the nanoparticle bind to receptors on
tumor cell membranes and the cell immediately internalizes
it, because it thinks it's getting the vitamin it
needs. But while it's bringing folate across the
cell membrane, the cell also draws in the methotrexate
that will poison it."
In conventional chemotherapy, drugs like methotrexate
must diffuse across a cell membrane to get inside
cancer cells, according to Baker. It's a slow process
and requires a high concentration of drug in the
extra-cellular fluid, which can damage normal cells
When tested in laboratory mice that had received
injections of human epithelial cancer cells, the
nanoparticle-based therapy using folic acid and methotrexate
was 10 times more effective at delaying tumor growth
than the drug given alone. Nanoparticle treatment
also proved to be far less toxic to mice in the study
than the anticancer drug alone.
"In our longest trial, which lasted 99 days, 30
percent to 40 percent of the mice given the nanoparticle
with methotrexate survived," says Jolanta Kukowska-Latallo,
Ph.D., a U-M research investigator and first author
of the study. "All the mice receiving free methotrexate
died – either from overgrowth of the tumor or from
toxic effects of the drug.
"We saw statistically significant tumor growth reduction
in all the mice given targeted nanoparticle therapy,
as opposed to mice receiving either free methotrexate
or the dendrimer alone," adds Kukowska-Latallo. "Effectively,
we achieved a 30-day tumor growth delay. Taking into
account the length of a mouse's life, that is significant.
One month for a mouse is about three years for a
Before they began to study the effects of targeted
nanoparticle therapy on cancer, U-M scientists injected
dendrimers with fluorescent tags into the bloodstream
of laboratory mice to determine where they would
be retained in the body. The results showed that
the kidneys quickly filtered free nanoparticles from
blood and eliminated them in urine. The researchers
found no evidence that nanoparticles were able to
leave the bloodstream and enter the brain. The nanoparticles
did not appear to generate an immune response in
mice in the study.
In future research, scientists at the Michigan Nanotechnology
Institute will determine the maximum therapeutic
dose, in research animals, of targeted nanotherapy
with methotrexate, and complete other preliminary
studies in preparation for the first human clinical
trial, which Baker says is scheduled to begin within
Researchers at the Michigan Nanotechnology Institute
also are planning to explore the use of nanotechnology-based
therapies using other chemotherapeutic drugs. "There
are many cancer drugs that are very effective, but
they can't be used now, because they are too toxic," Baker
says. "If these drugs can be delivered with a targeted
nanoparticle system, we may be able to overcome the
toxicity problem and provide a broader range of therapeutic
agents for people with cancer."
By attaching different targeting molecules and different
drugs to the nanoparticle, Baker believes scientists
eventually will be able to develop effective therapies
for many types of cancer, perhaps even personalized
therapy for an individual's specific cancer.
The research was funded by the National Cancer Institute.
The University of Michigan has filed a patent application
on targeted nanoparticle technology. A licensing
agreement is currently being negotiated with Avidimer
Therapeutics, a biopharmaceutical company in Ann
Arbor, Mich. Baker holds a significant financial
interest in the company.
Other U-M collaborators in the research study are
Zhengyi Cao, M.D., and Shraddha S. Nigavekar, Ph.D.,
U-M research associates; Istvan J. Majoros, Ph.D.,
research investigator; and Thommey P. Thomas, Ph.D.,
assistant research professor. Additional collaborators
who were formerly with the U-M are Lajos P. Balogh,
Ph.D., Kimberly A. Candido, and Mohamed K. Khan,