Nanoparticles Home in on Brain Cancer in rats

http://www.sciam.com/article.cfm?chanID=sa002&articleID=F81F74A8-E7F2-99DF-325025A7F2F3416A

November 17, 2006
Nanoparticles Home in on Brain Cancer

Call them laser-guided smart bombs for brain tumors. Researchers at the
University of Michigan announced the testing of a drug delivery system
that involves drug-toting nanoparticles and a guiding peptide to target
cancerous cells in the brain. Their study finds that via this method more
of the drug can be delivered to a tumor's general vicinity. They report
their findings in the November 15 issue of Clinical Cancer Research.

The researchers used a pharmaceutical called Photofrin, which is
photodynamic, meaning it is activated by a laser after it has entered the
bloodstream. As its primary side effect, the drug renders patients
photosensitive, and they must remain out of bright sunlight and even
unshaded lamps for up to 30 days after receiving treatment. Despite this
major drawback, Photofrin is used in the treatment of esophageal, bladder
and skin cancers. But their novel delivery system, which relies on the
intravenous delivery of 40-nanometer-wide particles to carry the drug, may
actually avoid much of the photosensitivity, because less Photofrin
circulates in the bloodstream thanks to a peptide called F3. A sequence of
31 amino acids broken off of the protein HMGN2 (high mobility group
protein 2), F3 has the ability to penetrate cell membranes. "This peptide
acts as a "zip code" in that it enables the binding of the nanoparticles
only to blood vessels within the tumor and not normal blood vessels," says
Alnawaz Rehemtulla, a radiologist and environmental health scientist who
co-authored the study. F3 can detect the expression of a protein called
nucleolin, which is a marker on the surface of tumor cells.


Another problem the researchers avoided was having to deliver their
medicine in such a way that it could cross the blood-brain barrier, which
keeps many substances from entering the brain from the bloodstream.
Typical chemotherapies must penetrate this shield to treat tumors. In this
case, however, the nontoxic polyacrylamide particles didn't have to cross
over via the bloodstream. "The nanoparticles do not need to cross the
blood-brain barrier as they were specifically designed to target the blood
vessel cells within the tumor," explains radiologist Brian Ross, one of
the study's authors. "The treatment should be thought of as an
antivascular treatment thereby shutting off the tumor blood flow resulting
in the death of the tumor cells through starvation of oxygen and energy
sources."

To test the delivery method, researchers divided 34 rats--all who received
injections of cancerous cells into their brains--into different groups.
Those that received no treatment or got only the laser fared poorly, dying
on average within 8.5 days. Those that got Photofrin either intravenously
or encapsulated in nanoparticles had a median survival time of 13 days.
The group that got F3 with the Photofrin-carrying nanoparticles came
through the best: they lived for, on average, 33 days; three of the five
in this grouping lived for 60 days, and two of those three appeared
tumor-free after six months. By using iron oxide as a contrast agent--to
more easily detect where the nanoparticles ended up via MRI--the group
determined that twice as much drug with the F3 peptide attached reached
the tumor site--10 percent of the total amount administered--compared with
when nontargeted nanoparticles were injected.

Ross says that based on the success of the study, the team is
investigating if this delivery technology will work for nonphotodynamic
therapies. Rehemtulla adds that if other FDA-approved chemotherapeutic
agents reach their targets as successfully as Photofrin did, "then we will
have developed a way to make cancer drugs more 'tumor-specific,' because
they will only get into tumor vasculature and not normal vasculature. This
will spare patients from normal tissue toxicity that is commonly
associated with almost all chemotherapy." --Nikhil Swaminathan


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