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Fatty Spheres Loaded With siRNA Shrink
Ovarian Cancer Tumors in Preclinical Trial
A molecular "off" switch packaged
in a tiny sphere penetrates deeply into ovarian cancer
tumor cells, stifling a troublesome protein and drastically
reducing the size of tumors, researchers at The University
of Texas M. D. Anderson Cancer Center report in the
Aug. 15 edition of Clinical Cancer Research.
The mouse model experiment, featured on the cover of
the journal, demonstrates a potent delivery system for
short interfering RNA (siRNA) to attack cancer, says
senior author Anil Sood, M.D., associate professor in
the Departments of Gynecologic Oncology and Cancer Biology
at M. D. Anderson.
"Short interfering RNA is a great technology we
can use to silence genes, shutting down production of
harmful proteins," Sood says. "It works well
in the lab, but the question has been how to get it
into tumors." Short pieces of RNA don't make it
to a tumor without being injected directly, and injection
methods used in the lab are not practical for clinical
use.
The research team took siRNA that targets a protein
that helps ovarian cancer cells survive and spread and
rolled it into a liposome -- a lipid ball so small that
its dimensions are measured in nanometers (billionths
of a meter).
Getting the siRNA inside tumor cells is important, Sood
said, because the targeted protein, focal adhesion kinase
(FAK), is inside the cell, rather than on the cell surface
where most proteins targeted by cancer drugs are found.
"Targets like FAK, which are difficult to target
with a drug, can be attacked with this liposomal siRNA
approach, which penetrates deeply into the tumor,"
Sood said.
Mice infected with three human ovarian cancer cell lines
derived from women with advanced cancer were treated
for 3-5 weeks. They received liposomes that contained
either the FAK siRNA, a control siRNA, or were empty.
Some mice received siRNA liposomes plus the chemotherapy
docetaxel.
Mice receiving the FAK-silencing liposome had reductions
in mean tumor weight ranging from 44 to 72 percent compared
with mice in the control groups. Combining the FAK-silencing
liposome with docetaxel boosted tumor weight reduction
to the 94-98 percent range.
These results also held up in experiments with ovarian
cancer cell lines resistant to docetaxel and to the
chemotherapy drug cisplatin.
The FAK-silencing liposome and the liposome with chemotherapy
also reduced the incidence of cancer by between 20 and
50 percent in all tested cancer lines.
In addition to its anti-tumor effect, the researchers
found that the therapeutic liposome attacked the tumor's
blood supply, especially when combined with chemotherapy.
By inducing cell suicide (apoptosis) among blood vessel
cells, the treatment steeply reduced the number of small
blood vessels feeding the tumor, cut the percentage
of proliferating tumor cells and increased cell suicide
among cancer cells.
Sood and Professor of Molecular Therapeutics Gabriel
Lopez-Berestein, M.D., an expert in liposomal therapeutics,
cite at least two factors for the success of the anti-FAK
liposome.
"This particle is so small, it has no problem getting
through the tumor's vasculature and into the tumor,"
Lopez-Berestein says. The FAK-targeting liposome ranges
between 65 and 125 nanometers in diameter. Blood vessels
that serve tumors are more porous than normal blood
vessels, with pores of 100 to 780 nanometers wide. Normal
blood vessel pores are 2 nanometers or less in diameter.
Second, the liposome -- a commercially available version
known as DOPC -- has no electrical charge. Its neutrality
provides an advantage over positively or negatively
charged liposomes when it comes to binding with and
penetrating cells.
The next step for the FAK siRNA-DOPC liposome is toxicity
testing. "So far it appears to be very well-tolerated,"
Sood says. "We hope to develop this approach for
clinical use in the future."
In addition to ovarian cancer, FAK is overexpressed
in colon, breast, thyroid, and head and neck cancers.
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