RNA Interference Delivered Using Nanoparticles
Hits Target
in Human Patients
April 21, 2010
http://www.physorg.com/news191047320.html
(PhysOrg.com) -- A
multi-institutional team of researchers and clinicians has published the first
proof that a targeted nanoparticle can traffic into tumors, deliver
double-stranded small interfering RNAs (siRNAs), and turn off the production of
an important cancer protein using a mechanism known as RNA interference (RNAi).
Moreover, the team provided the first demonstration that this new type of
therapy, infused into the bloodstream, can make its way to human tumors in a
dose-dependent fashion, that is, a higher number of nanoparticles sent into the
body leads to a higher number of nanoparticles in the tumor cells. These two
findings were achieved in phase I clinical trials in which the investigators are
testing a nanoparticle-siRNA construct as an anticancer therapy.
These results, which were published in the journal Nature,
demonstrate the feasibility of using both nanoparticles and RNAi-based
therapeutics in patients, and open the door for future "game-changing"
therapeutics that attack cancer and other diseases at the genetic
level, says team leader Mark E. Davis of the California Institute of
Technology. Dr. Davis is also a member of the Nanosystems Biology Cancer Center,
a National Cancer Institute Center for Cancer Nanotechnology Excellence.
The discovery of RNAi, the mechanism by which double strands
of RNA silence genes, won researchers Andrew Fire and Craig Mello the 2006 Nobel
Prize in Physiology or Medicine. The scientists first reported finding this
novel mechanism in worms in a 1998 Nature paper. Since then, the potential for
this type of gene inhibition to lead to new therapies for diseases such as
cancer has been highly touted.
"RNAi is a new way to stop the production of
proteins," says Dr. Davis. What makes it such a potentially powerful tool,
he adds, is the fact that its target is not a protein, the typical target for anticancer
drugs. The vulnerable areas of a protein may be hidden within its
three-dimensional folds, making it difficult for many therapeutics to reach
them. In contrast, RNA
interference targets the messenger RNA (mRNA) that encodes the information
needed to make a protein in the first place.
"In principle," says Dr. Davis, "that means
every protein now is druggable because its inhibition is accomplished by
destroying the mRNA. And we can go after mRNAs in a very designed way given all
the genomic data that are and will become available."
Still, there have been numerous potential roadblocks to the
application of RNAi technology as therapy in humans. One of the most problematic
has been finding a way to ferry the therapeutics, which are made up of fragile
siRNAs, into tumor
cells after direct injection into the bloodstream. Dr. Davis, however, had a
solution. Even before the discovery of RNAi, he and his team had begun working
on ways to deliver nucleic acids to cells via the blood stream. They eventually
created a four-component system, featuring a unique polymer called cyclodextrin,
that self-assembles in the presence of RNA into a targeted, siRNA-containing
nanoparticle. The siRNA delivery system is under clinical development by Calando
Pharmaceuticals, Inc., based in Pasadena, California.
"These nanoparticles are able to take the siRNAs to
the targeted site within the body," says Dr. Davis. Once they reach their
target, in this case, the cancer cells within tumors, the nanoparticles enter
the cells and release the siRNAs.
As part of their study, the team was able to detect and
image nanoparticles inside cells biopsied from the tumors of several of the
phase I trial's participants. In addition, Dr. Davis and his colleagues were
able to show that the higher the nanoparticle dose administered to the
patient, the higher the number of particles found inside the tumor cells—the
first example of this kind of dose-dependent response using targeted
nanoparticles. Even better, Dr. Davis says, the evidence showed the siRNAs had
done their job. In the tumor cells analyzed by the researchers, the mRNA
encoding the cell-growth protein ribonucleotide reductase - the target of the
siRNA encapsulated in the nanoparticle - had been degraded. This degradation,
in turn, led to a loss of the protein.
More to the point, the mRNA fragments found were exactly
the length and sequence they should be if they'd been cleaved in the spot
targeted by the siRNA, notes Dr. Davis. "It's the first time anyone has
found an RNA
fragment from a patient's cells showing the mRNA was cut at exactly the right
base via the RNAi mechanism," he says. "It proves that the RNAi
mechanism can happen using siRNA in a human."
This work, which is detailed in a paper titled,
"Evidence of RNAi in humans from systemically administered siRNA via
targeted nanoparticles,"
was supported in part by the NCI Alliance for Nanotechnology in Cancer, a
comprehensive initiative designed to accelerate the application of
nanotechnology to the prevention, diagnosis, and treatment of cancer.
Investigators from the Jonsson Compresensive Cancer Center, the University of
California, Los Angeles, South Texas Accelerated Research Therapeutics
(START), the City of Hope Comprehensive Cancer
Center, and Calando Pharmaceuticals also participated in this study.
An abstract of this paper is available at the
journal's Web site.
Provided by National Cancer Institute (news
: web)
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