(Press-News.org) CAMBRIDGE, Mass. — Nanoparticles that deliver short strands of RNA offer a way to treat cancer and other diseases by shutting off malfunctioning genes. Although this approach has shown some promise, scientists are still not sure exactly what happens to the nanoparticles once they get inside their target cells.
A new study from MIT sheds light on the nanoparticles' fate and suggests new ways to maximize delivery of the RNA strands they are carrying, known as short interfering RNA (siRNA).
"We've been able to develop nanoparticles that can deliver payloads into cells, but we didn't really understand how they do it," says Daniel Anderson, the Samuel Goldblith Associate Professor of Chemical Engineering at MIT. "Once you know how it works, there's potential that you can tinker with the system and make it work better."
Anderson, a member of MIT's Koch Institute for Integrative Cancer Research and MIT's Institute for Medical Engineering and Science, is the leader of a research team that set out to examine how the nanoparticles and their drug payloads are processed at a cellular and subcellular level. Their findings appear in the June 23 issue of Nature Biotechnology. Robert Langer, the David H. Koch Institute Professor at MIT, is also an author of the paper.
One RNA-delivery approach that has shown particular promise is packaging the strands with a lipidlike material; similar particles are now in clinical development for liver cancer and other diseases.
Through a process called RNA interference, siRNA targets messenger RNA (mRNA), which carries genetic instructions from a cell's DNA to the rest of the cell. When siRNA binds to mRNA, the message carried by that mRNA is destroyed. Exploiting that process could allow scientists to turn off genes that allow cancer cells to grow unchecked.
Scientists already knew that siRNA-carrying nanoparticles enter cells through a process, called endocytosis, by which cells engulf large molecules. The MIT team found that once the nanoparticles enter cells they become trapped in bubbles known as endocytic vesicles. This prevents most of the siRNA from reaching its target mRNA, which is located in the cell's cytosol (the main body of the cell).
This happens even with the most effective siRNA delivery materials, suggesting that there is a lot of room to improve the delivery rate, Anderson says.
"We believe that these particles can be made more efficient. They're already very efficient, to the point where micrograms of drug per kilogram of animal can work, but these types of studies give us clues as to how to improve performance," Anderson says.
Molecular traffic jam
The researchers found that once cells absorb the lipid-RNA nanoparticles, they are broken down within about an hour and excreted from the cells.
They also identified a protein called Niemann Pick type C1 (NPC1) as one of the major factors in the nanoparticle-recycling process. Without this protein, the particles could not be excreted from the cells, giving the siRNA more time to reach its targets. "In the absence of the NPC1, there's a traffic jam, and siRNA gets more time to escape from that traffic jam because there is a backlog," says Gaurav Sahay, an MIT postdoc and lead author of the Nature Biotechnology paper.
In studies of cells grown in the lab without NPC1, the researchers found that the level of gene silencing achieved with RNA interference was 10 to 15 times greater than that in normal cells.
Lack of NPC1 also causes a rare lysosomal storage disorder that is usually fatal in childhood. The findings suggest that patients with this disorder might benefit greatly from potential RNA interference therapy delivered by this type of nanoparticle, the researchers say. They are now planning to study the effects of knocking out the NPC1 gene on siRNA delivery in animals, with an eye toward testing possible siRNA treatments for the disorder.
The researchers are also looking for other factors involved in nanoparticle recycling that could make good targets for possibly slowing down or blocking the recycling process, which they believe could help make RNA interference drugs much more potent. Possible ways to do that could include giving a drug that interferes with nanoparticle recycling, or creating nanoparticle materials that can more effectively evade the recycling process.
INFORMATION:
The research was funded by Alnylam Pharmaceuticals and the National Heart, Lung, and Blood Institute.
Written by: Anne Trafton, MIT News Office
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SAN ANTONIO (June 24, 2013) — Patients with type 2 diabetes fare significantly better if they are started on three medications at the time of diagnosis than if they are prescribed a single drug and have other therapies added later, a San Antonio researcher said June 22 at the 73rd Scientific Sessions of the American Diabetes Association in Chicago. The findings, from a study funded by the association, could revise the way physicians manage the endocrine disease.
Comparison
UT Medicine San Antonio physician Ralph DeFronzo, M.D., chief of the Diabetes Division in the ...
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The study by Darren E. Koenig, OD, PhD, and colleagues of University of Houston College of Optometry defines ...
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Evolution, it seems, sometimes jumps instead of crawls.
A research team led by a University of Chicago scientist has discovered two key mutations that sparked a hormonal revolution 500 million years ago.
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Researchers found that those who were open-minded didn't change their view if they heard arguments for only one side of the issue.
People who are relatively more closed-minded did not change their mind regardless of the messages they received, or what their original views were. There was also no evidence of open-minded people becoming less supportive of government intervention, ...
Bacterial DNA may integrate into the human genome more readily in tumors than in normal human tissue, scientists have found.
The researchers, affiliated with the University of Maryland School of Medicine's Institute for Genome Sciences, analyzed genomic sequencing data available from the Human Genome Project, the 1,000 Genomes Project and The Cancer Genome Atlas.
They considered the phenomenon of lateral gene transfer (LGT), the transmission of genetic material between organisms in a manner other than than traditional reproduction.
Scientists have already shown ...
ROCHESTER, Minn. -- Rural women with breast cancer are less likely than their urban counterparts to receive recommended radiation therapy after having a lumpectomy, a breast-sparing surgery that removes only tumors and surrounding tissue, a study by Mayo Clinic and others found. The difference is one of several rural disparities in breast cancer diagnosis and treatment the researchers discovered. The findings are being presented at the AcademyHealth Annual Research Meeting in Baltimore.
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Several studies have shown that how much parents say to their children when they are very young is a good predictor of children's vocabulary at the point when they begin school. In turn, a child's vocabulary size at school entry strongly predicts level of success throughout schooling even into high school and college.
A new study by psychologists at the University of Pennsylvania now shows that early vocabulary improvement is likely to have more to do with the "quality" of the interactions in which the words are used rather than the sheer quantity of speech directed ...
Just what size is a "small" drink—8 ounces, 12 ounces, 16 ounces? The truth is, those are all "small" sizes depending on what restaurants and fast food joints you go to. As customers, we are used to ordering food based on relative size, but according to a new study from Cornell University, these seemingly standard labels impact our entire eating experience.
Dr. David R. Just and Dr. Brian Wansink of the Cornell Food & Brand Lab designed a study to understand how portion labels impact what you're willing to pay for your food as well as how much you actually eat. The researchers ...
