Molecular hitchhiker on human protein signals tumors to self-destruct

July 24, 2017, Vanderbilt University
This microscopy photo demonstrates penetration of a fluorescent-labeled siRNA-L2 vs. synthetic nanoparticles into a three-dimensional tumor sample. Credit: Vanderbilt University

Powerful molecules can hitch rides on a plentiful human protein and signal tumors to self-destruct, a team of Vanderbilt University engineers found.

Their research gives oncologists a better shot at overcoming the problems of drug resistance, toxicity to patients and a host of other barriers to consistently achieving successful gene therapy for cancer. It is particularly promising for patients with , an aggressive type that makes up about 15-20 percent of cases.

Craig Duvall, associate professor of biomedical engineering, put the effectiveness of a specialized ribonucleic acid hitchhiking on the human protein up against jetPEI nanoparticles, the mostly widely used synthetic carrier for the task of tumor gene silencing.

His findings, reached with Samantha Sarett, a recent Ph.D. graduate, are published today in the Proceedings of the National Academy of Sciences.

Ribonucleic acids can control the behavior of cancer cells, but they require a carrier to get them to the target. Duvall's team made a simple modification to a small-interfering ribonucleic acid molecule, called siRNA-L2, allowing it to rapidly load into an albumin pocket typically reserved to ferry fatty acids around the body.

They found that the siRNA-L2, using albumin as its carrier, has no apparent dose-limiting toxicity, a significant problem for synthetic nanoparticles. That means a higher dose of the anti-cancer drug can be delivered to the tumor without potentially harming the patient.

"We used albumin because it's the highest-concentrated protein in your blood," Duvall said. "Our molecule, siRNA-L2, binds into the fatty pocket of albumin. If we put siRNA directly into the body without a carrier, it's cleared out by the kidneys in two minutes. If we load siRNA into synthetic nanoparticles to avoid that, then they're filtered out by the liver. Albumin circulates in the body for days, making the siRNA-L2 more available for delivery into tumors."

Because cancer cells show higher metabolic activity, the albumin that's carrying siRNA-L2 travels to tumors and gets to work quickly. The molecule's smaller size allows it to penetrate tumors at a higher rate - with 100 percent of tumor cells testing positive for siRNA-L2 as opposed to only 60 percent when the molecule was carried by jetPEI. Once there, Duvall's molecule silences a gene crucial to the tumor's growth and survival.

He said he used the synthetic carrier as a comparison because polymer-based jetPEI represents the gold standard available.

To make sure their results were translatable to human therapy, the team - in collaboration with Vanderbilt University Medical Center biologist Dana Brantley-Sieders—tested siRNA-L2 in human breast tumor tissue removed from the donor. The Vanderbilt molecule remained more effective, with siRNA-L2 more than three times as present in the tumor than siRNA delivered with synthetic nanoparticles.

Brantley-Sieders said their research has the potential of overcoming the biggest barriers to clinical application of gene-silencing .

"What fascinates and excites me most about this approach, in addition to improved tumor penetration, is lack of toxicity at a relatively high dose," she said. "We could potentially use our siRNA delivery system to target several genes simultaneously or sequentially. Most cancers are driven by multiple abnormal genes, so targeting one often leads to activation of others as the adapts."

Explore further: Precise and persistent cell sabotage: Control of siRNA could aid regenerative medicine, cancer therapy

More information: Samantha M. Sarett el al., "Lipophilic siRNA targets albumin in situ and promotes bioavailability, tumor penetration, and carrier-free gene silencing," PNAS (2017). www.pnas.org/cgi/doi/10.1073/pnas.1621240114

Related Stories

Precise and persistent cell sabotage: Control of siRNA could aid regenerative medicine, cancer therapy

August 27, 2012
Some of the body's own genetic material, known as small interfering RNA (siRNA), can be packaged then unleashed as a precise and persistent technology to guide cell behavior, researchers at Case Western Reserve University ...

Iron key to brain tumor drug delivery

June 2, 2011
Brain cancer therapy may be more effective if the expression of an iron-storing protein is decreased to enhance the action of therapeutic drugs on brain cancer cells, according to Penn State College of Medicine researchers.

Recommended for you

Gut bacteria play key role in anti-seizure effects of ketogenic diet

May 24, 2018
UCLA scientists have identified specific gut bacteria that play an essential role in the anti-seizure effects of the high-fat, low-carbohydrate ketogenic diet. The study, published today in the journal Cell, is the first ...

New blood test to detect liver damage in under an hour

May 24, 2018
A quick and robust blood test that can detect liver damage before symptoms appear has been designed and verified using clinical samples by a team from UCL and University of Massachusetts.

Selective neural connections can be reestablished in retina after injury, study finds

May 24, 2018
The brain's ability to form new neural connections, called neuroplasticity, is crucial to recovery from some types of brain injury, but this process is hard to study and remains poorly understood. A new study of neural circuit ...

Space-like gravity weakens biochemical signals in muscle formation

May 23, 2018
Astronauts go through many physiological changes during their time in spaceflight, including lower muscle mass and slower muscle development. Similar symptoms can occur in the muscles of people on Earth's surface, too. In ...

Eating at night, sleeping by day swiftly alters key blood proteins

May 21, 2018
Staying awake all night and sleeping all day for just a few days can disrupt levels and time of day patterns of more than 100 proteins in the blood, including those that influence blood sugar, energy metabolism, and immune ...

Hotter bodies fight infections and tumours better—researchers show how

May 21, 2018
The hotter our body temperature, the more our bodies speed up a key defence system that fights against tumours, wounds or infections, new research by a multidisciplinary team of mathematicians and biologists from the Universities ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.