Posted on March 28th, 2012 by
Therapeutic RNAs hold great promise for treating cancer and other diseases. But their potential has been limited by the lack of effective delivery mechanisms that both protect therapeutic molecules from the body’s natural defenses and target diseased cells. Now, a novel drug-carrying nanoparticle developed by scientists at Sandia National Laboratories and the University of New Mexico Cancer Center could change that.
In a study published in the March 27, 2012, issue of the scientific journal ACS Nano, UNM and Sandia researchers describe how they encapsulated small interfering RNAs (siRNAs) in cancer-targeting nanoparticles to selectively deliver them to liver cancer cells. The nanoparticles used in these experiments are the same innovative constructs that the UNM-Sandia team unveiled last spring in the journal Nature Materials.
siRNA plays an important role in RNA interference, a process within living cells that modulates gene activity. In particular, this class of RNA molecules has the ability to interfere with or “silence” specific genes. Because siRNAs can target genes of interest, many researchers are working to harness these molecules to fight cancer and other diseases in which gene expression is a key component. Developing siRNA-based therapies has proved challenging, however, because nucleic acids are vulnerable to enzymatic digestion in the body.
In the UNM-Sandia research, the nanoparticles sequestered their siRNA cargo until the particles encountered, and were internalized by, their targets. Once inside the liver cancer cells, the nanoparticles released their deadly load, a mix of siRNAs that target genes involved in cell growth and survival. Within 48 hours, these genes were effectively silenced, and the liver cancer cells were on the path of self-destruction.
“The great news is that our targeted nanoparticles address many of the deficiencies that currently limit the clinical use of siRNAs,” says C. Jeffrey Brinker, PhD, a Sandia Fellow, UNM Regents’ Professor of Chemical and Nuclear Engineering and member of the UNM Cancer Center. “We believe these novel nanoparticles could unlock the potential of therapeutic RNAs and other therapeutically promising agents for which there are, as yet, no reliable methods of delivery.”
Dubbed a “protocell,” the team’s nanoparticle has the same basic structure as a living cell, though it is much simpler and many times smaller. Its sponge-like core has vast storage capacity relative to its tiny size, and can efficiently soak up and carry a wide variety of substances.
Surrounding the core and keeping its contents intact is a lipid bilayer, similar in composition to a cell membrane. This membrane is an innocuous form of “packaging” that protects the protocell from attack by the body’s immune and filtration systems, allowing the particles to circulate long enough to encounter cancer cells. The bilayer surface can be modified with a variety of molecules, including ones that target specific cancers and others that promote the release of the protocell’s contents once the particle is inside the cancer cell.
In order to benchmark the efficacy of their targeted protocells, the researchers compared the particles’ performance with that of lipid-based nanoparticles, or “liposomes,” prepared using state-of-the-art techniques. The new nanoparticles were a dramatic improvement over existing cutting-edge technology.
“Our siRNA-loaded protocells killed liver cancer cells at lower doses than corresponding liposomes, with much less impact on normal liver cells,” explains Carlee Ashley, PhD, the paper’s lead author and a Truman Fellow in the Biotechnology and Bioengineering Department at Sandia Labs.
The protocells were not only able to encapsulate greater amounts of siRNA than liposomes; they proved to be more stable vessels, retaining 95% of siRNA in a simulated body fluid. And they were also more efficient at releasing their cargo once inside target cells.
While siRNA-loaded protocells were highly effective killers of cancer cells, they largely bypassed normal liver cells. That’s because the particles’ surfaces are modified with targeting molecules that specifically recognize, and bind to, receptor molecules that are over-expressed on the surface of cancerous liver cells. It is this ligand-receptor complementarity that allows protocells to precisely target a given type of cancer cell, ignoring normal cells (which do not share the cancer cells’ receptor characteristics).
The team says their latest results are further exciting proof of the versatility and efficiency of the protocell, a novel nanostructure pioneered in recent years by material scientists, biologists and cancer researchers at UNM and Sandia. In last spring’s Nature Materials publication, the researchers demonstrated that their targeted nanoparticle could be efficiently loaded with a chemotherapy cocktail and used to selectively kill liver cancer cells in the lab with one million times the effectiveness of existing nanocarriers, while sparing normal cells.
The new research demonstrates the successful delivery of another type of cancer therapy via the protocell. The challenges presented by “macromolecule” siRNAs are quite different—and more daunting—than those posed by small-molecule chemotherapy drugs. Yet the protocell’s structural and chemical characteristics make it a delivery vehicle of unmatched effectiveness for both types of therapeutic cargo.
The editors of ACS Nano highlighted the team’s results in an upfront write-up, as well as featuring the protocell on the cover of the March 27, 2012, issue. “Systemically delivering cancer therapeutics that hone in on their targets remains one of the holy grails of medicine,” they observe. The new nanoparticle is a “step toward this goal.”
“We believe we’re coming close to an ideal targeted delivery platform that could one day revolutionize the treatment of cancer and other diseases,” explains Dr. Brinker. “The success of our work with siRNA-loaded protocells, following on from our earlier spectacular results with encapsulated chemotherapeutic agents, strengthens the case for the protocell as a ‘universal nanocarrier’ that could make a wide range of promising therapeutic agents available for testing and, eventually, clinical use.”
The researchers have partnered with the leukemia-focused research group led by Cheryl Willman, MD, Director and CEO of the UNM Cancer Center, to develop targeted protocells to treat acute lymphoblastic leukemia (ALL), the most common childhood leukemia. Funded in part by a prestigious grant from the National Cancer Institute’s Nanotechnology Platform Partnership, the researchers hope to move ALL-targeting protocells into clinical trials within five years.
Carlee E. Ashley, Eric C. Carnes, Katharine E. Epler, David P. Padilla, Genevieve K. Phillips, Robert E. Castillo, Dan C. Wilkinson, Brian S. Wilkinson, Cameron A. Burgard, Robin M. Kalinich, Jason L. Townson, Bryce Chackerian, Cheryl L. Willman, David S. Peabody, Walker Wharton, and C. Jeffrey Brinker, “Delivery of Small Interfering RNA by Peptide-Targeted Mesoporous Silica Nanoparticle-Supported Lipid Bilayers,” ACS Nano 2012, 6 (3), pp. 2174–2188. Read the abstract online.
Tags: UNM CC Press Releases
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