Implant Bacteria, Beware: Researchers Create Nano-sized Assassins

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ScienceDaily (June 28, 2009) — Staphylococcus epidermidis is quite an opportunist. Commonly found on human skin, the bacteria pose little danger. But S. epidermidis is a leading cause of infections in hospitals. From catheters to prosthetics, the bacteria are known to hitch a ride on a range of medical devices implanted into patients.

Inside the body, the bacteria multiply on the implant's surface and then build a slimy, protective film to shield the colony from antibiotics. According to a study in the journal Clinical Infectious Diseases, up to 2.5 percent of hip and knee implants alone in the United States become infected, affecting thousands of patients, sometimes fatally.
More ominously, there is no effective antidote for infected implants. The only way to get rid of the bacteria is to remove the implant. "There is no [easy] solution," said Thomas Webster, a biomedical engineer at Brown University.
Now, Webster and Brown graduate student Erik Taylor have created a nano-sized headhunter that zeroes in on the implant, penetrates S. epidermidis's defensive wall and kills the bacteria. The finding, published in the International Journal of Nanomedicine, is the first time iron-oxide nanoparticles have been shown to eliminate a bacterial infection on an implanted prosthetic device.
In lab tests, Taylor, the lead author, and Webster, associate professor of engineering and orthopaedics, noted that up to 28 percent of the bacteria on an implant had been eliminated after 48 hours by injecting 10 micrograms of the nanoparticle agents. The same dosage repeated three times over six days destroyed essentially all the bacteria, the experiments showed.
The tests show "there will be a continual killing of the bacteria until the film is gone," said Webster, who is editor-in-chief of the peer-reviewed journal in which the paper appears.
A surprising added benefit, the scientists learned, is the nanoparticles' magnetic properties appear to promote natural bone cell growth on the implant's surface, although this observation needs to be tested further.
To carry out the study, the researchers created iron-oxide particles (they call them "superparamagnetic") with an average diameter of eight nanometers. They chose iron oxide because the metallic properties mean the particles can be guided by a magnetic field to the implant, while its journey can be tracked using a simple magnetic technique, such as magnetic resonance imaging (MRI). Moreover, previous experiments showed that iron seemed to cause S. epidermidis to die, although researchers are unsure why. (Webster said it may be due to iron overload in the bacteria's cell.)
Once the nanoparticles arrive at the implant, they begin to penetrate the bacterial shield. The researchers are studying why this happens, but they believe it's due to magnetic horsepower. In the tests, the researchers positioned a magnet below the implant, producing a strong enough field to force the nanoparticles above to filter through the film and proceed to the implant, Webster explained.
The particles then penetrate the bacterial cells because of their super-small size. A micron-sized particle, a thousand times larger than a nanoparticle, would be too large to penetrate the bacterial cell wall.
The researchers plan to test the iron-oxide nanoparticles on other bacteria and then move on to evaluating the results on implants in animals. The research was funded by the private Hermann Foundation Inc. In addition, Taylor's tuition and stipend are funded through the National Science Foundation GK-12 program.
Adapted from materials provided by Brown University.

Making Gene Therapy Safer: Delivering Genes Via Polymers

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http://www.sciencedaily.com/releases/2007/09/070907095614.htm

Science Daily — In work that could lead to safe and effective techniques for gene therapy, MIT researchers have found a way to fine-tune the ability of biodegradable polymers to deliver genes.

Gene therapy, which involves inserting new genes into patients' cells to fight diseases like cancer, holds great promise but has yet to realize its full potential, in part because of safety concerns over the conventional technique of using viruses to carry the genes.
The new MIT work, published this week in Advanced Materials, focuses on creating gene carriers from synthetic, non-viral materials. The team is led by Daniel Anderson, research associate in MIT's Center for Cancer Research.
"What we wanted to do is start with something that's very safe-a biocompatible, degradable polymer-and try to make it more effective, instead of starting with a virus and trying to make it safer," said Jordan Green, a graduate student in biological engineering and co-first author of the paper.
Gregory Zugates, a former graduate student in chemical engineering now at WMR Biomedical, Inc., is also a co-first author of the paper.
Gene therapy has been a field of intense research for nearly 20 years. More than 1,000 gene-therapy clinical trials have been conducted, but to date there are no FDA-approved gene therapies. Most trials use viruses as carriers, or vectors, to deliver genes.
However, there are risks associated with using viruses. As a result, many researchers have been working on developing non-viral methods to deliver therapeutic genes.
The MIT scientists focused on three poly(beta-amino esters), or chains of alternating amine and diacrylate groups, which had shown potential as gene carriers. They hoped to make the polymers even more efficient by modifying the very ends of the chains.
When mixed together, these polymers can spontaneously assemble with DNA to form nanoparticles. The polymer-DNA nanoparticle can act in some ways like an artificial virus and deliver functional DNA when injected into or near the targeted tissue.
The researchers developed methods to rapidly optimize and test new polymers for their ability to form DNA nanoparticles and deliver DNA. They then chemically modified the very ends of the degradable polymer chains, using a library of different small molecules.
"Just by changing a couple of atoms at the end of a long polymer, one can dramatically change its performance," said Anderson. "These minor alterations in polymer composition significantly increase the polymers' ability to deliver DNA, and these new materials are now the best non-viral DNA delivery systems we've tested."
The polymers have already been shown to be safe in mice, and the researchers hope to ultimately run clinical trials with their modified polymers, said Anderson.
Non-viral vectors could prove not only safer than viruses but also more effective in some cases. The polymers can carry a larger DNA payload than viruses, and they may avoid the immune system, which could allow multiple therapeutic applications if needed, said Green.
One promising line of research involves ovarian cancer, where the MIT researchers, in conjunction with Janet Sawicki at the Lankenau Institute for Medical Research, have demonstrated that these polymer-DNA nanoparticles can deliver DNA at high levels to ovarian tumors without harming healthy tissue.
Other MIT authors on the paper are Nathan Tedford, a former graduate student in biological engineering now at Epitome Biosystems; Linda Griffith, professor of biological engineering; Douglas Lauffenberger, head of biological engineering, and Institute Professor Robert Langer. Sawicki and Yu-Hung Huang of the Lankenau Institute are also co-authors.
The research was funded by the National Institutes of Health, the Department of Defense and the National Science Foundation.
Note: This story has been adapted from a news release issued by Massachusetts Institute of Technology.

Fausto Intilla

www.oloscience.com