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Nanopharmaceuticals Open Up Brand New Field Of Study

Drug-binding molecules tiny enough to travel through the body's smallest capillaries may provide a way to spare the heart and other organs from the toxic effects of drug overdose.

These are among preliminary laboratory findings by University of Florida scientists.

UF medical, engineering and chemical researchers see "enormous potential" in the medical applications of nanotechnology -- specifically in the use of drug-uptake particles 10,000 times smaller than the diameter of a human hair or 700 times smaller than the diameter of a human red blood cell. Nano refers to nanometer, which equals one-billionth of a meter.

"We have shown that some of the nanopharmaceuticals developed by our team will markedly reduce the effects of toxic drugs in beating hearts removed from rats by lowering the free concentration of the drugs," said Donn Dennis, M.D., the Joachim S. Gravenstein professor of anesthesiology and medical director of the research project.

Dennis said the latest experiments involved rodent hearts that were perfused with an oxygenated salt solution containing essential blood elements to keep them beating while selected drugs (widely used by people and known to be toxic to the heart) were infused.

The drugs, for which no antidotes are available, were delivered to the point that researchers could measure damaging effects on the heart's electrical activity. Within five minutes after the nano-sized drug-uptake molecules were administered, the adverse effects were significantly reduced.

"We believe this type of work is only the tip of the nanotechnology iceberg in terms of how nano can be used to modulate drug transport, both for drug uptake and delivery applications," Dennis said. "We are focusing on drug overdose, for which quicker lifesaving and organ-sparing treatments are desperately needed, and we're initially concentrating on reversing cardiac toxicity, which is probably the most common reason why drug overdose kills people."

In the United States, more than 300,000 people per year are admitted to emergency rooms for drug-related complications. Potential applications also include aiding the recovery of people exposed to excess amounts of pesticides, industrial pollutants or chemical weapons.

"This technology (UF's development of nanopharmaceuticals) is very promising in the effort to save lives of people exposed to severe drug poisonings," said Denise Wedel, M.D., a professor of anesthesiology at the Mayo Foundation and past president of the American Society of Regional Anesthesia and Pain Medicine. "In anesthesiology, the inadvertent injection of potentially toxic doses of local anesthetics into the bloodstream during routine nerve block placement is a dreaded complication that can have catastrophic effects on the patient. In the worst case, death can occur due to impaired electrical function of the heart. Unfortunately, we currently have no good treatment options for these individuals other than to provide supportive therapy."

The Florida team's effort to design, evaluate and mass-produce various detoxifying agents is supported by a five-year, $4.1 million grant awarded by the National Science Foundation to UF's Engineering Research Center for Particle Science and Technology.

Brij Moudgil, Eng.Sc.D., director of the center, says the project represents UF's first major foray into the biomedical applications of nanotechnology. It also involves collaborators at Columbia University, Clarkson University and the University of South Florida.

Dennis, along with engineering Professor Dinesh Shah, Ph.D., (co-director of the project) and colleagues, have designed and filed patent applications on several "nano-bullets" that bind to harmful drugs circulating in the blood and reduce their free concentration in the bloodstream. They recently have discussed preliminary findings at several scientific conferences.

Shah, who is the first Charles A. Stokes professor of chemical engineering and anesthesiology at UF, says nanoparticles represent "a whole new scale of materials that previously could be made only by nature -- not by man. With modern tools, including the electron microscope, we can now see, characterize and produce materials this tiny. We can manufacture particles as small as five to 10 nanometers, which can be delivered via the blood to any part of the body."

Despite the initial success, Dennis cautioned this technology is in its infancy, and a number of hurdles remain prior to bringing these therapies into the clinical arena.

"The ideal nanopharmaceutical agent for detoxification must be safe, biocompatible, biodegradable and stealthy-disguised well enough that the body's immune system will not recognize it as foreign," he said. "The ultimate agent will recognize the toxic drug molecules, attract and bind them quickly, reduce the free drug concentration and, in the process, trigger the heart to function normally. Reaching our goal requires that we achieve a very delicate balance between successful detoxification and preventing toxicity with the nanopharmaceuticals.

"We do not know yet how drug uptake nanoparticles affect organs, tissues and cells, or how they will act at the genetic level," Dennis said. "In any case, we are developing this new concept cautiously -- by assembling nanoparticles with many components already designated by the U.S. Food and Drug Administration as safe, and by choosing to apply the various nanoparticle drug-removal agents to life-threatening drug overdose situations for which few, if any, therapies are currently available."

The UF-designed nanopharmaceuticals now being studied in rodents include soft absorbent nanoparticles packed with enzymes that act like "smart sponges" to identify and cling to drug molecules, then break them down and render them inactive, as well as sponge-like nanoparticles with rigid shells and oily interiors that absorb drug particles.

Nanotechnology is becoming a major research priority of the federal government. Last year, the United States, through its National Nanoinitiative Program, invested close to $1 billion in this field.

Nanotechnological applications in medicine are now the major focus area of a new bioengineering institute within the National Institutes of Health. - By Arline Phillips-Han






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