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Finding the Magic Bullet
CHORI Scientists Build on Drug Delivery Breakthroughs

"The magic bullet is a drug that is directed toa specific target and delivers an effective dose. It was first proposed at the beginning of the 20th century, but our work is a major step toward accomplishing this goal."

CHORI scientists Robert Ryan, PhD, and David Iovannisci, PhD, of the Center for the Prevention of Obesity, Cardiovascular Disease & Diabetes, have hit pay dirt with their latest discovery in the ongoing development of a novel, nanodisk drug delivery system, published in the December issue of Biochemical and Biophysical Research Communications.

Dr. Ryan and colleagues have already patented the nanodisks in question - nanoscale sized complexes of apolipoprotein and phospholipid that can transport drugs throughout the body.

"It's modeled after a natural phenomenon in the body - high density lipoprotein particles, or HDL, whose job it is to pick up cholesterol from body tissues and deliver it to the liver for excretion or recycling," explains Dr. Iovannisci.

To date, Drs. Ryan, Iovannisci and their colleagues have been able to successfully utilize this nanodisk technology with common drugs such as amphotericin B (AMB) and all trans retinoic acid (ATRA). (See our Nov 2008 story on this research.) What they hadn't yet achieved was a way to target the nanodisks to a specific cell or tissue in the body.

"We'd shown that we could load nanodisks with drugs and that the drugs could still be effective, at much lower doses. But we hadn't yet found a mechanism to direct nanodisks to go to one cell and not another," says Dr. Iovannisci. "Now we are much closer to achieving that mechanism."

Drs. Iovannisci and Ryan were able to utilize a single chain variable fragment of a monoclonal antibody and genetically link it to the protein component of their nanodisk complexes, creating an apoliprotein chimera capable of targeting specific cells.

"Antibodies are very large molecules that can be challenging to work with, but scientists have found that fragments of these antibodies can be cloned," explains Dr. Iovannisci.
"Rather than having a large molecule, scientists can utilize single chain variable fragments that contains only the portion of the antibody that is involved in recognizing a target."
While the particular single chain variable fragment Dr. Iovannisci used in this study had already been engineered, this is the first time that anyone has used an antibody fragment in combination with nanodisks to direct them to a specific target.

"This was a huge step," says Dr. Iovannisci. "it's basically a proof of principle. We showed that we can make the chimera, we can express it in bacteria, that the single chain antibody fragment still recognized its antigen, the chimeric lipoprotein still formed nanodisks and the nanodisks still recognized the single chain antibody target. This means we now can direct nanodisks to a specific target."

The potential application of this new technology is staggering, and represents the closest discovery yet to that magic bullet drug delivery system first envisioned at the turn of the 20th century.
"One of the big problems with many current drugs is their toxicity," explains Dr. Iovannisci. "Amphotericin B, for example, has a very narrow margin of safety. But if we could load our nanodisks with it, and use a single chain antibody fragment to specifically target a particular infection, we could hopefully bypass entirely the toxicity of the compound."

Similar toxicity issues exist with many cancer drugs, and the nanodisk drug delivery, combined with chimeras that can directly target cancer cells, could revolutionize current cancer treatment options. The next step in finally harnessing the magic bullet of nanodisk drug delivery, however, will be to demonstrate that combining nanodisks loaded with drugs with a specific single chain antibody fragment will result in payload deliver of a drug to its target.

"We need to show that we can still load nanodisks with the drug and deliver it to a target in amounts that would be therapeutically effective," says Dr. Iovannisci, who, along with Dr. Ryan, is already working toward making that goal a reality - and providing along the way the potential at last for realizing the dream of the magic bullet.

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Tuesday, May 17, 2011 8:19 AM

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