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Blazing New Trails
CHORI Scientists Develop Synthetic Nano-LDL as Drug Delivery Vehicle for Brain Tumors

"Our studies are the first to ask whether one can make artificial LDL nano-particles and direct them to cancer cells for targeted drug delivery."

Traditional treatment of the brain tumor gioblastoma multiforme, or GBM, has met with limited success, resulting in no better than a 1-year survival rate from the time of diagnosis. CHORI scientist Trudy Forte, PhD, and her colleagues may well have discovered a new trail to alternative treatment options with far greater potency by demonstrating for the first time that synthetic low density lipoprotein (LDL) particles can be used to directly target GBM.

Recent studies had identified LDL as a potential drug delivery system, because GBM cell lines have demonstrated upregulated LDL receptors while normal brain tissue cells present with relatively few LDL receptors. True LDL derived from plasma, however, is very difficult to work with. This particle has a very large protein called, apolipoprotein B100, that recognizes the LDL receptor.

"There are approximately 4,500 amino acids in apolipoprotein B100 on natural LDL - you could never synthesize it in a test tube," explains Dr. Forte. "The nano-LDL, or nLDL, we've created uses a very very small protein, only 29 amino acids long, that recognizes the LDL receptor."

As a result, nLDL is easy to produce, but even more critically important, it behaves exactly as Dr. Forte and her colleagues hoped it would, targeting directly to the LDL receptors in the GBM cells. Dr. Forte could then load the nLDL with a potent cancer-killing drug, paclitaxel oleate (PO), to see if the nLDL would deliver its payload.

"When you target a specific protein on the cell surface, such as an LDL receptor, what you really want is for it to be taken into the cell. We show here that this drug delivery method should work - the nLDL incorporated the drug, recognized the LDL receptors, was internalized into the cell along with the PO, and then killed the cancer cells," Dr. Forte explains.
"It's also really cheap and highly reproducible to manufacture - everything you want if you're making a drug delivery system."
The next step is to translate the results into animal studies.

"All of this had been done on human GBM cell lines to show that what we had proposed should work if we went into animal models."

Once the safety and efficacy has been established in animal studies, clinical studies would follow, hopefully providing new hope for cancer patients and opening a whole new frontier in the treatment of GBM as well as other cancers.
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Monday, May 16, 2011 11:33 PM

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