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RNAi delivery system crosses blood-brain barrier to target brain cancer

Researchers have combined novel molecular targeting technologies to deliver gene-silencing therapy specifically to tumor cells shielded by a normally impermeable obstacle, the blood brain barrier.

In the June 1 issue of the journal Clinical Cancer Research, William Pardridge, M.D., UCLA, reported that a delivery packet equipped with two specific antibodies first recognizes the transferrin receptor, a key protein portal in the blood brain barrier, and then gains entry into brain cancer cells with the second antibody targeting the human insulin receptor.

Using the antibody keys to traverse both the blood brain barrier and the tumor cell membrane, the delivery packets--called liposomes--deposit a genetically engineered non-viral plasmid in the brain cancer cells. The plasmid encodes a short hairpin RNA (shRNA) designed to interfere with the expression of the epidermal growth factor receptor, EGFR, a potent proponent of tumor cell proliferation. The use of shRNA to silence gene expression is RNA interference (RNAi) technology.

When treated with a weekly intravenous dose of Dr. Pardridge's targeted therapeutic, mice with brain tumors survive almost twice as long compared to mice that do not receive the treatment.

"This is the first drug delivery system that demonstrates that by using RNA interference technology, you can prolong life threatened by cancer," said Dr. Pardridge, Professor of Medicine at UCLA. "By solving the delivery problem, powerful molecular tools and therapies such as RNA interference can be moved to clinical trials where they can be tested to see how much benefit the patient gets."

The delivery system designed by the Pardridge research team is much like a minute parcel with a primary delivery address, a forwarding delivery address, and a message that halts proliferation of the tumor cells.

Liposomes are the parcel. Composed of lipid, or fat, molecules that align to form an enclosed membrane much like a
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Contact: Russell Vanderboom
vanderboom@aacr.org
215-440-9300
American Association for Cancer Research
1-Jun-2004


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