Modifications Enhance Cancer-fighting Ability of Targeted siRNA

The possibility of treating cancers with targeted strands of RNA (small interfering RNA, or siRNA) that block the action of cancer-specific genes has been given a boost by the results of experiments to modify and enhance the activity of these compounds.

Investigators from the University of Iowa (Iowa City, USA) worked with a chimera, a synthetic molecule constructed from an aptamer (a small length of nucleic acid) specific for prostate-specific membrane antigen (PSMA), which is expressed by prostate cancer cells, and a siRNA directed against certain cancer genes. They reported in the August 23, 2009, online edition of the journal Nature Biotechnology that modifications made to the chimera, including adding 2-nucleotide 3'-overhangs and optimizing the thermodynamic profile and structure of the molecule as well as reducing the length of the aptamer, increased the effectiveness of the compound. Furthermore, the addition of a polyethylene glycol moiety extended the chimeras' circulating half-life.

The new compound could be injected into the bloodstream rather than directly into the tumor. When this was done to a group of athymic mice carrying PSMA-expressing tumors, the chimeras caused pronounced regression of the tumors.

"Our goal was to make siRNA deliverable through the bloodstream and make it more specific to the genes that are overexpressed in cancer,” explained senior author Dr. Paloma Giangrande, assistant professor of internal medicine at the University of Iowa.

"If you want to use siRNA effectively for clinical use, especially for cancer treatment, you need to deliver it through an injection into the bloodstream, reduce the amount of side effects, and be able to improve its cost-effectiveness. Our findings may help make these things possible.”

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