Nanoparticles Carry siRNA into Tumors

Of the hundreds of genes that may be overexpressed in a tumor, only a handful may be good therapeutic targets. One of the best ways to verify that a gene is a good target is to silence it in vivo, and watch for an effect on the tumor. However, genetic engineering of mice for this purpose is laborious, and screening a single gene can take from 9 months to 2 years.

William Hahn, MD, PhD, associate professor of medicine at Harvard Medical School and deputy chief scientific officer at Dana-Farber Cancer Institute in Boston, and his colleagues have uncovered many potential therapeutic targets in ovarian cancer, including a gene that codes for the transcriptional regulator ID4. This gene is amplified in 32% of high-grade ovarian cancers, and the researchers found that it could convert normal fallopian cells into cancer cells in vitro.

To establish the function of the gene in vivo, Hahn wanted to do an RNA interference test, but he wanted to speed the process. So he turned to Sangeeta Bhatia, MD, PhD, professor of health sciences and technology at Massachusetts Institute of Technology and a member of the Koch Institute for Integrative Cancer Research, who was working on nanocomplexes for RNA delivery.

Bhatia developed tumor-penetrating nanocomplexes made up of ID4-silencing RNA decorated with 2 types of peptide. One peptide domain binds to p32 protein found on the cancer-cell surface. The other domain combines several sequence components that aid the nanocomplexes in crossing the cell membrane, including one taken from HIV and another from herpes simplex virus.

The investigators injected the nanocomplexes into mice carrying ovarian tumors. The mice had no adverse immune reactions and the injections led to 90% decreases in ID4 expression, and 82% tumor growth suppression (Sci Transl Med 2012;4:147ra112). “These experiments take 2 to 3 months start to finish,” says Hann. “You're speeding up the pace by about 5-fold.”

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