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New Delivery Tech Targets siRNA to Breast Cancer Cells to Suppress HER2-Positive Tumor Growth

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An international team of researchers this month reported on the development of a targeted delivery system capable of shuttling siRNAs into breast cancer cells, resulting in suppression of HER2-positive tumor growth and metastasis with no evident toxicity.

According to Harvard Medical School's Judy Lieberman, who is one of the paper's authors and a co-developer of the technology, the results are highly promising but further development work will likely need to be conducted in collaboration with an industry partner.

“It's a very broad platform with a lot of possible applications,” she told Gene Silencing News this week. “It's ideally suited to this idea of personalized therapy where you can mix in any siRNAs with the delivery vehicle and change what you knock down depending on the person's disease."

However, academia “isn't really the place where you should do drug development,” she said, adding that “it's hard … to get postdocs to work on [something] that's not what will develop their careers.”

As such, she said she is on the lookout for a partner interested in advancing the RNAi approach into the clinic.

The technology, which originated in Lieberman's lab, involves binding an siRNA to protamine, a peptide that packages DNA in sperm. The protamine is then joined to an antibody fragment that can be used to target specific cells.

In 2005, Lieberman and colleagues reported in Nature Biotechnology on the use of the approach to target HIV-infected or envelope-transfected cells.

In that work, “the fusion protein was designed with the protamine coding sequence linked to the C terminus of the heavy chain Fab fragment of an HIV-1 envelope antibody,” and the siRNAs only induced silencing in cells expressing the HIV-1 envelope.

“Additionally, siRNAs targeted against the HIV-1 capsid gene gag inhibited HIV replication in hard-to-transfect, HIV-infected primary T cells,” according to the paper's abstract. Meantime, intratumoral or intravenous injection of the complexed siRNAs in mice targeted HIV envelope-expressing B16 melanoma cells, but not normal tissue or envelope-negative B16 cells.

In the latest paper, which appeared in Science Translational Medicine, Lieberman and investigators from Sun Yat-Sen Memorial Hospital in China adapted the delivery approach for use against breast cancer, specifically targeting the gene polo-like kinase 1.

PLK1-targeting siRNAs were packaged in protamine, which was joined to an antibody fragment against the HER2 protein, which is expressed on the surface of certain breast cancer cells.

In HER2-positive breast cancer cell lines, the complexed siRNAs silenced target gene expression, reduced proliferation, and induced apoptosis without triggering an interferon response. When administered intravenously to orthotopic HER2-positive breast cancer models, the molecules concentrated in the tumor tissue and “persisted for at least 72 hours, leading to suppressed PLK1 gene expression and tumor cell apoptosis,” according to the paper.

The intravenously injected siRNA complexes also slowed HER2-positive breast tumor growth, reduced metastasis, and prolonged survival without apparent toxicity.

“Basically, what this paper shows is that this method of targeted delivery actually works very effectively for both suppressing a primary tumor and in a model of metastasis,” Lieberman said.

“Because of the specificity of delivery, we were able to target a gene that is essential to dividing cells, without any obvious toxicity,” the paper's authors wrote. “Antitumor benefits were shown in the challenging conditions of already established tumors and experimental metastatic disease. Our method could be easily adapted to deliver other therapeutic siRNAs into cancer cells to suppress not only oncogenes, but also other genes vital to cell
survival, either as single agents or as siRNA drug cocktails.

“The approach … could also be easily modified by changing the fusion protein antibody to target delivery to other cancer cell types via cell surface molecules they specifically over-express,” they concluded.

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