Nucleic-acid agent siRNA can be attached to the outside of nanoparticles. The nanoparticles also contain pores where anti-cancer drugs also can be stored, enabling co-delivery of siRNA and anti-cancer drugs. In the current experiment, siRNA against TWIST was attached to mesoporous silica nanoparticle (MSN) coated with polyethyleneimine (PEI).
In an advance toward developing a novel therapy for cancer, scientists from UCLA and the City of Hope used nanoparticles to deliver a nucleic acid known as small interfering RNA, or siRNA, into tumor cells to inhibit the expression of a specific protein and cause inhibition of tumor growth in an animal model.
The protein, TWIST, is a master regulator of a cancer program called epithelial-to-mesenchymal transition (EMT) that is implicated in tumor metastasis. Delivering siRNA into tumor-bearing mice inhibited the expression of TWIST, which in turn shut down the EMT program and dramatically reduced the size of tumors. “This demonstrates the effectiveness of targeting EMT for cancer therapy,” says Fuyu Tamanoi, PhD, professor of microbiology, immunology & molecular genetics and director of the signal transduction and therapeutics program at UCLA’s Jonsson Comprehensive Cancer Center.
In previous studies, siRNA has been shown to effectively shut down gene expression in tumor cells grown in the laboratory. But the technique had not been effective in living organisms because enzymes in the blood called nucleases degrade siRNA before it can reach tumor cells. To circumvent that problem, the UCLA and City of Hope researchers attached siRNA to the outside of a particular type of nanoparticle developed by Jeffrey Zink, PhD, professor of chemistry and biochemistry and a member of UCLA’s Jonsson Comprehensive Cancer Center. The nanoparticles are comprised of mesoporous silica coated with a substance called polyethyleneimine, which acts to bind and protect the siRNA when the particles are injected into the blood. As a result, the research team, led by Carlotta Glackin, PhD, at the City of Hope, found that the nanoparticles could accumulate in the tumor cells, and the siRNA could go to work inhibiting the cells’ expression of TWIST.
The study found that giving mice siRNA-loaded nanoparticles once a week for six weeks inhibited tumor growth and that it shut down not only TWIST, but also other genes under the control of the EMT process. The result confirms the critical importance of TWIST and the EMT process in cancer progression, the scientists say. TWIST is re-activated in a number of metastatic cancers, including triple-negative breast cancer, melanoma and ovarian cancer. By shutting down the EMT process, Drs. Zink, Tamanoi and Glackin may develop new therapy options for these cancers.
Another important finding was that shutting down TWIST expression enabled cancer cells to overcome their resistance to cancer drugs, suggesting that the therapy can be an effective way to sensitize cancer cells to anti-cancer drugs.
“Mesoporous Silica Nanoparticle Delivery of Chemically Modified siRNA against TWIST1 Leads to Reduced Tumor Burden,” Nanomedicine: Nanotechnology, Biology and Medicine, May 2015