Two-stage Vectors Deliver Gene Silencing Therapy to Tumors
Breast cancer patients with the so-called triple negative form of the disease have the lowest survival rate among all breast cancer patients, in large part because this type of cancer does not respond to most anti-cancer agents. Recent studies have shown, though, that triple negative breast cancers are susceptible to agents that interfere with DNA repair pathways, especially a protein known as ATM. Now, a research team from The Methodist Hospital Research has capitalized on this weakness with promising results.
Haifa Shen and Mauro Ferrari led a team of investigators that created a two-stage delivery vehicle capable of ferrying an agent that targets this protein to triple negative breast tumors. When administered to mice bearing human breast tumors, the drug-bearing vector stopped the production of the ATM protein and greatly inhibited the growth of what otherwise is an aggressive cancer. The researchers published the results of their work in the journal Small. Dr. Ferrari is co-principal investigator of the Texas Center for Cancer Nanomedicine, one of nine Centers of Cancer Nanotechnology Excellence funded by the National Cancer Institute.
To stop the production of ATM, the researchers created a short interfering RNA (siRNA) that targets the messenger RNA that codes for this protein. siRNA-based therapies have shown promise for treating cancer, but delivering them to tumors at therapeutic levels has proven challenging. Dr. Shen and Dr. Ferrari solved this problem using a two-stage delivery vehicle consisting of a nanoscale liposome and a disc-shaped, nanoporous silicon microparticle. The researchers use the liposome to encapsulate the siRNA agent and they take advantage of the biocompatible silicon microparticles to safely ferry the liposomes through the blood stream and deposit them just outside of the tumors.
Because of their disc shape, the silicon microparticles accumulate efficiently in the blood vessels that surround tumors. In earlier work, Dr. Ferrari and his Texas Center for Cancer Nanomedicine colleague Paulo Decuzzi had shown that approximately between six and 10 percent of an injected dose of silicon microparticles accumulate in the tumor vasculature compared to less than 0.1 percent of conventionally administered drug. Once the microparticles settle around the tumor, they gradually degrade into non-toxic materials and slowly release the liposomes. The liposomes then migrate into the tumors, where they are taken up by cancer cells and release their siRNA payload.
While experiments in tumor bearing mice showed that this two-stage delivery system was effective at suppressing tumor growth, they also demonstrated that it did not trigger a potentially dangerous immune response that is often seen with siRNA therapies. Additionally, during the four-week experiments, body weight, blood chemistry, and tissue histology did not reveal significant toxicities which are often associated with chemotherapies.
This work, which is detailed in a paper titled, "Multistage Vectored siRNA Targeting Ataxia-Telangiectasia Mutated for Breast Cancer Therapy," was supported in part by the NCI Alliance for Nanotechnology in Cancer, a comprehensive initiative designed to accelerate the application of nanotechnology to the prevention, diagnosis, and treatment of cancer. An abstract of this paper is available at the journal’s website.View abstract