For nearly 70 years, chemotherapy has been one of the primary methods used to treat cancer and has saved or prolonged countless lives. Anyone who has personal experience with cancer can attest, however, that chemotherapy drugs have many well-known and potentially fatal side effects. Cancer researchers have, therefore, been trying for more than three decades to direct therapeutics to cancer cells to treat the disease without killing normal cells and tissues. Unfortunately, little progress has been made.
“Cancer cells are more similar to normal cells than they are different,” says Sandia researcher and Harry S. Truman Fellow Carlee Ashley (8621). “This makes targeted drug delivery really challenging because it’s difficult to identify targeting molecules that will bind to cancer but not to anything else.”
Carlee, in collaboration with Jeff Brinker (1002) and the University of New Mexico (UNM) Cancer Center, may have found the solution in virus-like particles (VLPs), protein nanoparticles derived from naturally occurring viruses or bacteriophages (viruses that infect bacteria). See the April 22, 2011, issue of Sandia Lab News for a related story on this research.
Cell-specific delivery of diverse cargos
In a paper titled, “Cell-specific delivery of diverse cargos by bacteriophage MS2 virus-like particles,” featured on the cover of the July 26 issue of ACS Nano, Carlee and her co-authors reported the use of 30-nm VLPs, derived from MS2 bacteriophage, to selectively deliver chemotherapy drugs as well as new-generation therapeutics like small interfering RNA (siRNA) and protein toxins to human hepatocelullar carcinoma (HCC), a form of liver cancer. In addition, they delivered quantum dots used for imaging and diagnosis of early-stage cancer.
“We observed highly specific delivery of these therapeutic molecules to liver cancer cells as opposed to control cells, like normal liver cells, cells that line the blood vessels, and several types of immune cells,” Carlee says. “The end result was that we only need two or three of these VLPs to be taken up by a cancer cell in order to kill it.”
To create the tiny but powerful VLPs, the researchers remove the bacteriophage RNA that normally allows it to replicate inside bacteria and replace it with chemotherapeutic drugs or anything else they want to deliver to cancer cells. They then modify the VLP shell, which is composed of protein, with peptides that bind to cancer cells and promote uptake of drug-loaded VLPs.
“The main advantage of MS2 VLPs, in comparison with other VLP delivery systems, is that we can encapsulate drugs in the interior volume rather than conjugating them to the exterior surface of the particle,” explains Carlee. “Then we use well-established genetic manipulation techniques to display targeting peptides on the VLP surface. The end result is that we can kill cancer with almost absolute specificity.”
Identifying peptide sequences
Identifying peptide sequences that bind to cancer cells but not to anything else is one of the biggest challenges in the field of targeted drug delivery. The molecules expressed by cancer can vary from patient to patient and as the disease progresses from benign to metastatic states, further complicating the problem.
To address this issue, David Peabody, professor of molecular genetics and microbiology at UNM and corresponding author of the ACS Nano article, has created a library of 10 billion VLPs, each displaying a randomized peptide on its surface. “We don’t need to know the peptide sequence that binds to a specific cancer cell. We can simply expose the library to a cell of interest and see which VLPs bind to it,” Carlee explains. “This method enables easy identification of targeting peptides when there are no known sequences that bind to a particular type of cancer.”
A very versatile system
Once VLPs with high affinity targeting peptides are identified, researchers can then use the exact same particles for drug delivery. “Our particles are the only ones developed to date that can do both,” she says. “This strategy can be used to rapidly identify peptides that target primary and metastatic tumor cells, as well as peptides specific for an individual patient. It’s a very versatile system.”
With Oscar Negrete (8621), Carlee is working on a related project supporting Sandia’s biodefense work that seeks to use VLPs to target cells infected with Nipah virus, a bio-safety level (BSL) 4 select agent with potential for use as a weapon by our adversaries. The idea, she says, is to deliver siRNA to Nipah-infected cells to silence the expression of viral proteins that enable viral replication.
In a parallel project, they are developing VLPs to vaccinate against Nipah and related viruses. “These two projects give us a very comprehensive way to treat viral infections using a single particle. Using VLPs, we can potentially prevent an infection, as well as treat an infection that has already occurred,” she says.
“The hepatocellular carcinoma and Nipah virus projects provide a very powerful example, demonstrating how advances developed in the fight against cancer can also be applied to Sandia’s important national security effort to counter biological threats,” adds Glenn Kubiak, director of Sandia’s Biological and Materials Sciences Center 8600.
Carlee and the UNM team are now working toward Federal Drug Administration approval of MS2 VLPs as delivery vehicles, which is a very long road. They hope to start the first phase of human clinical trials at the UNM Cancer Center within five years.