Developing nanoscale materials to outsmart cancerous tumors

Emily Day, an assistant professor of biomedical engineering at the University of Delaware, has received a National Science Foundation (NSF) Career award to engineer membrane-wrapped nanoparticles for targeted ribonucleic acid (RNA) delivery to breast cancer cells.

The grant, which is expected to total $500,000, will start on May 1, 2018 and last until April 30, 2023.

Day studies how nanoparticles, which measure about one-thousandth the width of a human hair, can be used in cancer treatment. For example, she is known for her previous research on the use of gold nanoparticles for heat-based treatment of cancer and for gene regulation of cancer.

For this project, Day is making novel nanoparticles containing special ribonucleic acid (RNA) molecules. These RNA molecules can silence genes inside cancer cells that would otherwise help them grow and proliferate, making them exciting tools for cancer treatment. Unfortunately, delivering this RNA cargo to a tumor made of breast cancer cells is a very difficult task.

For one, “upon administration into the bloodstream, RNA is extremely susceptible to degradation before it ever reaches a tumor,” Day said.

And even when the therapeutic RNA makes it to a tumor, it may not be able to enter any cancer cells. This is because the membranes or protective outer layers around cancer cells are designed to keep many other molecules out. To overcome these two barriers, the RNA needs to be protected and disguised so that it remains stable in circulation long enough to reach the target tumor and then enter its cells.

Day has a clever idea to achieve this goal: Load the RNA into nanoparticles she has fabricated to provide enhanced stability, and then extract membranes from cancer cells and wrap them around the novel RNA-loaded nanoparticles. By cloaking the nanoparticles with cancer cell-derived membranes, Day aims to trick tumors. The cancer cells in each tumor may accept the wrapped nanoparticles as if they were their own.

“The idea is that the body will see these membrane-wrapped nanoparticles as a cell and not recognize it as foreign material,” she said. In addition to preventing premature clearance from the bloodstream, the membrane coating will also enable cancer cell-specific binding of the nanoparticles.

Upon binding the cancer cells within the tumor, the nanoparticles’ contents can be released, and the tumor-suppressive RNA can go to work reducing the expression of harmful genes—and ultimately shrinking the cancer cells and the tumor they comprise.

She will test these exciting new materials in both in vitro and in vivo models of triple-negative breast cancer.

Day will study the properties of these cancer cell membrane-wrapped nanoparticles and how those properties affect their ability to infiltrate tumors and release their contents. For example, she wants to understand the mechanisms by which the nanoparticles engage receptors on the targeted cancer cells to facilitate cargo delivery. Because this interaction happens on a scale the human eye can’t detect, Day will utilize super-resolution microscopy at the Delaware Biotechnology Institute to see it all.  She hopes that performing detailed studies of the structure/function relationships of her nanoparticles will enable her to develop design rules that could guide the development and use of membrane-wrapped nanoparticles for RNA interference in triple-negative breast cancer—the type of cancer cell she is studying—and other types of cancer, too.

Day is not the first person to make membrane-wrapped nanoparticles—this is a “rapidly growing area,” said Day. Other research groups have cloaked nanoparticles in membranes derived from red blood cells, for instance, which enabled them to circulate in the bloodstream far longer than unwrapped nanoparticles. However, Day will be the first person to make membrane-wrapped nanoparticles for RNA delivery to tumors, which requires them to be made in a new way that is distinct from prior efforts.

In addition to performing the research supported by the CAREER award, Day will also create new educational efforts to increase knowledge of nanoscale biomaterials for cancer management. For example, she will share her knowledge about membrane-wrapped nanoparticles for cargo delivery in an undergraduate biomedical engineering course, Engineering Biomedical Nanostructures. She will also work with UD students to develop demos for use in outreach to elementary, middle and high school students, and she will engage high school and undergraduate students from groups underrepresented in STEM in bio-nanomaterials research through internships.

Beyond the use of membrane-wrapped, RNA-loaded nanoparticles, Day hopes to make discoveries that could have a wider impact on cancer treatment. For example, by studying how her novel nanoparticles interact with cancer cells, Day expects to uncover insights about structure/function relationships. Day’s findings could pave the way for creation of new nanoparticle-based cancer treatments that are far more effective than existing treatments.

Ultimately, the end goal of any cancer-related research is to help people live longer and better. Day is conducting this research project in a model of triple-negative breast cancer, a particularly devastating and difficult-to-treat form of breast cancer. Women with triple-negative breast cancer have lower four-year survival rates than women with other types of breast cancer, according to a study recently published in the journal Cancer Epidemiology, Biomarkers & Prevention. Day was inspired to study this particular cancer type after a 2015 report suggested that Delaware has the highest incidence of triple-negative breast cancer in the U.S.

Day has been passionate about the use of nanoparticles in cancer treatment since she was an undergraduate student in physics at the University of Oklahoma. One summer, she participated in a Research Experience for Undergraduates (REU) program at Rice University, where she got the opportunity to work with nanoparticles in biomedical applications. She was so excited by the work that she went back the next year, and she eventually attended graduate school at Rice. There, she had opportunities to observe cancer treatments, such as surgery and radiation, at the nearby MD Anderson Cancer Center.

“As an engineer, you look at the treatments available and think—there’s got to be a better way,” she said. Nanoparticles hold a lot of promise because they can find their way into spaces that surgeons can’t reach, and they can increase the amount of therapeutic drugs that ultimately reach a tumor.

Biomedical engineering on the rise at UD

Day is just one of the early-career biomedical engineers at UD who is quickly rising to the upper echelon in her field. The NSF Career Award is among the most prestigious grants for junior faculty members, and John Slater, also an assistant professor of biomedical engineering at UD, received one in March 2018. Day also recently received the prestigious NIH R35 award, which supports outstanding investigators with a particularly significant and ambitious program of research.

“Emily Day’s work with membrane-wrapped nanoparticles will yield new insights for cancer drug delivery and one day should impact patient care,” said Dawn Elliott, chair of the biomedical engineering department at UD. She added: “Our department is proud that two of our assistant professors have received NSF Career Awards this year – this is a major step for us.”

 Photo by Evan Krape | Research images by Emily Day | Photo illustration by Joy Smoker 

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