Antibodies have emerged as invaluable tools for the study and treatment of cancer because they can manipulate, with high specificity, the signaling pathways that drive cancer progression.

“However, although they’re effective, antibodies are extremely expensive and require high dosages that can produce adverse side effects, both of which limit their therapeutic success,” says Emily Day, assistant professor of biomedical engineering at the University of Delaware.

To overcome these limitations, antibodies can be conjugated, or chemically linked, to nanoparticles, enhancing their ability to bind to targets through a property known as multivalency.

Multivalent binding involves the interaction of multiple complementary functionalities. In the case of antibody-nanoparticle conjugates, multiple antibodies on each nanoparticle can bind with multiple targeted cell surface receptors, which increases the overall binding strength.

Day and her doctoral student Rachel Riley hypothesized that multivalent binding could be exploited to specifically bind targeted cells and thus enhance the inhibition of oncogenic, or tumor-causing, cell signaling.

The results of their work to test this hypothesis are reported in a paper, “Frizzled 7 Antibody-Functionalized Nanoshells Enable Multivalent Binding for Wnt Signaling Inhibition in Triple Negative Breast Cancer Cells,” co-authored by Day and Riley. The paper was published on May 22 in Small, a top multidisciplinary journal covering a broad spectrum of topics at the nano- and microscale.

Day and Riley chose to test their hypothesis on triple negative breast cancer (TNBC) because this subtype accounts for 15 to 20 percent of diagnosed breast cancer cases and is associated with earlier relapse, higher mortality rates and significantly decreased progression-free survival compared to other types of breast cancer.

“The cells in TNBC tumors lack expression of the estrogen, progesterone and human epidermal growth factor 2 receptors, rendering the disease unsusceptible to conventional targeted or hormonal therapies, so it’s critical that effective therapies be developed specifically for this disease,” Day says.

She explains that a promising therapeutic target for TNBC is the Wnt signaling pathway, an ancient pathway that regulates a number of cellular-level processes during embryonic development. Defective Wnt signaling is a causative factor for a number of cancers and birth defects.

Antibodies to a Wnt receptor known as “Frizzled-7” are overexpressed in more than two-thirds of TNBC tumors, so the goal of this research was to demonstrate that Frizzled 7 antibodies attached to nanoparticles are more effective at targeting TNBC cells and suppressing the Wnt pathway than the same antibodies delivered freely.

“The findings reported in this paper confirm our hypothesis and contribute to an exciting new era of investigation regarding the use of antibody-functionalized nanoparticles in cancer therapy,” Day says.

“Our approach could ultimately result in cheaper and safer treatment, making it an excellent platform for management of triple negative breast cancer,” adds Riley.

About the researchers

Emily Day is an assistant professor with appointments in UD’s Department of Biomedical Engineering, UD’s Department of Materials Science and Engineering and the Helen F. Graham Cancer Center and Research Institute.

Rachel Riley is a doctoral student in biomedical engineering at UD.

About the research

This work was supported with funding from the University of Delaware Research Foundation, by grant #IRG-14-251-07-IRG from the American Cancer Society, and by a Maximizing Investigator’s Research Award (MIRA) from the National Institute of General Medical Sciences (NIGMS) of the National Institutes of Health (NIH) under grant number R35GM119659. Additionally, the Delaware INBRE program supported this project, with a grant from NIH NIGMS (P20-GM103446).