When used together, though, the UD team found that these treatments
show powerful synergy, meaning they provide greater than an additive
therapeutic effect when compared to the individual treatments. Together,
they required lower dosages and produced more natural cell death
(apoptosis) than the kind of cell death caused by injury or disease
(necrosis). The latter, which can often trigger harmful inflammation and
lead to recurrence of disease is a cell death mechanism that Day and
Rosenthal were actively trying to avoid.
This dual approach has not been used in clinical trials yet and more
research is needed before that step can be taken. The agent used in the
photothermal therapy is already in use in clinical trials, Day said. But
the PDT agent — a water-soluble biladiene complex synthesized in
Rosenthal’s lab — is new.
The connection between these two UD labs started about two years ago
when Day heard a presentation by one of Rosenthal’s doctoral students,
Andrea Potocny, during the Biomedical Engineering Graduate Student
Seminar Series. Potocny was discussing efforts to develop water-soluble
molecules to use in photodynamic therapy.
Photodynamic therapy (PDT) works by turning the regularly stable
oxygen molecules (triplet) within a cell into a more energetic form
(singlet) that rapidly reacts with and degrades organic material. This
therapy has been used to kill viruses and bacteria and treat some kinds
of malignant cancers.
Rosenthal’s lab had developed a complex that would produce the toxic
singlet oxygen that could trigger destruction of cancer cells. They
needed a water-soluble molecule that could be used in a real tumor in
its regular biological context.
Day, whose lab was working with nanoparticles for photothermal
therapy (PTT), realized she could help. She had extensive experience
working with models of triple-negative breast cancer with which to test
the new PDT approach, as well as examine its combined application with
It was a remarkable success – a hat trick of advances, including easy
preparation, biological compatibility and excellent potency. The new
biladiene complex was effective in a small dose and had a much higher
phototoxicity score than PDT agents in current use.
Upon demonstrating that the biladiene PDT agent developed by the
Rosenthal lab was both extremely safe and effective, another question
emerged – what would happen if they combined the photodynamic therapy
with the photothermal therapy?
That work led to uncharted territory and two publications – one in the journal Inorganic Chemistry on the new PDT approach and one in the journal Nanomaterials on the combined PDT and PTT approach.
To combine the two approaches, the labs used nanoshells (silica
spheres coated with thin, gold shells) to enable photothermal therapy
and used the biladiene photosensitizer developed by the Rosenthal lab to
enable photodynamic therapy. The treatments were applied either
independently or together to cell culture models of triple-negative
breast cancer, and their safety and efficacy were then examined.
An undergraduate student in Day’s lab — senior Rachel O’Sullivan — noticed unexpected results.
“When we were testing the treatments, out of the blue I noticed that
when we put them together it was more effective at killing cells than
each on their own,” she said. “I went and talked to Rachel [Riley] in
the lab about it and she was surprised. I asked her if I did something
wrong and she said, ‘No! If it’s working synergistically, that’s really
Further studies by the Day and Rosenthal team demonstrated this was
indeed the case. The combined therapies could synergistically inhibit
triple-negative breast cancer cells.
Support for the research came from the University of Delaware
Strategic Initiative Grant, the Delaware Federal Research and
Development Grant Program, the National Science Foundation, the National
Institutes of Health, a University of Delaware Graduate Fellowship and
the American Association of University Women.
About the researchers
Emily Day is an assistant professor of biomedical engineering,
who earlier won a National Science Foundation Early Career Award. Her
research focuses on nanomedicine, gene regulation, photothermal therapy
and translational cancer research. She earned her bachelor’s degree in
physics at the University of Oklahoma, her doctorate in bioengineering
at Rice University and worked as a postdoctoral fellow at Northwestern
University before joining the UD faculty in 2013. The students in her
lab who worked on this project include Rachel O’Sullivan (a senior
undergraduate in biomedical engineering) and Rachel Riley (a 2018
doctoral graduate from biomedical engineering who is now a postdoctoral
researcher at the University of Pennsylvania).
Joel Rosenthal is an associate professor of chemistry and
biochemistry and associate chair of Graduate Studies and Research. He is
an expert in photochemistry and electrochemistry and through his
research seeks to address issues related to catalysis, molecular energy
conversion and the improvement of human health. He earned his bachelor’s
degree from New York University, his doctorate in inorganic chemistry
at the Massachusetts Institute of Technology and served as an NIH
postdoctoral research fellow at MIT before joining the UD faculty in
2010. Among his awards to date are an NSF Early Career Award, an Alfred
P. Sloan Research Fellowship and selection as a Gerard J. Mangone Young
Scholar. The student in his lab who worked on this project is Andrea
Potocny, a doctoral student in chemistry and biochemistry.
Article by Beth Miller; photos by Evan Krape; video by Jeffrey C. Chase