The Center for Biomanufacturing Science and Technology brings together faculty at the University of Delaware that tackle a wide array of problems and fundamental challenges in areas ranging from: cell culture processes and bioreactors; high-end and scalable purification processes; product formulation and stability; drug delivery; manufacturing; and analytical technologies, instrumentation, and algorithms to support all of these areas. The Center supports cutting edge research facilities on campus, educational activities including seminars, workshops, and shortcourses, as well as industrial research consortia.
SHINING A LIGHT ON GENE REGULATION
UD engineers lay groundwork for cutting-edge cancer drugs
Cancer treatments—from radiation to surgery to chemotherapy—are designed to remove or kill cancerous cells, but healthy cells often become collateral damage in the process. What if you could use lasers to pinpoint the treatment area and deliver medicine to cancer cells only? A research team at the University of Delaware, led by Emily Day, an assistant professor of biomedical engineering, is laying the groundwork for a method to inhibit cancer-promoting genes in cancer cells while leaving healthy cells intact. In a new paper published in Nano Letters, the team reveals unprecedented insights into this promising method, which involves coating nanoparticles with gene-regulatory agents and then exposing them to a dose of laser light to unleash that material. Because the nanoparticles hold the gene regulatory agents inactive until their release is triggered on-demand with light, they have substantial potential to enable high precision cancer therapy while minimizing impact to non-irradiated healthy cells. Day and her team tested their new method against brain tumor cells by using the nanoparticles to silence the expression of green fluorescent protein (GFP) in the cells.
A new way to combine lasers and nanoparticles
Like scalpels and sutures, lasers are often used in medical procedures. Ophthalmologists use lasers to reshape corneas in vision-correcting eye surgery. Dermatologists use lasers to fade scars on skin. Cardiologists use lasers to open clogged arteries. Oncologists use lasers to destroy cancerous cells and tumors. The Day Lab aims to combine lasers with light-responsive gene regulatory nanoparticles to strategically annihilate cancer cells and minimize collateral damage. They start with small interfering RNAs, known as siRNAs, which are molecules consisting of complementary strands of RNA that can reduce the expression of certain genes in cancer cells. The siRNAs are coated on nanoparticles made of silica and gold, which measure smaller than the width of a human hair. These particles protect the siRNAs until they reach the desired treatment area. The question is—how do you release them at exactly the right spot? Read UDaily article…
FACULTY SPOTLIGHT: APRIL KLOXINApril Kloxin, assistant professor of chemical and biomolecular engineering and materials science and engineering at the University of Delaware, is the ACS Division of Polymer Chemistry Researcher of the Month for May 2018. Her research group seeks to design dynamic materials, including novel biomaterials, and use them to understand and direct important biological signals in tissue regeneration and disease. Kloxin was also recently featured on the Susan G. Komen 3-Day Blog for her work addressing the issue of late recurrence for breast cancer survivors. In 2016, she received a Career Catalyst Research Award from the Susan G. Komen Roundation for this work. “My research group is working to develop materials that mimic the body tissues where breast cancer recurrence is likely to occur,” she said in the blog post. “Our team is trying to understand how the environment of these tissues causes dormant breast cancer cells to ‘wake up’, leading to recurrence.” Kloxin also shared why breast cancer is personal to her and her family. Her mother is a breast cancer survivor who is now 13 years disease-free, giving her insight into the challenges patients and survivors face. “When my mother was diagnosed, I looked at literature to learn about the latest treatment options for her type of ER+ breast cancer,” she said in the blog post. “I realized that patients face a constant concern of recurrence, even after successful initial treatment. Therefore, I decided to focus my research efforts on addressing this outstanding issue of late recurrence.” Kloxin and her lab group organized a team to run and walk at the Komen Philiadelphia Race for the Cure on Sunday, May 13, 2018 in honor of those who have fought or are fighting breast cancer. In addition to her roles at UD, Kloxin is a member of the Breast Cancer Research Program at the Helen F. Graham Cancer Center and Research Institute in the Christiana Care Health System.
ENGINEERING’S EMILY DAY EARNS NSF CAREER AWARD
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. Read UDaily article…
PROGRAMMING DNA TO DELIVER CANCER DRUGS
Engineers control cellular proteins with biological computing
DNA has an important job—it tells your cells which proteins to make. Now, a research team at the University of Delaware has developed technology to program strands of DNA into switches that turn proteins on and off. UD’s Wilfred Chen Group describes their results in a paper published Monday, March 12 in the journal Nature Chemistry. This technology could lead to the development of new cancer therapies and other drugs.
Computing with DNA
This project taps into an emerging field known as DNA computing. Data we commonly send and receive in everyday life, such as text messages and photos, utilize binary code, which has two components—ones and zeroes. DNA is essentially a code with four components, the nucleotides guanine, adenine, cytosine, and thymine. In cells, the arrangement of these four nucleotides determines the output—the proteins made by the DNA. Here, scientists have repurposed the DNA code to design logic-gated DNA circuits. “Once we had designed the system, we had to first go into the lab and attach these DNA strands to various proteins we wanted to be able to control,” said study author Rebecca P. Chen, a doctoral student in chemical and biomolecular engineering (no relation to Wilfred Chen). The custom sequence designed DNA strands were ordered from a manufacturer while the proteins were made and purified in the lab. Next, the protein was attached to the DNA to make protein-DNA conjugates. The group then tested the DNA circuits on E. coli bacteria and human cells. The target proteins organized, assembled, and disassembled in accordance with their design. “Previous work has shown how powerful DNA nanotechnology might possibly be, and we know how powerful proteins are within cells,” said Rebecca P. Chen. “We managed to link those two together.”
Applications to drug delivery
The team also demonstrated that their DNA-logic devices could activate a non-toxic cancer prodrug, 5-fluorocytosine, into its toxic chemotherapeutic form, 5-fluorouracil. Cancer prodrugs are inactive until they are metabolized into their therapeutic form. In this case, the scientists designed DNA circuits that controlled the activity of a protein that was responsible for conversion of the prodrug into its active form. The DNA circuit and protein activity was turned “on” by specific RNA/DNA sequence inputs, while in the absence of said inputs the system stayed “off.” To do this, the scientists based their sequence inputs on microRNA, small RNA molecules that regulate cellular gene expression. MicroRNA in cancer cells contains anomalies that would not be found in healthy cells. For example, certain microRNA are present in cancer cells but absent in healthy cells. The group calculated how nucleotides should be arranged to activate the cancer prodrug in the presence of cancer microRNA, but stay inactive and non-toxic in a non-cancerous environment where the microRNA are missing. When the cancer microRNAs were present and able to turn the DNA circuit on, cells were unable to grow. When the circuit was turned off, cells grew normally. Read UDaily article…
MANUFACTURING USA HEADQUARTERS
Secretary of Commerce Penny Pritzker announces the National Institute for Innovation in Manufacturing Biopharmaceuticals.
Secretary of Commerce Visits UD to Announce New Institute
Secretary of Commerce Penny Pritzker visited the University of Delaware today, where she announced a new institute to advance U.S. leadership in pharmaceutical manufacturing. The Newark-based National Institute for Innovation in Manufacturing Biopharmaceuticals (NIIMBL) will be the 11th Manufacturing USA Institute. Biopharmaceuticals are prescription drugs made with living cells. Most drugs are chemistry-based and far easier to produce. The biopharmaceutical category includes vaccines, cancer drugs and drugs to treat autoimmune diseases, as well as emerging drugs for cell and gene therapies. The institute will focus on bringing safe drugs to market faster and on developing workforce training. The biopharmaceutical field has a negative unemployment rate, with more jobs available than there are qualified workers. A team of more than 150 companies, educational institutions, nonprofits and state governments will operate NIIMBL under a newly formed nonprofit. Expected total investment from all stakeholders totals $250 million, including $70 million of federal investment. The University of Delaware will handle administrative duties for the institute in partnership with the Commerce Department’s National Institute of Standards and Technology (NIST). Its headquarters will be on UD’s campus in a location to be determined. “In communities from coast to coast, the Manufacturing USA network is breaking down silos between the U.S. private sector and academia to take industry-relevant technologies from lab to market,” Pritzker said. “The institute announced today is a resource that will spread the risks and share the benefits across the biopharmaceutical industry of developing and gaining approval for innovative processes. The innovations created here will make it easier for industry to scale up production and provide the most ground-breaking new therapies to more patients sooner.” Read UDaily article…
STOPPING CANCER RECURRENCE
Susan G. Komen Grant to Support Research on Breast Cancer Recurrence
Although early detection and better treatments have resulted in more women with breast cancer surviving past the five-year mark, 20 percent of disease-free patients will experience a recurrence anywhere from five to 25 years later at a metastatic site — most often in the bone marrow or the lungs. And their chances of surviving this secondary cancer are lower because it is often quite advanced before it is detected. “There’s a significant clinical need to understand the mechanism of late cancer recurrence to determine disease markers and improve treatment strategies,” says the University of Delaware’s April Kloxin. “It has been hypothesized that late recurrences originate from tumor cells that disseminate to these other tissues in the body where they become dormant and are later re-activated.” Kloxin recently received a $450,000 grant from Susan G. Komen aimed at developing a better understanding of this dormancy and reactivation process so that ultimately recurrence can be prevented. “While estrogen receptor positive tumors typically have better initial outcomes, late recurrences are a concern,” she says. “If we can understand the mechanisms that drive the switch from dormancy to growth of this type of cancer, we can identify predictive biomarkers that may indicate which women are at risk and lay the foundation for the development of more effective treatment.” Kloxin’s team plans first to create materials that mimic various metastatic sites and then identify key signaling pathways in cancer dormancy within these 3-D microenvironments. Second, they will focus on determining what regulates re-activation of the cancer cells within this cultured system. Finally, they will establish commonalities of dormancy or activation of patient-derived tumor cells in the culture model. “This last goal is where we’re really excited about our collaboration with the Helen F. Graham Cancer Center and Research Institute in the Christiana Care Health System,” Kloxin says. “Evaluating cells from actual patients will provide us with the heterogeneity of real cases and enable us to compare our findings with the traditional markers observed by clinicians.” Read UDaily article…