Assistant Professor of Chemistry R. Bryan Sears recently reached a significant milestone in his scholarship - as part of a joint collaboration with his co-authors Bryan Spring (currently, Assistant Professor in the Department of Physics at Northeastern University) and Lei Zak Zheng (Massachusetts General Hospital) - with the publication of an article in the journal Nature Nanotechnology. The article highlights the research team's use of a new nanomedicine which combines photodynamic therapy (the use of light to trigger a chemical reaction) with a chemotherapy in the treatment of pancreatic cancer and other highly treatment-resistant tumors.
The work by Sears was performed at the Wellman Center for Photomedicine at Massachusetts General Hospital in the lab of Dr. Tayyaba Hasan, a Professor of Dermatology and of Health Sciences and Technology at Harvard Medical School. Sears, whose research interests lie in cancer therapy and light activated drugs, began this project as a Research Fellow at MGH/HMS in 2011 and continued his research after joining the faculty at Emmanuel College the following year.
Importantly, the study showed that a novel combination of chemotherapy significantly reduced the size of tumors in mouse models and also greatly suppressed the spread of cancer when compared to traditional treatments.
"This finding is significant because there have been very few advancements in treatment options for patients suffering from pancreatic cancer," Sears said. "In fact, many advances in treatment options have only proved to provide, at most, palliative care. Our approach to treatment and delivery gives hope that these therapies could one day significantly impact the outcomes in late stage pancreatic cancer patients."
While chemotherapy drugs have been effective in treating many cancers, Sears explained, the therapeutic index (the amount of a drug that causes the desired therapeutic effect to the amount that causes toxicity) is still problematic. It can limit dosage, result in unwanted side effects and interruptions in treatment. This is because chemotherapy often lacks specificity to tumors and has the potential to damage healthy cells in the body. In contrast, light activated therapies become toxic only when exposed to near-infrared light and therefore allow for controlled, localized effect only within the area of irradiation. The result is a treatment that can focus toxicity just within the tumor and, thereby, greatly reduce side effects.
In their paper, Sears and his co-authors report the combination of light activated therapies with more traditional targeted chemotherapies in a nano-sized delivery vehicle they called a nanoliposome. The nano-sized packaging (measuring ~1-billionth of a meter in diameter) allows for increased delivery of the drugs to the tumor and also, because of the light activated therapy, the ability to trigger the drug release and activation by irradiation with light. These nanoliposomes results in significant tumor reduction and better therapeutic outcomes compared to the individual drugs alone. In addition, by controlling the release of the payload chemotherapy in a nanoparticle, cancer cells that survive the first light activated therapy are quickly targeted and killed by the high local concentration of the potent chemotherapy agent.
"Often, when dosing chemotherapies, the drugs given in a treatment regimen travel through the body at different rates. Despite clinicians best efforts, drugs meant to work together in chemotherapy don't always arrive at the tumor at the same time," Sears said. "By packaging our drugs in this nanoformulation, we can ensure both drugs arrive at the right place and at the right time. This lowers the necessary therapeutic dose of the chemotherapy to one-thousandth the dosage needed to see effect in the traditional oral chemotherapy."
While Sears noted that this treatment has tremendous potential, it needs more validation before becoming a clinical treatment option. However, he and his co-authors are encouraged by their findings and will continue their test using this drug delivery method with an ultimate goal to provide better options for patients with advanced pancreatic cancers.
Structural Imaging of Nanoliposome
An especially significant moment in Sears' research is illustrated in the image to the right - a three-dimensional rendering of the nanoliposome, showing the encapsulation of the therapy drug-filled nanoparticle. The dashed circles in the two-dimensional cryo-EM tomogram slice below indicate the 3D-rendered objects.
Sears accomplished this research while teaching full-time. Sears teaches a significant number of the first-year students each year in his Principle of General Chemistry courses. He also runs his own on-campus research team which is made up of six undergraduates that range from freshmen to seniors.
"I love teaching," he said. "I've been at Emmanuel since 2012, and I've been inspired by the transformation in our students who arrive with little experience in science when I taught them freshman year, but four years later will stop me in the hallway to discuss their own research projects."
With his research group at Emmanuel, Sears hopes to expand his work on light-activated and combination therapies to treat other diseases, in particular, leishmaniasis, a parasitic disease found on the World Health Organization's list of neglected diseases. Spread by infected sand flies, cutaneous leishmaniasis causes skin lesions that are currently treated by costly injections - which are often both inaccessible and unaffordable to vulnerable populations. In this project, Sears hopes to develop a drug that can be applied topically, distributed easily and economically, and activated by the sun in regions without access to advanced medicine. The proposed name of the study? The Sunflower Project, in honor of Emmanuel, the Sisters of Notre Dame de Namur and their social justice mission.
"When all is said and done, my home base is here at Emmanuel," Sears said. "I get to bring all of this great research back here to share with my students and colleagues. I love that everything comes back to Emmanuel."
This study was supported by National Institutes of Health grants RC1-CA146337, R01-CA160998, P01-CA084203 and F32-CA144210.