|Nanodiamonds Battling Cancer: The New SLAS Endowed Fellowship at UCLA|
The New SLAS Endowed Fellowship at UCLA Pioneers New Technology for Nanomedicine through a Vibrant International and Interdisciplinary Network
From his lab at the University of California Los Angeles School of Dentistry, Professor Dean Ho, Ph.D., talks about his promising nanodiamonds research and reveals how it embraces the collaborative, multidisciplinary spirit of the Society for Laboratory Automation and Screening.
“It takes a community to get it done,” says Ho, whose new research laboratory resides within the UCLA School of Dentistry’s state-of-the-art Yip Center for Oral/Head and Neck Oncology Research. “This highly unique school and facility are a nexus of multidisciplinary, collaborative, translational research,” says Ho.
“The concept of nanodiamonds as a diagnostic and therapeutic tool is fascinating,” says SLAS Director of Education Steve Hamilton, Ph.D., “and like the SLAS scientific community, it embraces an enthusiastic versatility that combines intellectual curiosity with an inspiring sense of innovation and cooperation.”
Ho’s primary partner in leading the new SLAS-endowed research team is Professor Cun-Yu Wang, D.D.S., Ph.D., who is the No-Hee Park Endowed Professor and Chair of Oral Biology and Medicine at the UCLA School of Dentistry, and a fellow of the American Association for the Advancement of Science who was recently honored with election to the Institute of Medicine of the National Academies.
Their research initiative engages an ever-changing and evolving multidisciplinary network of collaborators that have included chemists, biologists, bioengineers, material scientists, clinicians, pharmacologists and even mechanical engineers. It also has attracted funding and other support from a wide variety of interested and international sources, including the National Institutes of Health and National Science Foundation to the European Commission as well as the recently announced commitment from the SLAS Endowment Fund.
Bloodstream Diamonds for Treating Disease
The new lab at UCLA is developing new therapeutic technologies for treating disease and developing new imaging agents for diagnosing and monitoring disease. Although a range of nanomaterials, including polymers and metals, also are employed and explored, the primary focus is on nanodiamonds.
Nanodiamonds are carbon-based particles that measure from 4 to 6 nanometers each. These simple and inexpensive byproducts of refineries, mining operations and quarries require relatively conventional processes in terms of preparation for use. The material is washed with acid to remove unwanted compounds, and then broken down into nanoparticles through ball milling and sonication.
Ho and his team of researchers have been working on the applications of nanodiamonds in drug delivery with his long-time collaborator, Eiji Osawa, Ph.D., of the NanoCarbon Research Institute in Nagano, Japan (who also serves SLAS as a JALA Scientific Advisor). Together they found nanodiamonds to be exceptionally useful for binding compounds. “Nanodiamonds are unique,” says Ho. “They look like soccer balls with sharper edges and their shape allows drugs to bind very tightly to them and they allow things like water to interact very potently with them. This can result in major improvements in the efficiency of therapy and imaging. They’re safe, versatile, scalable and fairly straightforward to process. This is very special material.”
Most cancer researchers struggle with the challenges of chemotherapy drugs and the “can’t live with them, can’t live without them” conundrum they cause. Ho’s work focuses on doxorubicin, which is a well known chemotherapy drug that kills unhealthy cells and, unfortunately, healthy cells. “Damage to healthy cells can obliterate immune systems, tear up blood vessels, damage hearts and can ultimately kill patients,” says Ho. “Doxorubicin binds really well to nanodiamonds. We call nanodiamonds with doxorubicin NDX, and when injected, NDX moves quite easily through the bloodstream and dramatically reduces unwanted side effect damage.”
Ho passively targets tumor sites by taking advantage of the leaky vasculature that surrounds them, feeds them and enables them to spread. “NDX achieves enhanced permeation and retention by remaining intact as it travels through the bloodstream,” says Ho. “Eventually, they dump out through the leaky blood vessels and move directly into the tumors, delivering the medicine directly to the unhealthy cells while reducing impact on the healthy cells.”
Ho and his colleagues worked with mice with drug-resistant breast and liver cancers to reach these conclusions. Drug resistance is the cause of more than 90% of treatment failures for metastatic cancers. “Many of the proteins responsible for drug resistance keep people healthy, but they can make cancer treatment impossible. They eject toxins and are just as adept at ejecting drugs like doxorubicin. When a drug isn’t having an effect on unhealthy cells, the cancer just keeps barreling forward like a freight train.”
When the drug-resistant mice were treated with doxorubicin by itself, which is the clinical standard for humans, “their tumors continued to grow nonstop. There was no effect at all,” says Ho. “When mice were treated with NDX, tumor growth was significantly delayed.” Taking things a step further, “when mice received a double dose of doxorubicin, it killed them. But, when mice received a double dose of NDX, every single one survived and their tumors became smaller.”
Another negative side effect of doxorubicin and other chemotherapy drugs is the decimation of white blood cells. When white blood cell counts drop dangerously low, drug therapies must be discontinued to avoid further damage to the immune system and the superinfections that usually follow and can lead to patient death. When Ho’s mice were treated with NDX, there were no changes in their white blood cell counts.
Ho says he and his collaborators have lots of ideas and avenues waiting to be explored and are working on binding other materials to nanodiamonds. “For example,” says Ho, “we’re adding proteins that are attracted to and bind to cancer cells. We’ve also achieved encouraging results using nanodiamonds to deliver proteins for wound healing. Using nanodiamonds to deliver DNA for gene therapy improved efficiency by 70 times.”
A Potential Game Changing Advance in Diagnostic Medicine
Nanodiamonds also offer impressive promise as new imaging agents for diagnosing and monitoring disease. In light of the FDA’s many ongoing warnings about the use of gadolinium as a contrast agent for magnetic resonance imaging (MRI), Ho and his team worked with Northwestern University Chemistry Professor Tom Meade and his group to bind gadolinium to nanodiamonds. The result was what Ho and his colleagues describe as a “turbo-charged MRI.”
“The contrast efficiency experienced an order of magnitude increase in relaxivity (or brightness), which is among the highest per-gadolinium increase ever reported in the literature,” says Ho. “This means it might be possible to make MRIs much safer for patients, because an order of magnitude reduction of the current levels of gadolinium would be necessary to be effective.”
Building the Bridge: From the Lab to the Clinic
“Our big focus now is on optimizing this nanodiamond system so we can start to think about what it will take to get it into the clinic. Our ultimate goal is to achieve these positive therapeutic and diagnostic results in human beings,” says Ho. His strategy for success continues to be collaborative and multidisciplinary. As noted at the beginning of this article, Ho believes “it takes a community to get it done” and that the UCLA School of Dentistry “is a unique and very catalytic place to do this kind of work.”
“Different schools focus on different priorities. UCLA is one of the world’s top health sciences campuses and improving the diagnosis and treatment of cancers are among its top priorities,” says Ho. “Plus, the School of Dentistry has a strong commitment to nanomedicine and nanotechnology research, and it brings together an enthusiastic community of researchers and promotes collaboration on a national and international level; lots of people who are willing to proactively form major collaborations across different disciplines. By proactive I mean committed to really trying to look at projects from different viewpoints.”
Currently, the UCLA School of Dentistry supports major breast cancer research initiatives, stem cell work, bone repair, infection therapy, wound healing and more. The translational nature of the environment allows for productive partnerships. For example, Ho expects to work closely in the near term “with clinicians who can help us understand design requirements to translate our work from the bench into the clinic. They can put us in their shoes to try to figure out how to effectively, efficiently and safely administer this drug. Inject it with a catheter? Implant something? Use a pill? Does it need to be in water? Or maybe another liquid or solvent? Does the drug remain active after it releases from the diamond? If so, for how long?”
Ho also looks forward to collaborating with contract research organizations “to move our research from mice to non-rodent mammals, such as dogs or monkeys, to further validate safety and efficacy, and satisfy the FDA’s requirements for third-party validation.”
For a sustainable supply of nanodiamond materials, Ho will continue his collaboration with Dr. Osawa and the NanoCarbon Research Institute in Japan. “Eiji’s group is renowned for studying the unique surfaces of nanodiamonds and is prepared to work with us to sustain our non-rodent mammal research and, ultimately, our clinical trials.”
The Role of Students
In the same way that SLAS respects and reaches out to the next generation of scientific thought leaders, Ho recognizes students as important members of the community that he believes is necessary for the advancement of his nanodiamond research. At any given time, one likely will find undergraduate students, graduate students and post-doctoral researchers hard at work in Ho’s laboratory.
“I can’t think of a better place than Dean’s lab for anybody interested in pursuing a future in research,” says Mark Chen, a student in the Duke University School of Medicine’s Medical Scientist Training Program and former member of Ho’s lab at Northwestern University.
“I started working in Dean’s lab during my first year of college. I wasn't set on any particular field, but I knew I wanted some kind of lab experience,” says Chen. “It was very serendipitous because Dean had just come to Northwestern and I got to be a part of building a brand new lab from day one. I remember working with the postdocs and putting together everything from the hood to the chairs.”
After Chen’s first year in the lab, Ho invited and encouraged Chen to present the lab’s work at the International Nanomedicine Conference. After that, with more encouragement from Ho, Chen authored and published several papers about their work. “Dean is all about opportunities for students and helping you become a better scientist,” says Chen, who stayed and worked in Ho’s lab for four and a half years and produced nine journal publications. “When I wasn’t in class or sleeping, I was in the lab. Nobody told me to do this, but the best mentors just have a way of bringing out the best in you. This was how it was for four and a half years and you don't stay somewhere for that long unless you really enjoy being there. Dean created that magnetic lab environment that made you want to keep coming back.”
“After the lab was set up,” said Chen, “the first projects involved developing biomimetic nanomembranes. In the second year, we began working with nanodiamonds and incorporating them into the membranes, among other nanodiamond projects. Nanodiamonds were really new then and hadn’t been explored much for medical applications, so the work was very pioneering.
“Staying with one lab as an undergraduate student gave me perspective and real understanding of how a lab works, how research really is done, how it evolves, and what careers in research are really all about,” says Chen. Chen's experiences in the lab ultimately determined his plans after college. “I ended up being torn between my goal of being a doctor and my passion for research. It was Dean who told me about M.D./Ph.D. programs and encouraged me to look into them, and ultimately that’s how I ended up where I am today – in the M.D./Ph.D. program at Duke.”
Chen’s goal is to earn his M.D./Ph.D. degrees at Duke and become a physician-scientist with his own lab. According to Chen, his experience with Ho and the collaborative nature of his nanodiamond initiatives gave him a true appreciation for what can be achieved in a multidisciplinary environment. Chen expects to earn his degrees by about 2020, at which time, says Chen “It would be really cool to see the different nanodiamond technologies we developed in Dean’s laboratory being used in the clinic helping people.”
The Magic Bullet?
Ho emphasizes “Right now it’s hard to declare which material is the magic bullet. There are lots of different materials out there to be explored. Cancer is going strong, but when it comes to specific applications, some particles can be more advantageous than others as there are inherent advantages found in all of the exciting platforms being investigated. What we’ve seen with doxorubicin and gadolinium are encouraging and significant improvements that nanodiamonds have enabled. The sheer versatility is exciting.”
An Appreciation for Versatility in Work and Life
About Professor Dean Ho
After earning a Ph.D. in biomedical engineering from UCLA, Ho began his academic career at Northwestern University in Evanston, IL as an associate professor in the Biomedical Engineering and Mechanical Engineering Departments, and as a member of the Robert H. Lurie Comprehensive Cancer Center. After just four years, he was granted tenure which is a rare occurrence within the University. According to Ho, he was always interested in the field of medicine, and when he joined Northwestern, he became especially interested in drug delivery. He is particularly grateful for the opportunities that the Northwestern community provided him with upon his arrival. “I consider myself blessed for having had the opportunity to work with some of the world’s best researchers and colleagues while at Northwestern. I’m deeply grateful for the support that my group members and I received to pursue our research vision amidst a community of collaboration and encouragement."
The innovative impact of Ho’s work is recognized worldwide. In addition to his professorship at the UCLA School of Dentistry, Ho is a visiting professor at Peking University, which is widely recognized as being among the best universities in China, and is a highly sought-after speaker. He has made plenary, keynote and invited lectures at the major nanodiamond, nanocarbon and materials conferences in locations all over the world.
Ho and his team of collaborators published a landmark paper that first introduced the concept of nanodiamond-based therapy in 2007. After that came a cover article in Science Translational Medicine in 2011 that demonstrated the translational significance of this novel molecular delivery approach. Ho also co-authored a recent article in Nature Nanotechnology that describes the properties and applications of this emerging platform.
Ho has published more than 100 peer-reviewed journal papers and proceedings papers in the areas of nanomedicine and drug development, among others. He and his nanodiamonds have been featured on the CNN homepage, NPR homepage, Reuters, Yahoo News, Chicago Tribune, Agence France and other international news outlets. Recently, he was featured on the National Geographic Channel’s “Known Universe” television program.”
Ho is the recipient of a National Science Foundation CAREER Award, Wallace H. Coulter Translational Research Award (Phase I and II), V Foundation for Cancer Research Scholars Award, John G. Bollinger Outstanding Young Manufacturing Engineer Award, UCLA School of Engineering Distinguished Young Alumnus Award and he was invited to attend the 2010 National Academy of Engineering Frontiers of Engineering Symposium.
About SLAS Member Dean Ho
“SLAS is proud to have Dean Ho as a member and active volunteer,” says SLAS CEO Greg Dummer. In line with his enthusiasm for multidisciplinary collaboration, Ho has been an active contributor for years.
Ho began as a member of the Association for Laboratory Automation (ALA, which united with the Society for Biomolecular Sciences in 2010 to form SLAS). Through the years, Ho served as a short course instructor at ALA conferences and assisted in securing important speakers for both ALA and SLAS conferences. After serving as guest editor for a special issue of the Journal of the Association for Laboratory Automation, Ho was named editor-in-chief of the journal, which is now known as the Journal of Laboratory Automation. In addition, Ho serves on the SLAS International Advisory Committee and was recently one of three keynote speakers at the 2012 SLAS Asia Conference in Shanghai, China.
About Dean Ho
Now that he’s back at UCLA, Ho enjoys life with his exceptionally supportive wife, Dr. Sarah Ahn, of whom Dean is equally supportive and proud. After earning a Ph.D. in neuroscience from UCLA and pursuing a research specialty in spinal cord injuries, Sarah shifted gears and founded NAMI Design. Since then, she’s worked her way to the fashion industry’s forefront as an energetic designer of contemporary women’s wear and has premiered her designs at runway shows during New York and Los Angeles Fashion Weeks.
In his spare time, Ho lifts weights – heavy ones. An avid weight lifter and fitness buff for years, Ho makes time for the gym no matter which part of the world he is in. In fact, he usually hits the gym immediately upon arrival to all of his international destinations to beat jet lag, no matter what time of day it is. He’s also a very frequent flier. Each year, Ho racks up at least 200,000 miles, overseeing his research teams; giving national/international lectures on his group’s discoveries; working with collaborators in the U.S., Europe and Asia; meeting with current and potential collaborators from different fields and continents to exchange information and ideas; and supporting his wife Sarah whose work also takes them to exciting events and destinations in the world of fashion.
Ho and Sarah are contributors to many charitable initiatives, which have included causes as diverse as UCLA Unicamp, the official student philanthropy of UCLA and California camp for children from low-income families; Habitat for Humanity; and others.
Like Ho, his father, Professor Chih-Ming Ho, built an internationally recognized career as a world leader in the field of microfluidics for applications in biology and medicine. He is currently the Ben Rich-Lockheed Martin Professor of Mechanical and Aerospace Engineering at UCLA and a member of the prestigious U.S. National Academy of Engineering. He has also directed many multi-institutional research centers funded by the NIH and NASA. Dr. and Mrs. Ho, an accomplished opera singer, distinguished community leader and community liaison for the Torrance Memorial Medical Center, and Sarah’s father and mother also live in the Los Angeles area.
Expect to hear more about Dean Ho’s SLAS-endowed nanodiamond research through SLAS annual conferences, scientific journals and the SLAS Electronic Laboratory Neighborhood (SLAS ELN).