Engineering Hope in the Fight Against Brain Cancer
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Matthew Dowling is designing targeted, nanoparticle drug delivery systems to battle brain cancer. |
Brain cancer is one of the most devastating diagnoses a person or family can receive. Bioengineering doctoral candidate Matt Dowling is using new methods to attack an illness for which there have been few other treatment options than surgery and radiation, and for which there is a high rate of reoccurrence. His proposal, "Gelatin Nanoparticles Containing Stabilized Vesicles: A Novel Chemotherapuetic Delivery System for Treatment of Malignant Glioma," earned him the 2005 Fischell Fellowship in Biomedical Engineering.
Trying to tackle a particular cancer provides Dowling with motivation and focus. The brain creates a very specific environmental challenge, and influences the design of his solution. If he is successful, however, others could build on and adapt his methods to other situations and treatments.
Dowling's research centers around vesicles, nanocontainers which form spontaneously in aqueous environments, encapsulating other molecules in their hollow centers. Our bodies use them to route nutrients, metabolites and chemical signals within and between cells. For this reason, scientists have been interested in their potential use as vehicles for targeted drug delivery—the ability to load the vesicles with the appropriate medication, and control where, when and how that medication is released.
Unfortunately, vesicles produced in the laboratory tend to be quickly targeted and "captured" by the macrophages in our immune system when injected into the bloodstream, greatly limiting their ability to reach their destinations. They are also unstable structures. Previous research has found the vesicles can be stabilized and spend more time in the bloodstream by coating their surface with a synthetic polymer known as polyethylene glycol (PEG). To combat glioma, however, Dowling is instead encasing the vesicles in gelatin nanoparticles, a natural polymer.
This is because gelatin nanoparticles have a rare advantage: they are one of the few that can traverse the blood-brain barrier, a tight seal which keeps toxins (including things perceived as toxins, like drugs) out of the brain, and only allows the passage of oxygen and nutrients. "The idea behind my proposal, says Dowling, "is to further explore the use of gelatin nanoparticles in treatment of brain cancer while adding a significant twist to the strategy: instead of just using the gelatin to carry the drug, it will also be a camouflage which allows a much more versatile drug container, the vesicle, to get into the brain tissue from the blood stream. This could result in an injectable form of therapy for malignant glioma, which would be immensely preferable over brain surgery."
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A chitosan "mothership" capsule (light blue) attaches and delivers drug-filled vesicles (dark blue) to a tumor. This capsule may be targeted to tumor cells either by antibodies (the Y- shaped spines) on its outer surface or by magnetic nanoparticles (dark red) inside. These two targeting systems effectively act as navigators, taking the capsules "along for the ride" to precise locations where the drugs are needed. |
Currently, Dowling is working with cell cultures, studying the conditions under which nanoparticle uptake occurs, and he is also experimenting with what he calls "mothership microcapsules" made out of another natural polymer, chitosan. Like their gelatin counterparts, the chitosan capsules protect the drug-carrying vesicles, but on a much larger scale: one "mothership" microcapsule may contain hundreds of vesicles. If ferromagnetic nanoparticles are added to the chitosan-vesicle mix during capsule formation, Dowling has found, they can then be guided to specific locations in the body with an electromagnetic field. He has also shown that the surface of his microcapsules can easily be joined with antibodies—immune system proteins whose mission is to target and evict specific threats, like viruses; or in this case, cancer cells. This combination may further increase the tumor-targeting capabilities of his drug delivery system. Future work will include translating this system down to the nanoscale and testing its ability to cross the blood-brain barrier.
Dowling is advised by Associate Professor Srinivasa R. Raghavan (Chemical and Biomolecular Engineering). He divides his time between Raghavan's Complex Fluids & Nanomaterials Group in College Park, and the Center for Nanomedicine and Cellular Delivery, part of the University of Maryland-Baltimore (UMB) School of Pharmacy, where does biological evaluations of his materials. Being able to work with the School of Pharmacy on these tests, he says, provides "a unique advantage" to his research.
During his undergraduate studies, Dowling, a chemical engineering major, became interested in bioengineering projects that would address a human need—and he felt his academic background provided the right foundation on which to build new and soundly-designed solutions to medical problems. Being able to help people in need of treatment for a difficult illness, he says, held an appeal for him far stronger than the traditional industrial applications of chemical engineering. He senior year was "almost pre-med" as he prepared for the next phase of his education, taking courses in biology, cell biology, and bioprocess engineering.
Dowling was drawn to the Clark School to continue his studies because of its grounding in society. "The Clark School has collaborations you don't find anywhere else," he says, "with industry, the [UM] medical school, the [UM] pharmacy school, NIST, NIH, and the [Robert H. Smith School of] Business...It's unique. The Fischell Fellowship embodies that—it makes things real and viable as opposed to academics for academics' sake—a lot of universities wouldn't be able to support what we do here. We have really good professors who not only have a sense of research, but also know what’s going on in industry—a lot of them are plugged into what's going on. You're also able to do consulting for real businesses as part of your graduate studies."
Dowling was one of the guest speakers at the ceremony to honor the Fischell family for their $31 million gift to the Clark School, which was used to establish the Fischell Department of Bioengineering. He had the opportunity to meet Dr. Robert Fischell at the event. "He's a really inspiring guy," Dowling says of him. "Someone described him as a 'human dynamo', and he is....I think one of the most important things about him is that he has a really positive, can-do attitude....He's got the same motivations I do—he really wants to help people with his smarts. At the ceremony he said helping people is the most rewarding thing—and seeing someone become healthy because of something you've done is not worth any amount of money."
For more information about Matt Dowling and his research:
"WJZ Covers New Chitosan Blood Clotting Product" »
UM $50K Business Plan Competition Winners Announced »
For more information about vesicle-oriented research at the Clark School:
"Tiny Containers That Make and Pack Themselves" »
An overview of vesicle research for everyone.
The Complex Fluids and Nanomaterials Group web site »
Information about Dr. Raghavan's lab, current research, and publications. The site also features movies of vesicles, liquid crystals, and hydrogels in action.
