Yale-New Haven Children's Hospital
Convection-Enhanced Delivery of Drug-Loaded Nanoparticles
for Treatment of Brain Tumors in Children
Brain tumors are the second leading cause of cancer death in children, and new treatments are desparately needed. Surgery is not appropriate for many children with brain tumors, particularly when the tumor is in the brainstem. Additionally, the effectiveness of chemotherapy is limited due to the blood-brain barrier. To address the critical for better treatments, an interdisciplinary group of bioengineers, physicians, and surgeons at Yale is working to develop new methods for safe and effective delivery of drugs in the brain. Outcomes from this research will provide new options for the treatment of brain tumors in children.
Although the blood-brain barrier usually limits the effectiveness of chemotherapy in pediatric brain tumors, it is now known that drugs can be delivered locally—directly into the brain, beyond the blood-brain barrier. In adults, this is accomplished with a dime-size degradable wafer (Gliadel®) that is placed in the tumor resection bed during surgery. Gliadel® slowly releases the drug for several weeks after placement in the brain. But Gliadel® has limitations. It requires surgical placement. Further, because it relies on diffusion of an alkylating agent (BCNU) into the tissue as the wafers release the drug, high levels of active drug can be achieved only within a few millimeters of the wafer (Figure 1a).
Areas of tumor cell infiltration in the surrounding brain may be several centimeters from the wafer and the drugs cannot reach them. Another approach, called convection-enhanced delivery (CED), potentially solves these problems by using fluid flow—through carefully placed catheters—to carry drug molecules through the brain. CED has been tested in adult patients and is currently being tested in pediatric patients. So far, the approach has not been successful in adults. Part of the problem with this method is that the infusion of drugs dissolved in liquid, by CED, does not provide the necessary duration of exposure of the drugs to the tumors. (Figure 1b).
The research team at Yale recognizes these limitations and is creating improved methods for local therapy. The team uses specially designed nanoparticles that are loaded with high doses of chemotherapy drugs. These nanoparticles have special properties: they flow easily through the brain when administered by CED and slowly release the drugs once introduced into the brain. This allows for a treatment that is unprecedented: nanoparticles gain access to targeted regions of the brain, and they release chemotherapy into this precisely defined volume for days to weeks (Figure 1c).
The Yale team has already tested this approach successfully in human tumors in animals. Given that the nanoparticles are composed of a polymer that is already approved by the FDA for human use, this approach has the potential to be rapidly adopted into neurosurgical practice and could change the way that malignant brain tumors are treated in children. This approach is uniquely suited for the treatment of pediatric tumors because it allows the placement of long-lasting, drug-releasing particles (minus surgery)
directly into the regions of the brain where the active drugs are needed.
The Yale research team includes surgeons, oncologists, and engineers, and each team member shares the common goal of producing new therapies for pediatric brain tumors. Team member Dr. Mark Saltzman, Goizueta Foundation Professor of Biomedical Engineering, Chemical & Environmental Engineering & Physiology, was a Program Leader on the research team that developed Gliadel®. His long-time collaborator, Dr. Joseph Piepmeier, Section Chief for Surgical Neuro-oncology, is an expert on CED and clinical testing of this new approach, and joins him on this research effort