Manipulating brain's protective barricade can help researchers

Neuroradiologists understand that high-grade tumors interrupt the blood-brain barrier, which presents as contrast enhancement on CT and MRI. Renewed interest in the phenomenon of permeability, however, has researchers looking beyond simple contrast enhancement and toward molecular mechanisms involved in permeability that may help them treat brain tumors more effectively.

"The key point of dynamic contrast-enhanced MRI is not just seeing blood-brain barrier changes, which is what we do every day when we look at postgadolinium images," said Dr. A. Greg Sorensen, director of the Center for Biomarkers in Imaging at Massachusetts General Hospital. "The key is the ability to quantify these changes in response to a therapy that might have a subtle effect."

Duke University researchers noted the most effective imaging techniques used to assess permeability and the strategies required to manipulate it (AJR 2005;185:763-767). Changes in permeability may serve as a surrogate marker for angiogenesis, signaling whether a particular therapy designed to shut down vascular growth is working, according to lead author Dr. James M. Provenzale, a professor of radiology at Duke. Familiarity with the molecular mechanisms behind permeability would aid in understanding how therapeutic agents enter the brain. Researchers could then increase permeability to enhance therapy.

"Manipulation of the blood-brain barrier may provide a means for selectively targeting tumors for drug delivery," Provenzale said.

Liposomes can be engineered for size, chemical affinity, and thermal sensitivity to optimize target-specific delivery of chemotherapeutic agents. The temperature sensitivity of liposomes raises interesting therapeutic possibilities, according to Provenzale. Physicians could apply heat to brain tumors after IV infusion of heat-sensitive liposomes. The ensuing hyperthermia would both increase permeability of the liposomes across the blood-brain barrier and act to promote release of liposome-borne therapeutic agents into the tumor.

Many therapeutic agents used to treat tumors show efficacy in vitro, but they typically fail when applied in vivo. Strategies that increase drug permeability sometimes permit nonselective opening of the blood-brain barrier, allowing substances to cross into normal brain tissue. Researchers note, however, that receptor-mediated agents such as bradykinin can increase permeability at the tumor site.

The Duke team pointed to a small study of patients with rectal cancer treated with a monoclonal vascular endothelial growth factor (VEGF) antibody. Patients showed a decrease in vascular permeability gauged by a decrease in tumor interstitial fluid pressure. Provenzale suggested that intracranial tumor permeability may be a surrogate marker as well for assessing effectiveness of VEGF antibodies in the brain.

T1-weighted dynamic contrast-enhanced MR is the most common imaging technique to assess leaks in the blood-brain barrier. It takes advantage of the abnormally leaky blood vessels of brain tumors, which allow gadolinium to permeate into the interstitial tissues around blood vessels. Neuroradiologists must determine if the contrast perfusion is due to increased blood volume in vessels, increased permeability, or both. Certain therapies may affect blood volume more than permeability, or vice versa. If researchers can quantify changes in blood volume and permeability, they may be able to better measure whether a tumor is responding to treatment, Provenzale said.

Many researchers choose to use a 3D spoiled gradient acquisition steady-state technique, which monitors gadolinium over several minutes, rather than observing the first-pass phenomenon such as in T2*-weighted imaging methods, according to the study. Because temporal resolution is low, investigators have used different analysis methods, such as calculating the T1 values before infusion of contrast material.