Piercing the body with precision pg. 5
Many cancer cells express a high density of peripheral benzodiazepine receptors (PBRs), named for their ability to bind anti-anxiety drugs like Valium and Xanax. To PK-11195, another compound that binds tightly to PBR, Bornhop attaches fluorescing complexes of lanthanide chelates.
In animal studies, the injected marker shows unique, dual capabilities: Bornhop’s hybrid shows up in MRI scans, and its fluorescent tag can be observed through the microscope. If it works in humans, the surgeon could match the fluorescence seen during surgery to the pre-operative MRI.
While PBR targeting also may be useful in the treatment of other tumors, including those of the breast and colon, it alone may not be enough, Bornhop cautions. A “cocktail” of chemicals will probably be needed—especially to monitor how a tumor is responding to therapy.
One possible avenue: cell adhesion molecules, which play important roles in inflammation, cell migration, cell signaling—and cancer.
About a decade ago, Hallahan and his colleagues at the University of Chicago observed that the inner linings of tumor blood vessels sprouted these distinctive glycoproteins (carbohydrate-protein complexes) when zapped by a dose of radiation. He wondered how he could capitalize on this phenomenon.
After moving to Vanderbilt to chair the Department of Radiation Oncology in 1998, Hallahan assembled a diverse team that included Todd D. Giorgio, Ph.D., associate professor of Biomedical Engineering and Chemical Engineering.
The researchers began searching for fragments of proteins—short sequences of amino acids called peptides—that would hone in on tumor blood vessels.
Hallahan hoped the peptides would bind specifically to these radiation-induced markers inside tumor blood vessels. When tagged with radioisotopes, these tiny guided missiles could be used to monitor the effectiveness of drugs designed to shut down the tumor’s blood supply. They also could deliver their own toxic payloads.
The researchers found an amino-acid sequence—arginine–glycine–aspartic acid or RGD—that bound specifically to the markers.
In a preliminary feasibility study, they labeled the peptide with a gamma ray-emitting radioisotope, injected it into patients receiving high-dose radiation to treat metastatic brain tumors, and watched the tumors light up in images taken by a gamma camera. “This study shows that it is feasible to guide drugs to human neoplasms by use of radiation-guided peptides,” they reported in 2001.
Next, the researchers coated “nanoparticles” (about the size of a virus) with fibrinogen, a blood-clotting protein that contains the RGD sequence, tagged the particles with a radioisotope, injected them into tumor-bearing mice, and blasted the tumors with radiation. Not only did the blood vessels light up, but the fibrinogen coating apparently triggered clots to form inside the vessels, blocking blood flow and causing the tumors to shrink.