Molecular Missiles

A search-and-destroy molecular machine that selectively locks on to cancer cells could make radiation treatments a thing of the past, at least for breast cancers. A team of researchers from Caltech; Technion, the Israel Institute of Technology, in Haifa; and the Cedars-Sinai Medical Center in Los Angeles have joined forces to develop a potentially much less traumatic treatment.

The method uses a chemical payload called a gallium corrole, mated to a protein carrier that seeks out a cancer-cell marker. Once it binds to the cell, the protein triggers endocytosis, a process in which the cell engulfs the corrole-carrier combo.

Corroles are very similar to the porphyrin molecules used in a cancer treatment called photodynamic therapy, in which they are injected into the body and activated by a laser. This prompts the porphyrins to produce highly reactive, tumor-killing oxygen radicals. But some corroles don’t require a laser boost to turn lethal, says Harry Gray, the Beckman Professor of Chemistry. “The striking thing about gallium corroles is that they apparently kill cancer cells in the dark,” says Gray. “We don’t yet know exactly how this works, but what we’ve seen so far tells us that it does work.”

The team paired the gallium corrole with a carrier protein that binds to human epidermal growth factor receptor 2, or HER2, which is found on about 25 percent of breast-cancer tumor cells and marks them as particularly aggressive and difficult to treat. Preparing this cancer fighter is a breeze—the corrole-carrier pairs spontaneously self-assemble in the test tube.

In trials in mice, the corrole was able to shrink tumors at doses five times lower than doxorubicin, the standard chemotherapeutic agent for HER2-positive tumors. Doxorubicin has to be injected directly into the tumor, because at high doses the drug can cause heart damage. This, of course, also means that you need to be able to actually see the tumor. By contrast, the corrole was simply injected into the bloodstream, where it circulated freely and could hunt down nascent metastatic tumors too small to be seen.

Gallium corroles fluoresce intensely when zapped with a laser, and Gray’s lab has been using them for many years to study electron transfer mechanisms. The new application resulted from trying to use the corroles as tracers to track the carrier protein’s journey through the body. “We were amazed to see that the tracer itself was killing the tumors,” says Gray.

The difficulty in getting to this point, notes Gray, is that corroles were tough to synthesize—until coauthor and Caltech visitor in chemistry Zeev Gross of Technion figured out how to make them in what passes for bulk in a biochemistry lab. “We went from being able to make a couple of milligrams in two years to being able to make two grams in less than a week. It really puts corroles on the map.”

The work appeared in the April 14 online edition of the Proceedings of the National Academy of Sciences. The paper’s lead author is Hasmik Agadjanian of Cedars-Sinai; the other authors are Jun Ma, Altan Rentsendorj, Vinod Valluripalli, Jae Youn Hwang of Cedars-Sinai; Atif Mahammed from Technion; Daniel Farkas, director of Cedar-Sinai’s Minimally Invasive Surgical Technologies Institute; Gray; Gross; and Lali Medina-Kauwe, who holds a joint appointment at the David Geffen School of Medicine at UCLA and Cedars-Sinai.

The work was supported by grants from the National Science Foundation, the National Institutes of Health, the U.S. Department of Defense, Susan G. Komen for the Cure, the Donna and Jesse Garber Award, the Gurwin Foundation, the United States–Israel Binational Science Foundation, and by the U.S. Navy Bureau of Medicine and Surgery. —LO