Pumping in cancer drugs

In In The News by Barbara Jacoby

Thumbnail for 8309By Bradley J. Fikes

From: utsandiego.com

Researchers have invented a microscopic pump that has the potential to transport cancer drugs from the blood into the heart of tumors, according to a new study.

The pump is created from an engineered antibody that attaches to a protein found in microscopic pouches lining the walls of blood vessels in mouse, rat and human tumors. Substances attached to this antibody are transported from the blood through the vessel wall into the tumor’s interior.

The study provides a proof of concept that the pump works in lung, mammary and prostate tumors. Next, more animal studies must be performed testing that the technology is therapeutically useful in animals — and eventually in people, said lead researcher Jan Schnitzer of the Proteogenomics Research Institute for Systems Medicine in San Diego.

The study was published Aug. 17 in the journal Nature Medicine. The first author is Phil Oh.

If the technology works, it would solve one of the biggest problems in cancer drug therapy: how to get a drug into the tumor at a high enough dose without harming normal cells.

Most cancer medications are injected into the blood, where they penetrate the tumor by diffusion. This is inefficient, Schnitzer said, and maximum levels of the drugs may actually be higher outside the tumor than inside it. But if the drug can be delivered more efficiently, lower doses can be given, reducing side effects while increasing toxicity to tumor cells.

The molecular pump should work with a vast range of medications, from small molecules to large ones such as antibodies like the breast cancer drug Herceptin, Schnitzer said.

The pump is able to push attached fluorescent substances through the pouches, called caveolae, into tumors at a concentration more than 100 times greater than what’s typically in the bloodstream, Schnitzer said.

“It is truly an active transport mechanism,” he said. “To be active, it has got to move the molecules from one side of a barrier to another against the concentration gradient. We could visualize and quantify this directly for the first time in tumors using a special microscope.”

Videos showing the pump in action are embedded in the paper’s online version.

The study tested the antibody’s activity with two imaging technologies, Schnitzer said.

The antibody was attached to gold nanoparticles, and then tissues infused with the combination were examined by electron microscopy. The gold, being dense, blocked the electrons much like lead blocks X-rays, Schnitzer said. It was found in the caveolae, indicating that the antibody reached its target.

In the other test, the antibody was linked with a fluorescent agent. Upon infusion, the agent quickly accumulated into the tumors. The differential between concentration levels in the blood and the tumor exceeded the imaging detector’s 256-fold range, Schnitzer said.

“Tumor fluorescence increased within minutes and grew steadily until about 30 minutes after injection, when the overall rate of delivery increased substantially,” the study said.

Researchers who read the paper said its findings are significant.

“It is a very novel and interesting approach and has great potential for drug delivery and hence outcome of the disease,” said scientist Inder Verma at the Salk Institute for Biological Studies in La Jolla.

Clark Chen, a UC San Diego neurosurgeon-scientist, said the dramatic increase in drug concentration inside tumors is especially impressive.

It should be possible to coat drug-delivering nanoparticles with the antibody and infuse these into the patients, Chen said.

“You could put your drug of choice inside the nanoparticles,” he added.

However, a lot of work needs to be done to translate this research finding into better cancer treatments, Chen said. More types of cancers need to be studied, and the potential for an immune reaction in people has to be addressed.