Imagine treating cancerous tumors by filling tiny sponges with drugs, attaching special chemical “linkers” that bond to the surface of tumor cells, and then injecting these sponges into the body.
That’s the idea behind a nanosponge delivery system developed by Eva Harth, associate professor of chemistry at Vanderbilt. “Effective targeted drug-delivery systems have been a dream for a long time now, but it has been largely frustrated by the complex chemistry involved,” says Harth. “We have taken a significant step toward overcoming these obstacles.”
When loaded with an anticancer drug, the delivery system is three to five times more effective at reducing tumor growth than direct injection, reports a paper published in the June 1 issue of the journal Cancer Research.
The study was a collaboration between Harth’s laboratory and that of Dennis E. Hallahan, a former professor of radiation oncology at Vanderbilt who is now at the Washington University School of Medicine. Corresponding authors are Harth and Roberto Diaz at Emory University, who was working in the Hallahan laboratory when the studies were done.
The tiny sponges, about the size of a virus, circulate around the body until they encounter the surface of a tumor cell, where they stick to the surface (or are sucked into the cell) and begin releasing their potent cargo in a controllable and predictable fashion.
Targeted delivery systems of this type have several basic advantages. Because the drug is released at the tumor instead of circulating widely through the body, it should be more effective for a given dosage. It also should have fewer harmful side effects because smaller amounts of the drug come into contact with healthy tissue.
“We call the material nanosponge, but it is really more like a three-dimensional network or scaffold,” says Harth. The backbone is a long length of polyester. It is mixed in solution with small molecules called cross-linkers that act like tiny grappling hooks to fasten different parts of the polymer together. The net effect is to form spherically shaped particles filled with cavities where drug molecules can be stored. The polyester is biodegradable, so it breaks down gradually in the body. As it does, it releases the drug it is carrying in a predictable fashion.
Many other systems unload most of their drug cargo in a rapid and uncontrollable fashion, making it difficult to determine effective dosage levels.
Another major advantage is that the nanosponge particles are soluble in water. Encapsulating the anti-cancer drug in the nanosponge allows the use of hydrophobic drugs that do not dissolve readily in water. Currently, these drugs must be mixed with another chemical, called an adjuvant reagent, which reduces the efficacy of the drug and can have adverse side effects.
It is also possible to control the size of nanosponge particles. This is important because research has shown that drug-delivery systems work best when they are smaller than 100 nanometers, about the depth of the pits on the surface of a compact disc.The other major advantage of Harth’s system is the simple chemistry required. The researchers have developed simple, high-yield “click chemistry” methods for making the nanosponge particles and for attaching the linkers, which are made from peptides, relatively small biological molecules built by linking amino acids. “Many other drug-delivery systems require complicated chemistry that is difficult to scale up for commercial production,” Harth says.
The drug used for the animal studies was paclitaxel (the generic name of the drug Taxol). The researchers recorded the response of two different tumor types—slow-growing human breast cancer and fast-acting mouse glioma—to single injections. In both cases they found that it increased the death of cancer cells and delayed tumor growth “in a manner superior to known chemotherapy approaches.”
Additional Vanderbilt participants in the study were Ralph J. Passarella, Daniel E. Spratt, John G. Phillips, Hongmei Wu, Li Zhou, Alice E. van der Ende and Vasanth Sathiyakumar. The research was supported by grants from the U.S. Department of Defense, National Science Foundation, and National Institutes of Health.