"Effective targeted drug delivery systems have been a dream for a long time now, but it has been largely frustrated by the complex chemistry that is involved," says Eva Harth of Vanderbilt, who led the nanosponge development team. "We have taken a significant step toward overcoming these obstacles." The current study was a collaboration between Harth's laboratory and that of Dennis Hallahan at the Washington University School of Medicine and Roberto Diaz at Emory University.
"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.
"Predictable release is one of the major advantages of this system compared to other nanoparticle delivery systems under development," says Harth. When they reach their target, many other systems unload most of their drug in a rapid and uncontrollable fashion. This is called the burst effect and makes 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. By varying the proportion of cross-linker to polymer, the nanosponge particles can be made larger or smaller. This is important because research has shown that drug delivery systems work best when they are smaller than 100 nanometers. The nanosponge particles used in the current study were 50 nanometers in size.
The targeting peptide used in the animal studies was developed by the Hallahan laboratory, which also tested the system's effectiveness in tumor-bearing mice. The peptide used in the study is one that selectively binds to a protein found on tumors that have been treated with radiation. The researchers used the nanoparticles to deliver paclitaxel to tumors in this study. 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."
The next step is to perform an experiment with repeated injections to see if the nanosponge system can stop and reverse tumor growth. Harth is also planning to perform the more comprehensive toxicity studies on her nanoparticle delivery system that are required before it can be used in clinical trials.