Fighting Cancer with Nanotechnology
By: Carol A. Rouzer, VICB Communications
Published: July 15, 2010
VICB investigators develop a nanoparticle-based tumor drug delivery system.
Anyone who has watched a friend or loved one undergo chemotherapy for cancer knows that often it seems that the “cure” is worse than the disease. This is because the overwhelming majority of cancer chemotherapeutic agents are toxic compounds intended to kill cancer cells. However, cancer cells are so similar to normal cells that the toxic effects usually extend to healthy tissues, leading to intolerable side effects such as nausea and vomiting, bleeding, susceptibility to infections, and hair loss. In fact, the side effects ultimately limit our ability to use these drugs to their full potential.
Figure 1. Nanotechnology has led to the development of a wide range of new materials with a diverse array of sizes, shapes, and chemical compositions. These materials are finding their way into all aspects of modern life, including drug development. Image is from the Open Source Handbook of Nanoscience and Nanotechnology h t t p : / /en.wikibooks.org/wiki/Nanotechnology and was obtained courtesy of Wikimedia Commons under the GNU Free Documentation License.
Recent advances in cancer research have led to the development of new drugs that are more selectively toxic to cancer cells. Such drugs have shown great promise for treating a small number of cancers. However, each kind of cancer is different, and even cancers arising in the same tissue or organ show considerable heterogeneity from patient to patient. As a result, these targeted therapies usually have a limited applicability. An alternative approach is to develop ways to deliver conventional chemotherapeutic agents directly to a tumor, thus avoiding damage to normal cells. The explosion of new opportunities offered by nanotechnology provides novel ways to achieve this goal. Now VICB member Eva Harth, in collaboration with the Dennis Hallahan laboratory, has developed a new nanoparticle-based drug delivery system designed to be used in conjunction with radiation therapy to target a drug directly to a tumor [Passarella et al. (2010) Cancer Research, 70, 4550].
The innovative drug delivery system was based on a discovery by the Hallahan lab that treatment of gliomas (a form of brain tumor) with radiation therapy leads to increased expression of a protein called GRP78 both in the glioma tumor cells and in the surrounding blood vessels. In conjunction with this discovery, the Hallahan lab found that a six amino acid peptide designated GIRLRG binds selectively to the GRP78 protein. Studies of gliomas and breast cancer cells grown in vitro and in vivo showed the high level of GRP78 and GIRLRG binding only after radiation exposure and only when blood vessel cells were also present. These results suggested that the GIRLRG peptide combined with radiation could be used to target a drug directly to a tumor.
Figure 2. Nanoparticle formation starts with polyester chains (blue) cross-linked (red) to form spherical particles (right) containing chemical groups to which the GIRLGR peptide can be attached.
The Harth lab coupled these findings with their expertise in designing nanoparticles to devise the specialized drug delivery system. They started with a polyester polymer which they crosslinked to form nanoparticles of the optimal size to prevent excessive clearance by the liver or spleen while allowing a reasonable rate of degradation to avoid toxicity (Figure 2 above). The cross-linked structure also provided a framework to encapsulate a drug and allow its slow delivery to a target cell. The polyester polymer chosen by the Harth lab provided multiple sites to chemically link the GIRLRG peptide so that each nanoparticle was decorated with approximately 37 peptides on its surface (Figure 3 below). Incubating the nanoparticles with the anticancer drug paclitaxel trapped the drug inside of the particles. The particles were then ready for administration to an irradiated tumor (Figure 4 below).
Figure 3. Simplified model of how the Gβγ subunit of G-proteins may promote Wnt signaling. Activation of Frizzled by Wnt binding leads, in turn, to activation of the Gprotein and binding of the Gβγ subunit at the cell membrane. In turn, Gβγ binds GSK3, recruiting it to the receptor complex and removing it from the destruction complex. GSK3 transfers phosphate groups to LRP6, which, along with Wnt binding promotes its activity
Figure 4. Cut away view of the completed particle showing polyester chains (blue) cross links (red), peptides (orange) and paclitaxel (yellow).
In vivo studies showed that the peptide-coated nanoparticles delivered paclitaxel to both glioma and breast tumors with higher efficiency than conventional systemic adminstration of paclitaxel. Concentrations of the drug reached higher levels and remained in the tumors longer when delivered by the nanoparticles. Furthermore, the nanoparticle-treated tumors showed in-creased cell death when compared to tumors treated with radiation alone, or radiation plus paclitaxel administered in the conventional way. As expected, the nanoparticles achieved these results only if the tumors had been irradiated.
In vivo treatment of irradiated tumors with th paclitaxel-containing peptide-linked nanoparticles resulted in marked decrease in tumor growth rate as compared to radiation alone or radiation plus conventional paclitaxel therapy. Together these results suggest that GIRKGRlinked nanoparticles, combined with radiation therapy, hold great promise as a tumor-specific drug delivery system with the potential for use in a wide range of tumors.