Cancer is usually lethal after it spreads throughout the body (metastasizes). A method that helps to prevent cancer metastasis would increase the chances of survival for cancer patients. Proteins on the surface of cancer cells provide insight into how this goal may be achieved.
A protein, known as ανβ-3, is present in unusually large numbers in cancer cells that tend to metastasize. It is also one of many proteins that help molecules enter cancer cells. Using ανβ-3 proteins as a Trojan horse is therefore a potential method to (1) deliver drug molecules to cancer cells, killing them, and (2) to stop cancer from spreading.
A team of scientists led by David Cheresh at the University of California (San Diego) attacks cancer with a nanoparticle-based delivery system. Their nanoparticles bind to ανβ-3 proteins, deliver their cancer killing drug, and suppress renal and pancreatic cancer metastasis in mice. This delivery system has few of the typically nasty side effects commonly caused by cancer drugs.
The nanoparticles.
The nanoparticles possess both a cancer targeting component and a drug delivery system. The cancer targeting system is the cRGDfK peptide (cyclic arginine-glycine-alanine-(D-phenylalanine)-lysine), which is a molecule that binds to ανβ-3 proteins. The drug delivery system is the nanoparticles, which are lipid-based and 105 nm in diameter. The nanoparticles contain doxorubicin, a drug molecule commonly used to treat cancer.
The cRGDfK peptide enabled the nanoparticles to bind to cancer cells within 2 hours, exhibiting maximum binding within 5 hours. After the nanoparticles were bound to the cancer cells, they released their drug cargo locally, killing the cancer cells.
Selective and effective warriors.
It was important that this method kill cancer cells (the enemy), and not healthy cells (the good guys). When injected locally into mice, the nanoparticles targeted primarily cancer cells in the pancreas. Nanoparticles did not accumulate in healthy pancreatic cells.
What about other organs besides the pancreas? The kidney, liver, and lungs were targeted to a minimal extent, whereas the brain, heart, and spleen were not targeted at all. This demonstrates that the nanoparticles are selective for cancer cells in the pancreas.
How effective was the treatment in combating cancer? While the nanoparticles only reduced overall mice pancreatic tumor growth by 23%, they reduced metastasis (body-wide spreading) by 82%. More frequent treatment with nanoparticles was more impressive, reducing tumor growth by 43% and metastasis by 90%. The nanoparticles effectively hinder the spread of cancer.
Advantages beyond selective killing.
Using less of a drug over the course of treatment reduces unpleasant side effects of chemotherapy, and is highly desired by doctors and cancer patients. Only 1 mg/mL of doxorubicin in the nanoparticles was required for killing cancer, and the mice only lost less than 1% of their weight.
In contrast, 15 mg/mL of "free" doxorubicin (no nanoparticles) was required to kill cancer cells, such a large amount that the mice lost 18% of their weight. Similar results were observed for renal cancer.
Using anti-cancer nanoparticles in the clinic.
These nanoparticles largely prevent cancer cells from spreading throughout the body. Additionally, a lower concentration of drug molecules is required, preventing obvious side effects from showing up.
These attributes, along with the fact that the nanoparticles are biocompatible, make these nanoparticles attractive and realistic for safely and effectively combating aggressive strains of cancer. They have the attributes of a real future clinical treatment, well beyond a strictly academic setting.
for more information:
Murphy, E. A.; Majeti, B. K.; Barnes, L. A.; Makale, M.; Weis, S. M.;
Lutu-Fuga, K.; Wrasidlo, W.; Cheresh, D. A. Nanoparticle-mediated
drug delivery to tumor vasculature suppresses metastasis.
Proc. Natl. Acad. Sci. USA 2008, 105, 9343-9348.