Tiny "Nanobee" Particles Deliver Cell-Killing Bee Toxin to Tumors in Mice
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Melittin is a small, toxic protein found in the venom of honeybees. It creates holes in cell membranes, resulting in cell death. Because of this cell-killing ability, cancer researchers have been interested in using melittin for cancer therapy. An important feature of melittin is that cancer cells are unlikely to develop resistance to it, as they do with many anticancer drugs, because it is difficult for them to find a way around the mechanism that this toxin uses to kill cells.
Because melittin can kill any cell it comes in contact with, researchers needed to find a way to deliver it selectively to cancerous tissue. A research team funded in part by the National Cancer Institute attached melittin to the surface of spherical nanoparticles measuring just a few millionths of an inch in diameter (or around 100 nanometers) that they made in the laboratory. Particles of this size are known to concentrate in solid tumors because of the "enhanced permeability and retention effect," or EPR. EPR is caused by the greater leakiness of blood vessels in the vicinity of the tumor, which allows substances such as nanoparticles to escape more readily from the bloodstream into nearby tissues, and the generally poor drainage of lymph from tumors, which helps trap substances in tumor tissue.
The researchers tested the effectiveness of these "nanobees," as they referred to the mellitin-carrying nanoparticles, against human breast cancer tumors implanted in mice that had defective immune systems. They found that tumor growth was reduced by approximately 25 percent in mice injected with the nanobees compared with tumor growth in control animals. In another experiment, they tested the nanobees against mouse melanoma tumors implanted in mice that had normal immune systems. In this case, tumor growth was reduced by 87 percent compared to tumor growth in control animals. The researchers attributed this increased effectiveness in immunocompetent mice to the important role that the immune system plays in the process of tumor regression. The treated mice did not show any signs of organ damage and had normal red blood cell counts. If enough melittin to kill tumor cells had been injected by itself into the bloodstream of mice, the animals would have died from widespread destruction of their red blood cells.
The researchers next investigated whether nanobees could be targeted more specifically to tumors and used to treat early-stage tumors or precancerous lesions. To create more-targeted nanobees, they added another type of molecule to the nanoparticle surface: one that binds specifically to a protein called integrin alpha-v beta-3, which is located on the surface of endothelial cells in growing blood vessels. Similar to established tumors, early-stage tumors and precancerous lesions entering a more aggressive phase are rich in growing blood vessels. Injection of the targeted nanobees into mice with precancerous skin lesions undergoing extensive new blood vessel growth led to an 80 percent reduction in the number of precancerous lesions compared with the number of lesions on the skin of control mice. Once again, the treated mice showed no signs of organ damage or of damage to red blood cells.
Together, these results show that nanobees can be used to safely deliver a toxic dose of melittin to tumors and precancerous lesions in mice. Nanobees are large enough to carry thousands of melittin molecules but small enough to travel through the bloodstream and deliver their poisonous payload to cancer cells. In addition, the melittin attached to nanoparticles is protected from protein-destroying enzymes in blood and, thus, stays in the bloodstream long enough to find and attack tumors.
The researchers note that this type of nanoparticle could be used to deliver other cell-killing substances to tumors, as well as imaging agents that would allow the monitoring of treatments. In addition, nanobees could potentially be designed to target specific tumor types and might ultimately be formulated for individual patients. Additional studies are needed before human trials of nanobees can be considered, including safety testing and determining the best way to target them to human tumor tissues.
Reference: Soman NR, Baldwin SL, Hu G, et al. Molecularly targeted nanocarriers deliver the cytolytic peptide melittin specifically to tumor cells in mice, reducing tumor growth. Journal of Clinical Investigation 2009; 119(9): 2830-2842.
More summaries of selected scientific advances from NCI-supported research are available at http://www.cancer.gov/aboutnci/servingpeople/advances.