January 9, 2006
Ultrasound Activates Nanoparticle Drug Delivery
Targeted nanoparticles, which bind to molecules found only on the surfaces of tumor cells, have shown tremendous promise for increasing the effectiveness of anticancer agents while reducing the potential for side effects. Now, investigators at Washington University School of Medicine have taken targeting one step further by using ultrasound to increase the efficiency with which that targeted nanoparticles deliver drugs into cells.
Reporting its work in the journal Ultrasound in Medicine and Biology, a team headed by Samuel Wickline, M.D., and Gregory Lanza, M.D., conducted its experiments using the liquid perfluorocarbon nanoparticles that it has been developing as targeted cancer drug delivery agents over the past several years. At least one such formulation is on track to begin human clinical trials within the next year or so. The investigators also used commercially available diagnostic ultrasound equipment, the same gear that obstetricians use today to generate sonograms of a developing fetus, to generate focused ultrasonic energy designed to enhance drug delivery.
In these experiments, the nanoparticles were constructed to display a molecule that binds specifically to a protein known as v3 (pronounced alpha-v-beta-three), which is found on the surface of certain types of cancer cells, including melanoma cells. The investigators loaded the nanoparticles with a fluorescent dye, rather than an anticancer drug, to follow the fate of the nanoparticles and their cargo when mixed with melanoma cells growing in culture.
After mixing the nanoparticles with cultured melanoma cells, the investigators applied ultrasonic energy for five minutes. Using a fluorescence microscope, the researchers observed that the cells subject to ultrasound took up approximately 10 times more of the fluorescent dye than when no ultrasound is applied. Indeed, the researchers obtained images of the dye streaming into the cell’s plasma membrane and on into the cytoplasm. Control experiments using ultrasound energy and no nanoparticles showed that cells were not damaged by the application of ultrasonic energy for five minutes.
The researchers note that these results support the hypothesis that ultrasound enhances the exchange of molecules between the fat-soluble nanoparticle components and the lipids (fatty molecules) that make up the cell membrane. They also comment in their paper that enhanced, nanoparticle-aided drug delivery using widely available ultrasound equipment could markedly improve the safety of cancer therapy while reducing the amount of drug used and lowering the cost of therapy.
This work, funded in part by the National Cancer Institute, is detailed in a paper titled, “Sonic activation of molecularly-targeted nanoparticles accelerates transmembrane lipid delivery to cancer cells through contact-mediated mechanisms: Implications for enhanced local drug delivery.” Dr. Wickline is the director of the Siteman Center of Cancer Nanotechnology Excellence. An abstract of this paper is available through PubMed.