Cancer cells can be reprogrammed by DNA, siRNA, and miRNA, if only these nucleic acids could cross through the cell membrane. A new study shows that cholesterol rafts can deliver genetic payloads into cancer cells.
“There are many promising therapeutic applications for nucleic acids, but because they can’t diffuse across cell membranes on their own, delivery to cancer cells has been a major challenge. Our method is a promising way to get these drugs inside cancer cells where they can do their work,” said Tom Anchordoquy, PhD, investigator at the University of Colorado Cancer Center in Denver and professor at the Skaggs School of Pharmacy and Pharmaceutical Sciences. This study was published in Therapeutic Delivery (2013;4:453-462).
The technology works by exploiting a relatively new understanding of what cell membranes look like. “It used to be that we thought about membrane proteins floating around in a disorganized two-dimensional soup. Now we know that different functions are clustered into domains we call rafts,” Anchordoquy said. Imagine these rafts like continents of the Earth, each presenting its own plant species. Perhaps a raft with palm trees but not spruce unlocks passage into a cancer cell?
Anchordoquy and colleagues are not the first to imagine particle-payload delivery systems, but when you engineer and introduce a nonrafted particle into the blood, it quickly becomes coated with blood proteins that can cover the membrane proteins (“palm trees”) needed to unlock passage into cancer cells. However, blood proteins do not bind to rafts and so particles with rafts continue to present the engineered bits rather than being silted over by the body’s proteins. Anchordoquy and colleagues make these rafts by boosting the concentration of cholesterol while forming particles for drug delivery.
“See, rafts are made of 30% to 50% cholesterol, about five times the level in the surrounding lipid. We’d shown in earlier experiments that rafts create more delivery of payload materials into cancer cells, but there was always the outside chance that the benefit was due simply to higher levels of cholesterol and not to the action of the rafts themselves,” Anchordoquy said.
The current study found an elegant fix: with longer tails on lipid molecules, particles will form rafts at lower cholesterol concentrations. The team used long-tailed lipids to form their particles, allowing them to keep cholesterol concentration low while showing the same benefit in delivering genes into cancer cells. This demonstrates that it is indeed the raft that facilitates delivery.
“We’ve used these synthetic rafts to deliver a gene inside these cells that makes the cells fluoresce,” Anchordoquy said. “That way we can see how much payload went in. But because we’re talking particles and not just individual molecules, in the future we can send other cargo like microRNAs that can reprogram a cell’s gene expression.”