DURHAM, N.C. -- Researchers at Duke University and Access Pharmaceutical Inc. of Dallas, Texas, are jointly devising microscopic beads that can dump drugs directly onto tumors by mimicking the way substances are secreted within cells.
"We've made essentially an artificial secretory granule," said David Needham, an associate professor of mechanical engineering and materials science who directs Duke's Cell and Microcarrier Engineering Research Facility.
"What you have is a drug delivery system that's like an exploding pill," added Patrick Kiser, a chemist with Access Pharmaceuticals who is currently studying for his Ph.D. under Needham.
Needham, Kiser and Glynn Wilson, Access Pharmaceuticals' vice president for research and development, have prepared a report on the work to be delivered by Kiser on Tuesday, April 15, during the American Chemical Society National Meeting in San Francisco.
In an interview at Duke, Needham and Kiser said their approach resembles the way large secretory molecules are encased within "granules" that bud from a cellular structure called the Golgi apparatus. These granules can later swell and secrete their contents on demand in response to a chemical signal.
In developing the patented technology, Access Pharmaceuticals researchers have in turn synthesized absorbent microscopic hydrogel beads that can take up and hold large concentrations of drugs.
Made of both natural and synthetic polymers, those beads have a very useful property for drug delivery. They will stay condensed and intact until they are exposed to the sodium in blood plasma. After encountering sodium, the beads will then swell and burst explosively, thereby releasing the entrapped drug.
If properly engineered, the microscopic beads could thus become like drug-filled cruise missiles that would roam the body until they encounter a tumor. In tests, the beads have already proven to be leak-proof carriers of doxorubicin, a potent anticancer drug.
"But if we just took those beads, loaded them with the drug and put them in the bloodstream, they would just immediately release the drug," Kiser noted.
So, working at Duke, he and Needham are also engineering ways to keep the beads from bursting prematurely.
Their method is to surround the beads with protective double-layered coatings or capsules composed of lipids, the same materials that make up cell membranes and secretory granules. These "bilayer" shells serve to insulate the beads from sodium-rich blood plasma for as long as the lipid covering stays intact.
To trigger the erosion of the lipid coating, the chemistry of the bilayer could be primed to react to "some aspect of the disease site," Kiser said. Pores could also be made to open in response to high pitched sound waves -- ultrasound -- beamed into the body through the skin, both added.
Needham has also investigated another delivery system using artificial lipid capsules known as "liposomes." Smaller than red blood cells, liposomes can also be filled with drugs and are tiny enough to penetrate small blood capillaries that keep tumors nourished.
Studies at Duke medical center have shown that, after reinforcement with other chemicals, liposome bilayers can remain intact for several days after injection into the bloodstream. That's long enough for large numbers of doxorubicin-filled liposomes to migrate to a tumor site and accumulate there, Needham said.
But a big problem remains: After 27 years of investigation, no one has found a way to make liposomes release a drug reliably just when and where it's needed. "It will leak out slowly," Kiser said. "But to get a lot of release quickly is tough."
So Needham and Kiser are working on strategies that would combine the best of both techniques to overcome that problem.
Because it carries an electric charge that varies with acidity or alkalinity -- chemists call that "pH" -- Access Pharmaceuticals' hydrogel bead can be made to both attract an oppositely charged drug and repel a like-charged lipid shell.
If the pH of its surroundings is properly manipulated, the bead can be made to take up as much as 200 percent of its own weight in drug. Protected with a lipid bilayer shell, the drug-loaded bead can then patrol the bloodstream.
When it is time to expel its drug, the bead can also engineer the quick and thorough destruction of its surrounding shell if it and the lipid's chemistries have been tailored to carry the same charge.
Since like charges repel, all the bead has to do is swell up until it touches the bilayer. "When the bead swells, the bilayer is now repulsed by the bead," Needham said. "Then the bilayer rolls into little blocks. You can actually disassociate the coating from the bead."
Once the bead swells and breaks, the drug can be expelled with a pressure as high as 12 atmospheres.
Meanwhile, Needham recently filed for a patent on a technique that uses a combination of chemicals to better protect lipid bilayers from damage. That damage can be caused by contents of both the blood on the outside and the drug cargo on the inside, he said.
Needham's lipid biotechnology research is supported by the National Institutes of Health, and Access Pharmaceuticals is sponsoring Kiser's Ph.D. studies at Duke. "Patrick represents a new type of graduate student," Needham said. "This is a new kind of interaction with a company that could be a paradigm for working with industry."