Artificial Cell Membranes Hold Promise for Medical Use

December 5, 1997

By Paul Preuss, [email protected]

Artificial cell membranes designed at Berkeley Lab have performed a variety of beneficial tricks in vitro, including detecting flu virus and blocking blood-vessel receptors that can trigger dangerous and painful swelling. Recently these lab-created cell membranes have moved out of the test tube and into their first in vivo test, where they have demonstrated significant blockage of inflammation in mice.

Jon Nagy with model

Jon Nagy with a computer model of an artificial liposome. Some glycoliposomes detect flu virus. Others can block inflammation.
Photo by Roy Kaltschmidt
Jon Nagy of the Life Sciences Division and his colleagues have built sets of self-assembling membranes that form spherical liposomes--shapes that may resemble the primitive precursors of living cells.

Nagy's work with artificial membranes began with flat films on solid supports when, with Mark Bednarski and Deborah Charych and other colleagues in the Lab's Materials Sciences Division, the researchers found that certain amphiphilic monomers (molecules with water-seeking and water-avoiding ends) form thin films of lipids which link together under exposure to ultraviolet light; the resulting thin-film polymer, polydiacetylene, has a deep blue color.

Sugars can be attached to the lipids to form glycolipids; the thin-film polymer becomes decorated with randomly spaced carbohydrates. Tailored glycolipids eagerly bind to specific proteins, including the coat proteins of influenza virus--and in the process the films turn pink, making for a quick diagnostic test of the presence of the disease agent.

Says Nagy, "After a year of working with glycolipid films, we found we could form nanosized glycoliposomes (particles measured in billionths of a meter) which change color in solution, not just on a solid support. And the color change is much more intense." In the case of influenza, "the viruses are really adhering tightly, as if we'd fooled them into thinking our liposomes were real cells."

Natural sialic acids on cell surfaces can be degraded by a flu-virus enzyme; the degradation process seems to be important in allowing flu-virus replicants to escape infected cells. But the carbohydrate used in the flu-detecting artificial liposomes is a form of sialic acid which cannot be easily degraded. Thus it may be possible to develop a therapeutic use for these liposomes--by incorporating them in nasal sprays, for example, which could soak up the virus and stop the spread of the infection.

Nagy started thinking about what other biological systems might be fooled by artificial cell membranes. Of several promising avenues of research, he chose to work first on anti-inflammatory agents.

When triggered by injury or infection, the delicate lining of blood vessels produces receptors for specific sugars found on the membranes of some white blood cells, called neutrophils, which rush to sites of infection and injury. Although essential to the body's defenses, excess white blood cells in the wrong place--or adhering to tissue at the wrong time--are implicated in rheumatoid arthritis, septic shock, and injuries that can follow clamping of blood vessels during surgery. A method of controlling neutrophil adhesion to the blood-vessel lining, the epithelium, could alleviate pain and tissue destruction--and in some cases save lives.

Even when not clustered in a matrix, some sugars bind weakly to epithelial receptors and thus partially interfere with neutrophil binding--but the same sugars incorporated into the polymerized membranes of artificial liposomes promise to be far more potent at preventing neutrophils from attaching to blood vessel walls. As the "matrix" lipid of the new membranes, Nagy chose 10,12-pentacosadiynoic acid, more conveniently known as PDA.

Working with other scientists, Nagy coated glass tubes with the natural receptor, then rolled white blood cells down this "model blood vessel" while gradually introducing glycoliposomes. "The more liposomes we add, the faster the neutrophils roll, indicating that fewer and fewer can find a receptor that isn't already blocked."

"We call it the Velcro effect," says Nagy. "It's a mat of interconnections, thousands of individual sugars on the liposomes binding to thousands of epithelial receptors in a concentrated patch."

"It takes very little of the scientist's time to make a highly active assembly of glycoliposomes," Nagy explains, "because we don't have to engineer every step. The membranes assemble themselves--all we do is decide what ratios of components to add, form them into balls, and shine ultraviolet light on them. On each liposome, we are giving the target receptors a buffet of sugars and other chemicals to choose from; the receptors themselves recognize the important ligands. This approach is less than rational, more like evolution, but it gets precise results."

Very recent, preliminary results of in vivo tests with laboratory animals indicate that sugar-surfaced, polymerized artificial liposomes have the potential to be powerful anti-inflammation agents. "The results are exciting," says Nagy, "and put Berkeley Lab in an excellent position to work with pharmaceutical companies to develop this technology."

The "Velcro effect" with glycoliposomes may find use in other therapies: to block allergic responses in mucus membranes, for example, or to retard cancer metastasis. Artificial structures that can mimic behaviors of living organisms, long a chemist's dream, are making their mark in the real world.

Nagy's artificial liposomes are the subject of a current patent application; earlier in vitro results are detailed in the Oct. 19, 1997 issue of the Journal of Medicinal Chemistry.

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