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Water Runs Through It

Before she was a pharmacologist,Terry Allen was an oceanographer. And while the world's great salt waters continue to have a fascination for her, she is also interested in a microscopic world in which she cloaks tiny packets of medication in water to sneak them past the body's defence systems.

Allen a professor of pharmacology has developed a patented "stealth" technology for the delivery of anti-cancer drugs. The breakthrough technology — analogous to the technical wizardry that makes aircraft invisible to radar — was recently approved by Health Canada and is now being used to greatly improve the effectiveness of the popular chemotherapy drug doxorubicin. The new technology not only decreases the damage to healthy cells, but reduces the side effects from the drug.

"It's a new way of administering an old drug," says Allen, who points out that the implications for the stealth technology are far-reaching: not only could it be used to strategically administer a variety of other cancer medications, it could also prove useful in gene therapy. Basic to the new technology are tiny membraneous spheres ("almost like tiny water-filled balloons," says Allen) that encapsulate the medication and protect it as it is carried through the blood. To prevent their triggering an immune system response, the spheres — known as liposomes — are designed to attract a cloak of water.

Allen's interest in liposomes predates her coming to the University in 1977 to accept a faculty appointment in pharmacology. Her arrival was a homecoming of sorts: her roots in the province run deep, to the earliest days of European settlement. In the late 1880s her great-grandfather established a cattle ranch in the Pincher Creek- Waterton area and settled his family in a log cabin built as part of the first NWMP post in the area. That cabin now exists only in memory; it was submerged when the Waterton I)am was built in 1963. Allen herself was born in Belleville, Ontario ("hut just because my mom happened to be passing through") and spent her early years moving from place to place according to the dictates of her father's air force career.

It was while she was living on the West Coast that Allen saw her future — albeit darkly — in the water of a tidal pool. Fascinated by the teeming life of the miniature waterworld, she set her sights on a career in oceanography. That led to the University of Ottawa, where she did a degree in biochemistry, and then to Dalhousie, where she earned a doctorate in oceanography.

Allen first encountered liposomes as a tool to help understand the biophysics and function of the membranes of the aquatic creatures she was studying. Gradually she began to become interested in liposomes in their own right, and she changed careers after becoming excited by the possibility of using liposomes to transport drugs in the body.

The technique for creating drug-filled liposomes is actually quite straightforward. Organic solvents are used to extract lipids — which are the basic component of animal fat and, by definition, insoluble in water — from a source such as the lecithin of egg yolk. Removal of the solvent leaves dry lipids, which can then he mixed with an aqueous solution of the drug. When the dry lipids come into contact with the aqueous solution, tiny spherical membranes containing the drug are formed as if by magic. This apparent alchemy is the result of a strange property of lipids: while their `heads' are water loving, their `tails' are water-hating. When lipids come into contact with water, their hydrophilichydrophobic split personality leads them to group together in a formation that eh poses only their `heads' to the solution. In so doing, they neatly encapsulate small amounts of the water — and anything disolved in it. Sonic disturbance is used to control the size of the liposomes. Those with which Allen works are so small that they must be with an electron microscope.

While production of drug-filled liposomes is not difficult, ensuring safe passage through the bloodstream proved more challenging. The body is not used to seeing a naked membrane surface, explains Allen, and in her initial attempts at administering drugs via liposomes, no sooner were the liposomes introduced to the bloodstream then the body mounted an immune system response. The liposomes were recognized as either foreign invaders or damaged cells that needed to be destroyed, and the macrophages (white blood cells) that line the blood vessels and the liver for just that purpos,were quickly called into battle. "The liposomes didn't have much chance to bring the drug to where we wanted it," recalls Allen.

In the mid-1980s Allen began disguising liposomes to sneak them past the watchmen of the immune system. "We had this idea to make their surface more like the surface of red blood cells," she says. Red blood cells, among the simplest cells that circulate within the bloodstream, have a "forest of glycolipids and glycoproteins, all sticking out" to protect their surface, says Allen.

As she and her associates began trying to replicate that   forest on the surface of their lipsosomes, they discovered that grafting the water-loving polymer polyethelene glycol to the membrane surface proved especially effective in circumventing immune system attacks. It was the starting point for the Stealth technology. Soon Allen's laboratory was manufacturing liposomes that attracted a complete shell of water, thus ensuring their sate passage through the bloodstream and past the white blood cells amassed in the liver.

With the technology in place to circumvent the body's, immune system, Allen turned to the challenge of getting her liposomes to the desired locations in the body. Targeting rumors, she soon found out, was no problem at all: "The solution was to let the body do it for you." Normal blood vessels, explains Allen, have tightlyknit walls, through which the liposomes are unable to pass. However, the new blood vessels that proliferate to support the rapid growth at tumorous sites are much more permeable, and the liposoines weak out through gaps between the cells of the vessel walls. "And they don't appear to go back," adds Allen. Instead, the liposomes remain in the cancerous tissue and gradually release their potent contents. Because the toxic medication is concentrated at the tumor site, the debilitating side effects associated with traditional chemotherapy are reduced, while the effectiveness of the treatment is multiplied many times.

Allen's stealth technology has now found its way from the laboratory and clinical trials to drugstore shelves. This Summer, Health Canada licensed a liposomal form of the chemotherapy drug doxorubicin with the brand name Caelyx. (The same drug had previously been approved in Europe and in the U.S., where it is sold under the brand name Doxil.)

Caelyx has been licensed specifically tor the treatment of Karposi's sarcoma a cancer found more commonly in people living with AIDS. The condition Occur, initially in the skin or tissue under the mucous membranes lining the mouth, nose or eye, but it can also spread to the liver, gastro-intestinal tract, and lymph nodes. People who stiffer from KS often develop disfiguring blotches or tumors on the skin or inside the mouth.

Clinical trials of 723 patients with AIDS-related KS showed Caelyx to be a particularly effective treatment. In up to 65 per cent of the cases it brought about some degree of remission. In a further 25 per cent of the patients, the disease was stabilized. Overall results showed that 48 per cent of patients experienced lesion flattening, 56 per cent had an improvement in lesion color, and 45 per cent experienced a reduction in pain.

Those results show that Caelyx approximately doubles the effectiveness of doxorubicin, says Allen. At the same time, none of the KS patients suffered hair loss, nausea or vomiting. Nor were clinicians able to detect any signs of cardiac toxicity, she says. Researchers at Edmonton's Cross Cancer Institute have also obtained encouraging results using Caelyx to treat other cancers. Clinical trials now underway have demonstrated its usefulness in treating patients with lung, breast and ovarian cancers.

While passive targeting is effective for treating patients with solid rumors, Allen knows that that's not going to work with cancers of the blood, and she is now exploring ways of "addressing" liposomes using antibodies to attach the liposomes to cancer cells.

Although her work with liposomes has taken her away from oceanography, Allen has not forgotten her love for the sea and, parallel to her liposomal work, maintains a program of research into the pharmaceutical properties of marine natural products. That research has recently led to a patented anti-asthmatic drug that is soon to be tested in clinical trials, and other substances are showing promise as anticancer agents. And some, she says, would be good candidates for liposomal delivery.

Dr, Allen's work is supported by SEQUUS Pharmaceuticals Inc, and by grants from the Medical Research Council, including a grant through MRC's University-Industry Grants Program.

Published Winter 1999.

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