NEWS

Folate Gains Momentum as a Vehicle for Drug Delivery

Brian Vastag

Mothers advising their young ones to take vitamins probably never had this in mind. Folate, one of the B vitamins, is sneaking onto the drug development scene as a possible Trojan horse, able to slip drugs, imaging compounds, or even DNA directly into unsuspecting tumors.

Abundant in leafy green vegetables and nuts, folate is essential for healthy chromosomes and cell division. Most normal cells soak it up via a finicky chemical pathway that rejects all but the purest form of the molecule.

But tumor cells need more and more of the vitamin for accelerated cell division, so they deploy thousands of special folate receptors on their surface. These hungry little portals, less discriminating than their normal-cell cousins, gobble up relatively huge quantities of folate. If a growing cadre of researchers have their way, this voraciousness may ultimately be used against cancer cells.

The reason? Folate has a chemical structure ideal for linking to other molecules. Chemists can easily manipulate the tube-like folate molecule like a microscopic Tinker Toy, tacking on a chemotherapy drug, a radioactive imaging molecule, or even a small, fat-wrapped package of DNA.



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Folic acid’s chemical structure is ideal for attaching a variety of other molecules. With the right manipulation, other molecules will form a covalent bond with a carboxyl group on the folate molecule.

 
The first paper to show this possibility, published by Purdue University’s Philip Low, Ph.D., and colleagues in the Proceedings of the National Academy of Sciences in 1991, reported that cancer cells absorb a million or more folate conjugates in just 2 hours. If each of these million molecules ferried a toxic drug, the cell would stand little chance of surviving.



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Dr. Philip Low

 
Folate stands as a clear underdog in the world of tumor-targeted therapies. Traditionally, the big pharmaceutical companies have poured their resources into developing monoclonal antibodies tuned to specific tumor receptors. The first two such antibodies approved for cancer treatment, rituximab (for lymphoma) and Herceptin (for breast cancer), ate up hundreds of millions of research dollars before their successes. Developing an off-the-shelf vitamin could dramatically cut costs.

And in a bizarre twist, before researchers targeted folate receptors with folate compounds, they aimed monoclonal antibodies at them. Until Low came along, apparently no one had thought to exploit the receptor’s ultimate weakness. And what a weakness it is. Folate binds to the receptor 100 times more tightly than a typical monoclonal antibody, according to Low, meaning that a higher proportion of molecules will eventually find their target.

Folate has a number of other advantages. "It’s a simple system to use," said Robert Lee, Ph.D., an Ohio State University researcher working on folate-DNA compounds. And folate is more stable than monoclonal antibodies, which need to be kept cold to avoid deterioration.

But folate’s biggest advantage may be its size. If an antibody is a battleship, folate is a dinghy, a mere 0.3% the weight of a typical antibody. And as any Navy SEAL will report, a rubber raft can sneak past enemy defenses better than a million-ton hunk of steel.

For tumor biology, that means a twofold advantage. First, folate does not elicit an immune response, unlike artificial monoclonal antibodies, which can spur the body to make antibodies that neutralize the monoclonals. The small size of folate compounds also means that they can penetrate tumors better.

These advantages must have enticed Low to try the experiments that led to his 1991 PNAS paper. But the oncologic implications were unforeseen. "We realized we could deliver virtually any attached molecule to the cells we were working with," Low said. "It turned out just by accident that we were working with cultured cells, and those are cancer cells. It was a perfectly innocent mistake."

Low’s dedication to turning his "innocent mistake" into a useful cancer-fighting tool is anything but an accident. Since 1991, he has published two dozen papers on the topic, and in 1996 he helped found a small biotech company, Endocyte Inc., which has patented a handful of his methods. The company went after research dollars from the big pharmaceutical companies, and in 1998 landed a deal with Rhône-Poulenc Rorer worth up to $40 million for Endocyte.

The first fruit of these efforts to reach human trials, an imaging compound using the radiotracer indium-111, detected 12 of 13 ovarian cancers (from a group of 35 women with suspected cancers) in its first clinical study. Additional multicenter studies are under way with a second-generation conjugate of folate and the isotope technetium-99, which the company’s Web site touts as less expensive, safer, and able to produce higher quality images than indium.

Low said his group initially focused on ovarian cancer, and there are "a number of other cancers" he wants to study, but they will have to wait for FDA approval.

In addition, Endocyte plans to start clinical trials of therapeutic folate combinations within a year. "We’re looking at a number of conjugates of folate with some of the classical therapeutic compounds. They’re all in preclinical trials, and one of them is working very well," said Low. "We don’t see any toxicity yet under conditions where we get good therapeutic effect. That’s astounding."

However, Ohio State’s Lee expressed concern that kidney toxicity could slow development of folate-bound therapies. "Some parts of the kidneys express high levels of folate receptors," he said, "so while you’re targeting the tumor, you’re also delivering the drug to the kidney."

But like Low, Lee remains enthusiastic. "Imaging agents are a nice first step, but I’d like to see more animal testing and more data on treating actual tumors. That, and overcoming the kidney toxicity, are the major areas we need to work on."



             
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