Purdue News

February 1995

Vitamins Deliver Cancer-Fighting Agents To Cells

WEST LAFAYETTE, Ind. — Vitamins someday may be used to help fight cancer.

Purdue University researchers are exploiting the cancer cell's huge appetite for vitamins to sneak past the cell's security system and deliver a variety of large molecules that can serve as anti-cancer therapies.

"Basically, we are using vitamins as Trojan Horses to carry virtually any molecule into a cancer cell," says Philip S. Low, professor of chemistry. "Because cancer cells often overexpress special receptors to increase their vitamin uptake, this method can be used to target cancer cells specifically."

The Purdue group has received two patents to use water-soluble vitamins, including folic acid and biotin, to deliver molecules into cells. The method can be used to insert drugs, genes, proteins, antibodies, enzymes, lipids or toxins—molecules that normally would not easily gain entry into a cell.

Laboratory tests with animals have shown that the method can be used to deliver cancer-fighting agents to cancer cells without disrupting normal cells. Human trials may begin within two years. Low notes that the applications originated from basic research on plants.

The technique makes use of one of nature's pathways designed to carry molecules across the plasma membrane that surrounds a cell. Called endocytosis (en-doe-cyTOE-sis), this process is used by cells to bring in selected materials—such as a few vitamins and hormones—from outside the cell.

The Purdue group found that attaching large molecules to folic acid—a member of the vitamin B complex and one of the few vitamins that uses endocytosis to enter cells—allows the large molecules to enter the cell.

"The method is similar to the Trojan Horse strategy used by the Greeks to gain entrance to Troy," Low says. "The vitamin can conceal the unrelated molecules and carry them past the gates of the cell membrane."

Low's group has observed that vitamin-linked molecules can survive and flourish for more than 24 hours after entering a cell—long enough for a protein or antibody to begin the process of modifying the biochemistry of the cell.

The researchers discovered the unique delivery system six years ago while conducting basic research on signal processes involved in transporting molecules across the cell membrane in plants. The studies, funded by the National Science Foundation, led to the first documentation of receptor-mediated endocytosis in plant cells, showing that endocytosis was triggered by special receptors exposed on the outside of the cell membrane.

"During the course of this work, we also discovered that if you attached a protein to biotin, the plant cell would take in the protein along with the vitamin," Low says. "We immediately recognized that this process could be used medically, for purposes such as drug delivery, if it worked in humans."

Though the initial results showed little effect in cultured mammalian cells, the researchers decided to try another water-soluble vitamin, folic acid, before abandoning the study. The studies showed that, when attached to folic acid, proteins and various other large molecules could be delivered into mammalian cells, thus indicating a potential for human health applications.

At that time, Low and his group were using cultured mammalian cells, which were primarily cancer cells.

"Cancer cells are easy to maintain in culture, because they divide very rapidly and are basically immortal," he says. "Normal cells divide slowly and die after a few divisions."

In 1992, researchers from other laboratories reported that many types of cancer cells contain special receptors for folic acid that are not found on the plasma membranes of normal cells. Folic acid is a vitamin required for DNA synthesis.

"Like all living systems, the cell will develop what it needs to survive," Low says. "Rapidly dividing cancer cells express these special receptors because they have an enhanced need for folic acid."

Normal cells also use folic acid, but because they do not require nearly as much of it, they take the vitamin in through a transporter protein located within the plasma membrane. This system is more selective than endocytosis, and will not allow folic acid to enter if other molecules are attached.

During the past two years, Low and his group have focused their efforts to determine what molecules can be delivered to cancer cells through endocytosis. Their studies are supported by grants from several major pharmaceutical companies.

The group has successfully delivered various toxins, chemotherapeutic agents, imaging agents, genes and antisense oligonucleotides—molecules that inhibit gene expression—to cancer cells in living animals. The researchers also have been able to deliver molecules through liposomes, specially created vesicles or "paper bags" that can be filled with any desired substance and delivered to the cell by attaching the bag to folic acid.

Low's vitamin-delivery method someday may be used to provide nontoxic, low-cost treatments for certain types of cancers, including cancers that occur in the ovaries, breasts, colon, kidneys, brain and lungs, as well as some blood cancers, such as leukemia.

"In cancer cells where the folate receptor may be abundantly expressed, a characteristic quite unique to cancer tissue, folate derivatization allows for a very nice homing device for targeting anything you want to the cancer," Low says.

The group also has continued studies to explore the possibility of using other vitamins to deliver molecules to cells. Possible applications include vaccines that can be taken orally. The technology also may be used to increase the efficiency of drugs that are poorly absorbed by the body, or to introduce proteins or enzymes into cells lacking these substances.

Low cautions, however, that medical applications of the technology in humans have yet to be tested.

Purdue News Service: (765) 494-2096; purduenews@purdue.edu