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For a new generation of cancer drugs, scientists look to targeted nanomedicine

thumbnail Thinking 'small'— A team at the Minneapolis VA Health Care System and the University of Minnesota, including (from left) Drs. Khalil Ahmed, Gretchen Unger, and Janeen Trembley, are working on a targeted nanomedicine approach to infiltrate and kill cancer cells without harming normal tissue. (Photo by April Eilers)

Chemotherapy for cancer has saved many lives. But at the same time, the treatment has a serious drawback: It can be toxic to healthy cells along with cancerous ones. That can cause short-term side effects that make treatment difficult to tolerate, such as hair loss, mouth sores, and anemia. And even when chemotherapy succeeds in curing cancer, it can leave in its wake permanent "collateral damage" such as sterility and a weakened immune system.

For years, scientists have been in hot pursuit of what they see as a way to overcome the challenge: "smart" chemotherapy that zaps bad cells without harming good ones.

A team at the Minneapolis VA Health Care System and the University of Minnesota is developing a form of smart chemotherapy they think holds special promise. It relies on a capsule so small that 40,000 of them could fit on the head of a pin. Both the capsule and the drug inside it are designed to home in only on cancer cells.

"[Our] concept is completely different than what's out there in the literature and what's being pursued in many labs," says lead investigator Khalil Ahmed, PhD.

Nanocapsule made from natural protein
The ultra-tiny capsule, or nanocapsule, is less than 50 nanometers in diameter (a nanometer is a billionth of a meter). It's the product of a collaborating lab, that of Gretchen Unger, PhD. A consultant to VA, Unger is also the founder and chief scientific officer of a Minnesota company called GeneSegues, which is now making the capsules for research. The technology is being used by scientists studying cancer, infectious disease, and other conditions.

Unlike capsules you buy at the drug store or vitamin shop, this one is invisible to the naked eye. Rather than being taken orally, the microscopic capsules would be suspended in a solution and given to patients intravenously.

Unger's company formulates the capsules in test tubes from a natural protein, or biopolymer. In lab experiments, the polymer breaks down within a few hours of entering a cell membrane. The cargo inside�a drug�is then freed to do its job in the cell nucleus.

The capsules enter cells through the "lipid raft" pathway. Lipid rafts are cholesterol-rich structures in cell membranes. They manage the traffic of proteins and other molecules into and out of the cell.

The nanocapsules act like commandos that slink past guards at a tightly controlled checkpoint, headed to their target. Because of their ultra-tiny size, the capsules slip through cell membranes without setting off immune responses that could degrade the capsule or its payload on the way to the nucleus.

There's another plus to the capsule: The protein from which it's made can be changed based on the target. Ahmed's studies use a capsule made from tenfibgen, derived from a larger protein called tenascin. Importantly, tenascin receptors are abundant in the membranes of cancer cells. The capsules are drawn to them like heat-seeking missiles.

"The concept is to target a receptor [a protein on the surface of cells that acts like a molecular docking site] that's elevated in cancer cells but that is not present in normal cells," says Ahmed.

Another plus of the nanocapsule is that it is able to penetrate tumor cells within organs, such as the prostate, as well as in areas of the body to which cancer has spread, such as lymph nodes or bone. That's an important factor, says Ahmed. "A particularly serious problem in cancer therapy is dealing with metastases, as they are difficult to target."

Lab tests suggest the tenfibgen-based nanocapsule would be safe in humans. Partly because the capsules are made from a natural protein, says Ahmed, "They don't generate immunotoxicity, and they don't affect blood chemistry."

Double dose of targeting
Ahmed's team has tried a couple of different "cargos" inside the nanocapsule�all designed to target a substance found in higher amounts in cancer cells. This boosts the chance that only cancer cells will be affected by the therapy.

The drugs inside the nanocapsule in Ahmed's experiments target a protein called CK2. More than a decade ago, Ahmed's lab became the first to discover this molecule as a marker of cancer cells. "It's elevated in virtually every cancer we've looked at," says the scientist.

Currently, the lab is focused on targeting CK2 with two therapeutic agents, both members of the nucleic acid family that includes DNA and RNA. The two agents are known as CK2 antisense and siRNA.

CK2 appears to be crucial for cell survival. So knocking it out in cancer cells ensures the death of those cells. While some other drugs might deliver a crippling blow to cancer cells, anti-CK2 drugs inflict a fatal wound�at least in cell culture and animal studies to date.

Some researchers have expressed concerns because CK2 is also found in normal cells, and the protein is essential for those cells to stay alive as well. So delivering an anti-CK2 therapy that is somewhat sloppy, that is not perfectly targeted to cancer cells, could be highly toxic and have dire side effects. Normal cells, however, show some resistance to undergoing down-regulation of CK2, as compared with cancer cells. Moreover, it appears that cancer cells are strongly "addicted" to CK2, such that blocking production of the molecule rapidly kills off these abnormal cells.

Packaging CK2 inhibitors in a nanocapsule, says Ahmed, is further insurance that only cancer cells would be zapped. In an article earlier this year in Cancer Letters, he and his coauthors wrote: "[Nanoencapsulation] of a CK2 small molecule inhibitor or siRNA would hold an even greater potential for elimination of tumor in a targeted manner and with minimal potential of host toxicity."

He hopes the pairing up of the anti-CK2 drugs with the nanocapsule will be the perfect marriage: a happy occasion for medical research, and one that spells doom for cancer.

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