Researchers Think They've Found the Next Chemo

Mayo Clinic oncologist and hematologist Svetomir Markovic had been working on monoclonal antibodies—lab-produced molecules engineered to seek out and "flag" cancer cells. Monoclonal antibodies are like a man-made immune system: They can act as substitute antibodies and are currently used in some types of immunotherapy treatment. Children with high-risk neuroblastoma brain tumors are routinely given monoclonal antibodies that flag cancer cells, which helps the child's immune system recognize and destroy the those cells. The antibodies can also be used to trigger the destruction of cancer-cell membranes, block immune system inhibitors or cell growth, prevent the growth of blood vessels, or even directly attack cancer cells.

But Markovic faced a challenge: How would he use these monoclonal antibodies to guide chemotherapy drugs directly to the affected tissue?

"The big issue in drug therapy with cancer is delivering drugs to the right tissue, not to healthy tissue—getting the right drug to the right cell. The maximum safe dose of the drug has always been based on what is maximally tolerated by the body, not what is maximally effective against the cancer," Markovic says.

Unfortunately, using these antibodies as drug carriers was much more difficult in practice than it was in theory. Attaching things like chemotherapy drugs to the monoclonal antibodies turned out to alter their affinity for cancer cells. In other words, giving these antibodies a package to deliver made them less interested in seeking out the correct cellular address and less able to bind to the cells in question.

Despite lots of research, antibody-directed chemotherapy still isn't ready for broad application, Markovic asserts, noting that the major hurdles include the instability of the substances used to link the antibody to the chemotherapy drugs and reduced toxicity of the drugs when they're bound to the antibody—meaning they can be less effective at killing the tumor.

It was when a pharmaceutical company began selling an older chemotherapy drug, paclitaxel, in an organic solvent that Markovic realized a potential solution to his problem of wandering, non-binding drugs. To overcome paclitaxel's hydrophobia (meaning it repels or refuses to mix with water), the drug company had begun packaging it in albumin, a common protein in blood plasma. The paclitaxel was reformulated as albumin-bound nanoparticles; each particle was about 130 nanometers on average. Albumin is known for its ability to carry a lot of other molecules, so Markovic thought he might be able to attach the cancer-seeking antibodies to the drug-filled albumin, which would act as a buffer so the drugs would stop interrupting the antibodies' binding abilities.

"An important challenge in treating cancer in general is to find a technology for a controlled targeted drug delivery and release to eradicate tumor cells while sparing normal cells," researchers from various universities in Florida and California explained in a recent paper. "The circulatory system can deliver a drug to almost every cell in the body; however, delivering the drug specifically into the tumor cell past its membrane and then releasing the drug into the tumor cells on demand without affecting the normal cells remains a formidable task."

Use of nanotechnology in the treatment and diagnosis of cancer is a rapidly growing area of nanomedicine. In fact, the National Cancer Institute now spends roughly $150 million a year on nanotechnology research. In addition, other National Institutes of Health groups spend about $300 million on researching nanotechnology to help treat and detect cancer, as well as a few other disorders. In 2015, the NCI launched a nanotechnology startup competition in the hopes of bringing promising cancer-fighting nanotechnology creations to the market.

In other studies, nanoparticles have also shown promise as effective drug-delivery systems. Those researchers from Florida used magnetoelectric nanoparticles to deliver paclitaxel directly to the malignant cells, ridding the mice they tested of all signs of cancer. Elsewhere, chemotherapy drugs have been attached to nanodiamonds, delivered via DNA-string "nanotrains," and encapsulated in liposome nanoparticles. Nanoparticles filled with gold have been engineered to attach themselves to cholesterol cells, essentially starving lymphoma cancer by preventing it from feeding on those cells. Hybrid nanofibers may be a successful topical treatment for melanoma skin cancer. A nanotech drug delivery conference is taking place in Japan next month.

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Back at the Mayo Clinic, Markovic discovered he could fit 700 of his monoclonal antibodies onto the surface of an albumin protein. He says it's easiest to think of his infinitesimal structure like a hollow ball: Inside are the chemo drugs and, outside, four-fifths of the surface area is covered with antibodies looking for cancer cells. The sphere is created to disintegrate after about 10 to 30 minutes. So the antibodies nestle the ball into the cancer cells, then the structure falls apart and releases the drugs.

"It's like when a kid goes down the lazy river, then grabs hold of the side and his tube flips over and flops him out," Markovic chuckles. "We're trying to slow down the molecule enough so it falls apart and delivers the payload of the drug in the right place."

When I heard the idea of a "nanoparticle delivery device," the image that immediately sprang to mind was The Magic School Bus, shrinking down to explore the inner recesses of the body. As I'm speaking with Markovic, the picture becomes even clearer. I imagine Ms. Frizzle and her students are powerful cancer-destroying drugs. Their bus has been kitted out with a swanky new GPS system that shows them the shortest route to Malignant Cells. Upon arrival at their tumor-y destination, their Trojan bus dissolves around them as the ginger, curly-haired teacher leads the fearsome schoolchildren into battle.

In their experiments on mice, Markovic's lab discovered that with the antibody coating, they could administer 20 percent more medication. Even more encouraging was that, despite increasing the amount of medication they administered, they saw far fewer side effects. They observed none of the weight loss or loss of appetite that tends to accompany traditional chemotherapy.

What's more, they found they could attach multiple drugs to the antibodies, and combining drugs can enhance the cancer-killing abilities of each one. The nanoparticles may also be able to deliver immune-modulating agents. By targeting immune cells, they might improve people's overall anti-cancer immunity.

Thanks to some "really cool data," as Markovic calls it, his team is currently in phase one of a clinical trial involving 12 people with melanoma. "Melanoma is notoriously recognized as being resistant to chemo. Nothing works on melanoma," Markovic says.

But the trial results have been so encouraging that his team has already gotten FDA approval to begin trials on ovarian cancer and non-Hodgkin's lymphoma patients. "We're definitely seeing fewer side effects than with standard chemo," Markovic says. "Antibody-directed chemotherapy offers an advantage over conventional chemotherapy because we're seeing increased efficacy and reduced toxicity."

Right now, these delivery structures are expensive to make because they create each one individually—the monoclonal antibody being the most expensive part, he says. If produced at a larger quantity, it may turn out to be significantly cheaper compared to other new cancer treatments. He says a big way to save money would be to go back and revisit some of the older, cheaper drug agents that were deemed too toxic to use with traditional chemotherapy delivery methods. Meaning "we could make better use of existing agents."

Markovic is hopeful about the future application of his nanotech to address all kinds of cancer: "There shouldn't be any malignancy that we can't treat this way."

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