CU researchers see golden opportunity for bladder cancer patients

October 19th, 2017
graphic that shows how gold nanorods with receptors bind with protein.
The team engineered their gold nanorods with receptors that bind with a protein that’s overactive in bladder cancer cells. Once bound, infrared laser light heats up the gold, killing the cancer cells (courtesy Won Park).

All that is gold does not glitter. But if an eclectic University of Colorado team’s work continues to pan out, invisibly tiny bits of gold could one day be the focal point of a revolutionary new bladder cancer treatment.

A collaboration between cell biologists in the CU School of Medicine in Aurora and laser engineers in the CU Department of Electrical, Computer & Energy Engineering in Boulder has yielded a promising way to attack bladder cancer: Use an infrared laser to heat up gold nanorods specially engineered to bind with bladder cancer cells. The nanorods then fry the rogue cells.

Thomas Flaig, MD, a urologic oncologist and associate dean for Clinical Research at the CU School of Medicine as well as chief clinical research officer of UCHealth, led the cell-biology effort in Aurora; Won Park, PhD, the N. Rex Sheppard Professor in the Department of Electrical, Computer & Energy Engineering at CU Boulder, spearheaded the nanophotonic work in Boulder.

Nanophotonic?

Park specializes in using light to change the behavior of nanoparticles – materials measured in terms of a few billionths of a meter, which gets down to the sizes of individual proteins (for perspective: a nanometer is to a meter what a hazelnut is to planet Earth). A decade ago, Park was spending a sabbatical at the University of Colorado Cancer Center, where Flaig specializes in bladder and other cancers. Over coffee, they got to talking.

Dr. Thomas Flaig, MD
Dr. Thomas Flaig, MD

The treatment for superficial bladder cancer (that is, cancer that hasn’t pierced the bladder’s lining into the muscle, which comprise about 70 percent of cases) hasn’t changed much since the 1980s, Flaig explained. You insert a catheter into the bladder and inject directly onto the tumors a strain of bacteria called BCG, which is also a tuberculosis vaccine. The technique’s ability to directly target cancer in the bladder  – unlike, say, chemotherapy, which sloshes about the entire body – presents a special opportunity in cancer care, and it does work, Flaig said. But given how common bladder cancer is, with about 75,000 new cases a year and about 16,000 deaths in the United States, medical science has been slow to develop alternative approaches.

“We really need innovation in bladder cancer,” Flaig said recently. “This would be a very practical way of delivering cancer therapy through administration of a nanotherapy route.”

Two facts

Park’s work focused on nanotherapy using lasers. The challenge with nanotherapy, though, was that if you infuse nanoparticles like a chemotherapy, the liver tends to clear them out. There were also open questions about possible collateral impacts of unleashing vast schools of nanoparticles into the bloodstream. But here in the bladder was a way to deliver nanoparticles directly to the cancer, and one which would involve the same sort of catheter-based treatment that Flaig and colleagues have used routinely for years in treating bladder cancers. And so the cancer-cell specialist and the laser expert decided to team up.

The effort hinged on two facts, the first having to do with optical physics, the second with biochemistry. The first was that gold nanorods can be engineered to vibrate and heat up when hit with a specific color of near-infrared light (in this case, Park tuned his nanorods to respond to laser light just a bit redder than the eye can see). In principle, it’s not too different than how your microwave oven warms up a neglected cup of coffee by blasting it with electromagnetic waves tuned to make water molecules vibrate.

The second fact, having to do with biochemistry, is that bladder cancer cells have a lot more epidermal growth factor protein receptors (EGFRs) poking through their cellular surfaces than healthy cells do.

The approach

The success of Flaig’s and Park’s collaboration would depend on their ability to exploit these two facts. They would have to somehow modify gold nanorods such that they could bind to EGFR receptors and then, once the nanorods were docked with the cancerous cells, hit them with infrared light such that they heated up and cooked while leaving healthy neighboring cells largely be.

Gold nanorods, as seen through a scanning electron microscope (courtesy Won Park).
Gold nanorods, as seen through a scanning electron microscope (courtesy Won Park).

Gold, a noble metal, is happy enough to bond to nothing at all, which is why it doesn’t rust. So festooning the nanorods with EGFR antibodies – essentially molecular keys that fit the EGFR’s molecular lock – was no easy trick. But by 2014, the team had figured out how to do it using something called pegylation. They called the resulting liquid solution “conjugated gold nanorods” (CGR), which, being a clear or blueish liquid, looks like nothing stored in Fort Knox. They also showed that, in petri dishes, CGR bonded to the EGFR receptors of bladder cancer cells. Now they had to hit it with a laser and show that it would work in living creatures.

This past August, Flaig, Park and colleagues reported their success with just that. They used mice engineered with bladder cancer to test the effectiveness of laser light on its own (lasers can, after all, do some damage), laser light with straight gold nanoparticles, and laser light with the CGR the team had invented. They found that only the laser-plus-CGR combination killed large numbers of surface bladder cancer cells. So in principle, the approach worked.

Up next

The team has applied for a patent on their conjugated gold nanorods and, as Flaig put it, “we really have an eye on moving this to a clinical application. We realize that is a big hurdle, but that is our goal.”

“It’s a really interesting way of addressing the problem,” Flaig said. Plus, he said, because it would also use catheters – to empty the bladder, to apply and remove excess CGR solution, and to apply fiber-optic-delivered laser light inside the bladder, “there’s very little change in the way we’ve treated local bladder cancer for decades” from the patient’s perspective.

There’s much work to do. Jared Brown, PhD, of CU’s Skaggs School of Pharmacy, has joined to the team. He specializes in nanotoxicology, expertise that will be vital in proving the approach’s safety before it can win U.S. Food and Drug Administration approval to start testing their exquisitely engineered nanorods in people. They also must establish how exactly the laser light and the golden solution will work in the human body, how thoroughly the technique will kill cancer cells, how the approach impacts adjacent healthy tissue, and how they’ll go about producing (or having someone else produce) enough CGR for clinical trials, among other things. Despite the challenges ahead, Flaig is optimistic that the long march from lab to clinic will yield better treatment for bladder cancer patients at UCHealth and beyond.

In the meantime, he says, he is enjoying what he described as “a fun and ongoing collaboration” among his and Park’s CU teams, who despite “almost no overlap in expertise” have produced a string of successes neither could have hoped for alone.

“To me, that’s one of the neatest parts of the whole project,” Flaig said.

 

 

About the author

Since 2008, Todd Neff has written hundreds of stories for University of Colorado Hospital and UCHealth. He covered science and the environment for the Daily Camera in Boulder, Colorado, and has taught narrative nonfiction at the University of Colorado. He was a 2007-2008 Ted Scripps Fellowship recipient in Environmental Journalism at CU.

His latest book, "The Laser That’s Changing the World," tells the story of the inventors and innovators who saw, and ultimately realized, the potential of lidar to help solve problems ranging from smokestack-pollution detection, ice-sheet mapping, disaster recovery, and, ultimately, autonomous-vehicle guidance, among many other uses. His first book, "From Jars to the Stars," recounts how Ball Aerospace evolved from an Indiana jar company - and a group of students in a University of Colorado basement - to an organization that managed to blast a sizable crater in the comet 9P/Tempel 1. "Jars" won the Colorado Book Award for History in 2012.

Todd graduated with a business degree from the University of Michigan, where he played soccer, and with a master’s degree from the Fletcher School of Law and Diplomacy at Tufts University. Before becoming a journalist at the turn of the millennium, he was an IT and strategy consultant. He once spoke fluent Japanese and still speaks fluent German.

When not writing, he spends time with teenage daughters and wife Carol, plays soccer, and allows himself to be bullied by a puggle he outweighs by a factor of seven.