Cornell dots, or C dots—fluorescent, nanometer-sized silica particles—can safely find tumors and illuminate them. They can potentially weaken tumors or deliver therapeutic drugs. With these uses and more, C dots are proving to be vastly versatile, paradigm-shifting tools.
C dots’ inventor, Ulrich B. Wiesner, Materials Science and Engineering, says it began serendipitously, with another researcher’s student—a visitor to Wiesner's lab who needed a project. At the University of Mainz, the student had been synthesizing mesopore silica nanoparticles. “This was in the late 1990s when research in drug delivery was becoming very interesting,” Wiesner says. “So we wrote a proposal about filling these particles with dyes and studying how the dyes leach out.”
The project was funded, and the student began making the particles in Wiesner’s lab. “One of my Cornell students at the time, Hooisweng Ow, and I thought: Rather than mixing the dyes into the particles, why don’t we just attach them covalently and see what happens?”
What happened was incredible. “The particles were unusually bright; the effects were enormous, an order of magnitude brighter,” Wiesner says. “That’s really the starting point for C dots.”
A Collaboration That Brought C Dots to Clinical Trials
In the mid-2000s, the discovery and refinement of the C dot technology put lots of things in motion for Wiesner and his lab. While his group made the dots smaller and easier to produce, Wiesner began collaborations with biologists and medical researchers to see whether C dots were tolerated in living organisms.
Wiesner struck up a partnership with Michelle S. Bradbury, Radiology, Weill Cornell Medicine/Memorial Sloan-Kettering Cancer Center (MSKCC). In collaboration with Bradbury, Wiesner’s student Andrew Burns showed that, in mouse models, C dots below 10 nanometers in size would effectively clear the body through the kidneys, minimizing potential side effects. Bradbury further showed that, appended with targeting moieties, C dots could either find and bind to tumors or quickly leave the body via renal clearance.
Wiesner and Bradbury presented this biodistribution data, along with successful toxicology studies, to the United States Food and Drug Administration (FDA) and were approved in 2010 to carry out early clinical trials. For a first safety study, the team chose melanoma patients.
C Dots, an Extraordinary Diagnostic Tool for Cancers
“My father died of melanoma when I was 20,” Wiesner says. “So I’ve seen the movie, and I mean, no disease is good, but it’s a really terrible disease. I always wanted to do something in that area, and that’s what we went after.”
In a phase zero trial, with only terminal patients, C dots were injected intravenously into patients with metastatic melanoma. The team tracked whether or not the dots were excreted safely. They were. The researchers found that they also targeted tumors. In a subsequent phase one trial, C dots were applied to lymph node mapping by injecting them locally around a primary lesion.
Primary melanoma lesions typically shed cancerous cells that escape through the lymphatic system. “So when surgeons take a primary lesion out, they always have to look for adjacent lymph nodes and decide whether to take particular nodes out,” Wiesner says. “There’s no engineering primer for that. The decision is pretty much based on the experience of the surgeon.”
By injecting C dots that bind to the cancer cells, surgeons can now track the cancer. “The C dots guide the surgeon to the node. If it stays fluorescent, it is taken out. If the fluorescence is transient, the node is left in,” Wiesner says. “The surgeons can find the lymph nodes faster and with fewer cuts, because they can see where they need to go. This provides surgeons with a tool to make more educated decisions.”
Wiesner and Bradbury are now extending this application to a trial in breast cancer patients. Breast cancer poses similar challenges to surgeons, and it can be addressed using the same C dots, targeting moieties, and route of administration.
Other diagnostic studies abound, including a promising clinical trial of C dots in brain cancers as well as the development of cocktails of C dots that would allow surgeons to label tumor and nerve tissues with different colors. This would reduce the likelihood that surgeons would nick an important nerve when removing a tumor.
In addition to imaging, the studies are providing information about tumors’ cell surface markers. “At the minimum, you can inject the particles before any surgery or therapy, and when you see the particles get stuck at the tumor, then you know that they’re recognizing a specific cell surface marker. You then know what kinds of markers are overexpressed,” says Wiesner, “and you can stratify patients to certain therapeutic regiments based on these markers.”
Wiesner wants C dots to be used in these ways as a diagnostic tool—but he has bigger dreams for C dots, too.
C Dots’ Therapeutic Power
Work is underway to attach therapeutic drugs to C dots. “We already know they go to the tumor, so we can use this knowledge to develop highly targeted nanoparticle radiotherapies or therapeutics,” says Wiesner.
Additionally, C dots have recently been found, at higher doses, to pack their own punch. “This was a very serendipitous finding,” Wiesner says.
Wiesner, in partnership with Bradbury’s team at MSKCC, have known that a three or four orders of magnitude higher dose of C dots would be needed for therapeutic purposes. Michael Overholtzer, cell biologist at MSKCC, set out to perform a baseline study in vitro, to see whether cells could essentially tolerate more dots. He found that the particles were well tolerated by cells under normal conditions—good news. Then Overholtzer studied the effects of the dots on stressed and nutrient-deprived cells, as they are in a well-developed tumor.
“Lo and behold, under these conditions, there’s this wave of cell death that goes through these cell cultures,” Wiesner says. Overholtzer found that the microporous particles carried iron into the cells, interfering with the iron metabolism, leading to cell death.
Bradbury built on this data and tested the C dots as a therapy for tumors in mouse models. “The tumors stopped growing or even regressed,” Wiesner says.
“Cancer is very complicated, so none of the therapies will work perfectly,” he continues, “but maybe if you do all of these things together, you knock out the tumor from so many angles that you can manage it. The more of these things you discover, the better it is. We’re really excited about it.”
Elucida Oncology, Inc. has licensed the technology and is currently raising funds for broader clinical trials—trials that could make these therapies and tools available to patients.
A Serendipitous Trek
Serendipity is a thread running through Wiesner’s scientific successes and extends to his career at Cornell. “It was serendipity entirely,” he says.
“If in my lifetime, I see that these particles would really be used in patients and improve surgeries and chance of life, that would just be awesome.”
Wiesner had been offered a tenured research position at the Max Planck Institute in Mainz and was prepared to go on the job market, exclusively in Germany, for a professorship. But one day, a director at the institute recommended he apply for an opening at Cornell. “In Germany, if a director of a Max Planck Institute tells you to do something, it’s very difficult to say no,” Wiesner says.
When he told his wife about Cornell, she didn’t know where it was located. “I said, ‘Somewhere in New York.’ So we opened an atlas, and we couldn’t find it. We had to actually buy a map of the state of New York to find Ithaca,” Wiesner laughs.
“Then I got to Cornell, and the rest is history,” he says. “I said, holy moly, this is a really nice place. Every day, every minute I spent at Cornell, I got more excited.”
Now, what excites and drives Wiesner is that the technologies he’s developed at Cornell could make a difference in the world. “If in my lifetime, I see that these particles would really be used in patients and improve surgeries and chance of life, that would just be awesome,” he says. “I want to contribute as much as I can to their success.”