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October 14, 2016

C dots not only tag, but kill cancer cells

Nanoparticles known as Cornell dots, or C dots, have shown great promise as a therapeutic tool in the detection and treatment of cancer. The tiny silica particles that fluoresce under certain conditions tag tumors in preparation for removal. The particles – developed more than a dozen years ago by Ulrich Wiesner, the Spencer T. Olin Professor of Engineering – now shownthey can do something even better: kill cancer cells without attaching a cytotoxic drug.

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During during safety testing of the C dots this remarkable new ability was discovered. When the peptide-coated C dots were introduced in high doses to tumor cells that were nutrient starved, they seemed to channel iron from the nearby environment into the inside of the tumor cells. This caused the nutrient deprived tumors to die due to their cells’ plasma membrane breaking up into multiple pieces. Healthy cells or well fed tumor cells were not afflicted.

The process not only works in a Petri dish, but in living animals as well, according to the Cornell website. When mice with tumors were exposed to high doses of the peptide-coated C dots, their tumors shrank while there were no noticeable side effects from the treatment.

This was shown in a study led by Michelle Bradbury, director of intraoperative imaging at Memorial Sloan Kettering Cancer Center and associate professor of radiology at Weill Cornell Medicine, and Michael Overholtzer, cell biologist at MSKCC, in collaboration with Wiesner.

The paper “Ultrasmall Nanoparticles Induce Ferroptosis of Nutrient-Deprived Cancer Cells and Suppress Tumor Growth,” published Sept. 26 in Nature Nanotechnology, details how C dots, administered in large doses and with the tumors in a state of nutrient deprivation, trigger a type of cell death called ferroptosis.

Nano particle cancer killer

Wiesner explains:  “If you had to design a nanoparticle for killing cancer, this would be exactly the way you would do it. The particle is well tolerated in normally healthy tissue, but as soon as you have a tumor, and under very specific conditions, these particles become killers.” Bradbury, co-director with Wiesner of the MSKCC-Cornell Center for Translation of Cancer Nanomedicines, adds that the study proofs for the first time the C dot particle has intrinsic therapeutic properties.

Wiesner originally designed the fluorescent silica particles (as small as 5 nanometers in diameter) to be used as diagnostic tools, attaching to cancer cells and lighting up to show a surgeon where the tumor cells are. Potential uses also included drug delivery and environmental sensing. A first-in-human clinical trial by the Food and Drug Administration, led by Bradbury, deemed the particles safe for humans.

During  further testing of the particles over the last five years Bradbury, Overholtzer, Wiesner and their collaborators made the surprise finding. When incubated with cancer cells at high doses – and, importantly, with cancer cells in a state of nutrient deprivation – Wiesner’s peptide-coated C dots show the ability to adsorb iron from the environment and deliver this into cancer cells. The peptide, alpha-MSH, was developed by Thomas Quinn, professor of biochemistry at the University of Missouri. The process triggers ferroptosis, a necrotic form of cell death involving plasma membrane rupture – different from the typical cell fragmentation found during a more commonly observed form of cell death called apoptosis.

Wave of destruction

The original purpose for studying the dots in cells was to see how well larger concentrations would be tolerated without altering cellular function,” according to Overholtzer. However, in 24 to 48 hours after the cancer cells were exposed to the dots, there was a wave of destruction’ throughout the cell culture. Tumors also shrank when administering mice with multiple high dose injections – without any adverse reactions, said Bradbury.

“We’ve found another tool that people have not thought about at all so far,” Wiesner believes. “This has changed our way of thinking about nanoparticles and what they could potentially do.” Future work will focus on utilizing these particles in combination with other standard therapies for a given tumor type, Bradbury said, with the hope of further enhancing efficacy before testing in humans. Researchers will also look to tailor the particle to target specific cancers. “It’s a matter of designing the particles with different attachments on them, so they’ll bind to the particular cancer we’re after,” Overholtzer said.

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