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Special, Life-Saving Delivery

June 14, 2016

A surgeon peers through an imaging device that magnifies the open abdomen of her patient, revealing a malignant mass that she carefully removes, leaving no visible evidence of disease behind.

Or so she hopes.

To eliminate all doubt, the surgeon flips a switch to turn on an ultraviolet light that shines across the surgical field where a fluorescent dye has attached to tumor cells, making them glow. Easily spotting every cluster of glowing cancer, she methodically vaporizes all traces of the disease with a laser.

Dr. Alessandro Santin pioneered the research that led to this technique for use in surgery for ovarian cancer, the most deadly of all gynecological cancers because of its recurrence and resistance to drugs.

“Ovarian cancers come back with a vengeance,” Santin said. “Because they survived the chemotherapy.”

Santin had discovered that the lining of ovarian cancer cells create a large number of two particular proteins — claudin-3 and claudin-4 — that are receptors for a bacteria called Clostridium perfringens enterotoxin, or CPE, that leads to a common form of food poisoning.

Santin and his team of researchers saw this as an opportunity to use CPE as a targeting agent to bind to ovarian tumors and help surgeons better locate them. Because injecting CPE through the bloodstream is toxic, the researchers learned how to attach a fluorescent label to a non-toxic portion of the binding area of CPE, a protein fragment called a peptide. A cluster of the peptides can be injected into patients before surgery, allowing them to accumulate on cancer cells that then glow under ultraviolet light.

“We have taken this type of research one step further,” Santin said. “Now we can visualize the disease. But can we kill the disease using this system?”

Using a WHRY grant in 2010 and the expertise of Dr. W. Mark Saltzman, Yale’s first chair of biomedical engineering, Santin’s team began working with nanoparticles. They have explored using these ultra-tiny non-toxic and biodegradable objects, coated with the non-toxic CPE peptide binding agent, as a method for locating ovarian tumors.

Years later and with additional funding from the National Institutes of Health, Santin has begun to show that not only can nanoparticles deliver a fluorescent dye to locate and highlight tumors, but they can deliver a small cargo of chemotherapy agents to the cancer cells and kill them from the inside.

“A nanoparticle is like a small cargo container,” Santin said. “We can place a lot of things inside, like chemotherapy agents. And make treatment highly effective and less toxic. The chemotherapy remains inside the shell of the particle until it’s inside the cancer.”

But the team will not stop there. Another method under development involves filling the nanoparticles not with chemotherapy drugs but a piece of DNA called a plasmid. Once transported to a CPE receptor site on a tumor, the nanoparticle can deliver a cargo that will instruct the cell to produce a natural toxin that will kill the cell from the inside.

And under this technique, the nanoparticle will also carry another piece of DNA called a promoter sequence that allows for the creation of the toxin only if inside a tumor cell and not any healthy tissues or organs.

“This is a safety measure to use a promoter in front of the toxin gene,” Santin said. “If a nanoparticle gets inside a liver cell or anything other than the targeted cancer cell, it’s not toxic. It remains un-transcribed DNA.”

Santin expressed confidence that he and his colleagues at Yale and around the world can answer at least one significant piece of President President Barack Obama’s recent challenge to cure cancer. And one that proves less damaging and more effective than many traditional cancer treatments.

“Our techniques involve specificity and safety,” he said. “We focus exclusively on the tumor and bypass its resistance. We can see disease, and we can try to kill it.”


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Submitted by Carissa R Violante on June 14, 2016