BGU researchers use novel chemo delivery to kill colorectal cancer liver metastases

Attaching chemo drugs to specially modified nano polymers that target tumors and avoid side effects also appears to prevent melanoma from spreading to lungs in mice

Renee Ghert-Zand is the health reporter and a feature writer for The Times of Israel.

Illustrative photo of a cancer patient receiving chemotherapy treatment. (via Shutterstock)
Illustrative photo of a cancer patient receiving chemotherapy treatment. (via Shutterstock)

A new study by a team of researchers at Ben-Gurion University of the Negev shows how they used a nanosized polymer to deliver a chemotherapy drug to safely and effectively eliminate colorectal cancer (CRC) metastases in the liver.

They also presented evidence of how they used a polymer, a large chain molecule, to minimize metastasis of melanoma to the lung.

CRC is the third-most diagnosed cancer and the third-most common cause of cancer-related death in both men and women in the United States. According to Health Ministry data from 2020, CRC is the third-most common cancer diagnosed among Israeli men and the second-most common among Israeli women. CRC is responsible for the second-largest number of cancer-related mortalities among men and the third-largest among women in Israel.

The peer-reviewed study, done on mice, was published this month in the Nano Today journal.

“Conventional chemotherapy involves the use of small-molecule drugs that are toxic to rapidly dividing cells. The problem is that the chemotherapy lacks cell specificity. The medication travels through the bloodstream and reaches not only the [cancerous] tumor but also healthy tissues, damages fast-growing healthy cells, and causes side effects,” said Prof. Ayelet David, who oversaw the research in her lab.

“Therefore, we were focused on developing a drug that would be more effective and have fewer side effects. We did this by trying to limit the distribution of the drug so that it would not reach healthy tissues and harm them. We wanted to bring the drug only to the right site and release it there so it could work specifically on that site,” she explained.

Prof. Ayelet David’s lab team at Ben-Gurion University (from right to left): Valeria Feinstein, Nenad Milošević, Yvonne Ventura, Marie Rütter. (Private album/BGU)

The liver is the most common site for CRC metastasis, with around 70 percent of patients ultimately developing liver metastases.

“When people are diagnosed with CRC, in about a quarter of the cases the cancer has already metastasized to the liver,” David said.

When possible, the metastatic tumors are removed by surgery. Patients often also require adjuvant chemotherapy or immunotherapy to try to completely wipe out the cancer. While there have been advances, the risk of toxicity for healthy tissues remains a problem.

Prof. Ayelet David. (Dani Machlis/Ben-Gurion University of the Negev)

The study, led by PhD candidate Marie Rütter, demonstrated that delivering a small-molecule chemotherapy drug with the help of a larger-molecule polymer in a targeted way overcomes the non-selective delivery and associated toxicity issue.

“First, we injected CRC cells into mice. Four days later, we could see, using imaging tools, that there were metastases in the liver,” David said.

The next step was to attach the chemotherapy drug to the macromolecule polymer (still tiny at two to five nanometers in size) and inject it into the bloodstream intravenously. The polymer, carrying the drug, was big enough so that it could not leak out of the blood vessels and reach healthy organs and damage them.

“At the same time, we wanted to target the metastases in the liver so that the drug could work on them. We looked for a specific marker that is not expressed on healthy blood vessels, but is up-regulated and exclusively expressed on blood vessels in cancerous and inflamed tissues,” David said.

The team identified a specific cell adhesion molecule, a protein called E-selectin, that is expressed on blood vessels that supply nutrients and oxygen to the tumors. The researchers then modified their polymer by adding to it a short sequence of amino acids that can bind specifically to E-selectin.

“Now our polymer with the chemotherapy drug worked like a guided missile that hits the blood vessels expressing this target. When the polymer binds to the target and enters the cells on blood vessels, it releases the chemotherapeutic drug, and kills the cells that feed the tumors,” David said.

“We selected a strategy to kill or harm the blood vessels that supply oxygen and nutrients to the tumor rather than directly target the cancer cells themselves. It was a very efficient method because once we cut off the blood supply to the tumors, it translated to the deaths of hundreds of cancer cells,” she noted.

Illustrative: Laboratory mice. (toeytoey2530/Istock via Getty Images)

According to David, imaging done two weeks after the mice with liver metastases were given a single shot of the chemo-carrying polymer indicated that the tumors were no longer visible. Half of the mice treated with the polymer went on to live the 100-day course of the experiment, appearing to have been cured of the cancer with no recurrence of the disease. The mice treated with the polymer also did much better than mice treated with conventional chemotherapy.

When asked whether the polymer could be given to prevent the cancer cells that originated in the colon from taking up residence in the liver in the first place, David said that her team tried that, but that it didn’t work.

“We also examined the option of treating mice with a polymer without the cytotoxic drug as a preventive therapy, to try to stop the cancer cells from getting out of the blood vessels and settling down in the liver,” David said.

“However, it was difficult for us to prove there was an advantage to this, probably since CRC cancer cells do not rely only on one cell adhesion molecule to facilitate the formation of metastasis. Some other components may contribute to the escape mechanism of cancer cells,” she said.

Illustration of the polymer in the bloodstream and its binding to E-selectin, which is expressed exclusively on cells lining the walls of blood vessels in areas of liver metastases. Once bound, the polymer enters the cells, releases a toxic drug and impairs the blood supply to metastases. (Nenad Milošević/Ben-Gurion University of the Negev)

However, the researchers were successful in using their polymer-based strategy to prevent the metastases of melanoma to mice’s lungs. First, the team saw that the polymer carrying a chemotherapy drug cured 50-80% of the mice (depending on whether they got one or two injections) with metastases in the lung.

After that, the team pre-treated the mice with the polymer — but without the chemo drug attached — before they were injected with melanoma cells.

“We got a significant reduction in the number of lung metastases. The fact that we could achieve this without using the toxic drug is fantastic because the polymer has no side effects. This demonstrates the ability to limit the metastatic spread of cancer cells that are already circulating in the blood in the case of melanoma,” David said.

“Unfortunately, preventing colorectal cancer from reaching the liver is more complicated,” she said.

The technology developed in David’s lab was recently licensed to Vaxil BioTherapeutics for further clinical development. It is conducting testing on large animals and hopes to initiate human clinical trials as soon as possible.

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