Researchers have developed polymers that bind to proteins that play a key role in cancer and inflammation, thus preventing - in mice - the formation of metastases and slowing down the progression of arteriosclerosis and hepatitis
Studies show that inflammation increases the risk of cancer and that both processes have much in common. In the inflammatory process and in cancer, the same proteins that play an important role in the progression of the disease are disrupted. Cancer cells are characterized by accelerated and uncontrolled division, work to produce and recruit blood vessels in their environment and can migrate in the bloodstream or lymph and in the process lead to the production of metastases. One of the proteins common to cancer and inflammation processes is E-selectin. This protein contributes to the adhesion of white blood cells (which belong to the immune system) to blood vessels in inflammatory situations, and also allows cancer cells to adhere to blood vessels in the microenvironment of the tumor, thereby contributing to the production of metastases.
What is the question? How can the development of malignant and inflammatory diseases be delayed without poisoning the body and causing side effects?
Prof. Ayelet David from the Department of Biochemistry and Clinical Pharmacology at Ben-Gurion University of the Negev and her team are developing new drugs to treat cancer and inflammation. In the past, they developed conjugates of a chemotherapy drug and a synthetic polymer (a giant molecule consisting of repeating subunits linked together), which led the drug precisely to the tumor area.
To improve the targeting of the drugs at the tumor site, they attached to the polymer a targeting molecule (peptide) that can bind to E-selectin expressed on blood vessels in the tumor environment. Thus, thanks to their size (nanometers), the polymer-drug conjugates stayed for a long time in the bloodstream of mice with metastases of skin cancer, bound mainly to the pathological blood vessels and destroyed them - and thus cured about 50% of the mice, and this without causing them significant side effects . The polymer conjugated to the peptide and the drug (P-Esbp-DOX) binds to the E-selectin protein, which is expressed on the surface of endothelial cells that line the blood vessels in the tumor environment, enters the cells, releases the drug inside them and kills them.
In their latest research, which won a grant from the National Science Foundation, the researchers examined the ability of the polymer bound to E-selectin to inhibit processes that lead to the production of metastases even without a chemotherapy drug. On the surface of melanoma cancer cells there are sugars that bind to E-selectin. The binding slows down the rolling of the cancer cells on the blood vessels and allows them to leave the blood stream to secondary tissues (metastasizing).
According to Prof. David, "Surgery to remove a cancerous tumor can encourage the formation of metastases due to the detachment of cancerous cells from the tumor, their penetration into the bloodstream and their migration to distant organs. E-selectin has a key role in the process, so we developed a preventive treatment that binds to it and blocks it, without causing significant side effects. The results obtained so far showed that in mice that received preliminary treatment with a polymer-peptide conjugate (without drug), in a one-time injection, melanoma metastases in the lungs were prevented."
Additional experiments performed by the researchers in mice with chronic inflammation (for example atherosclerosis and liver inflammation) demonstrated the adhesion's ability to prevent damage to the heart muscle, which results from increased filtering of inflammatory cells into sclerotic tissue mediated by E-selectin, without anti-inflammatory drugs. Thus, in one of their experiments, the researchers injected into mice with atherosclerosis the conjugate of a polymer with a ligand that binds to E-selectin, once a week, for a month. In the ultrasound and other tests done on the mice, it was found that the hardened arteries tightened, the plaque was less detached from them and thus embolisms were avoided, and the function of the heart muscle (its contraction) improved significantly compared to a group of control mice that were not treated.
Surgery to remove a cancerous tumor can encourage the formation of metastases due to the detachment of cancerous cells from the tumor, their penetration into the bloodstream and their migration to distant organs.
In another experiment, the researchers developed another polymer without any medicinal substance that binds to a protein that is highly expressed on the surface of cancer cells, which contributes to their migration and the formation of healthy metastases (named CD44v3). They injected breast cancer cells that express CD44v3 into the bloodstream of mice and pretreated them with a drug-polymer conjugate that binds to CD44v3. Thus, the cells' ability to migrate and produce healthy metastases decreased. "We examined the number of breast cancer colonies and saw that treated mice almost did not develop metastases. This is compared to control mice treated with a polymer that cannot bind to CD44v3, says Prof. David.
In other words, the researchers were able to develop polymers with biological activity that can block proteins that contribute to the formation of metastases, without using chemotherapy. According to Prof. David, "Although the primary tumor was not affected by drug-free polymers, they were able to inhibit the production of metastases - the main cause of death from cancer. That is, in the experiments described we developed a kind of phase II treatment, safe and non-toxic, which eliminates the ability of the tumor to continue developing. In the future we will try to incorporate non-chemotherapeutic drugs into it to delay an already established disease. In addition, we will examine the use of new unique polymers, without drugs, to inhibit other key molecules that contribute to the development of tumors."
Life itself:
Prof. Ayelet David, born in Moshav Nebatim, mother of a child, lives in the Yishuv Omer. In her free time she likes to sculpt, read books and travel.
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