Anti-cancer glue
"Molecular glue" based on a pair of proteins helped to create a new system for the delivery of drugs against cancer
RNF Press Service
Drugs to combat oncological diseases should not only selectively affect the tumor, but also have a minimal general toxic effect on the body. Russian scientists have proposed an elegant way to solve this problem using a pre-targeting approach. First, the neoplasm is "marked" with a non-toxic, harmless to the body targeted component, then a highly toxic component is introduced, which, binding to the precursor, accumulates precisely at the site of the tumor. And all this is thanks to the "molecular glue", the role of which is performed by two natural proteins — barnase and barstar. The results of the study, supported by a grant from the Russian Science Foundation (RNF), are published in the Journal of Controlled Release.
The scheme of the experiment. Source: Shramova et al. / Journal of Electroanalytical Chemistry, 2021.
According to the World Health Organization, cancer is among the ten most common causes of death in the world. So, in 2020, it led to the death of ten million people, so new ways to combat this disease are being actively developed. Drugs usually contain cytotoxic compounds — substances that stop the growth and division of cancer cells and cause their death. The difficulty of using such drugs is that they must act pointwise — only at the site of tumor formation, otherwise healthy cells will be destroyed. To date, there are a large number of drugs on the pharmaceutical market that affect cancer, but, unfortunately, have a high general toxicity.
Researchers from the M. M. Shemyakin and Yu. A. Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences (Moscow), the A. M. Prokhorov Institute of General Physics of the Russian Academy of Sciences (Moscow), the Research Institute of Human Morphology (Moscow), Tomsk Polytechnic University (Tomsk) and the Engineering Physics Institute of Biomedicine (Moscow) have developed a new method of stepwise drug delivery to tumor cells, which will reduce the general toxic effect of anticancer drugs. Scientists have proposed using two bacterial proteins: the enzyme barnase and its natural inhibitor (suppressor) barstar. They bind very quickly and firmly to each other and can serve as a "molecular glue" that allows you to connect in a living organism a non-toxic targeted component that recognizes a tumor and a highly toxic component that kills it. In order for these two components to meet in the body, one of the proteins of the molecular pair — barnase or barstar - was attached to each of them by genetic engineering methods. As the first targeted component, the scientists used an artificially created protein that recognizes the receptors of breast cancer cells. This protein has been linked to barnase. As a cell—killing substance, scientists used a bacterial toxin enclosed in artificial membrane vesicles - liposomes. In order for the liposome to find barnase in the body and contact it, barstar molecules were attached to the surface of the bubble.
The scientists tested the developed method on laboratory mice that were vaccinated with human cancers. First, sixteen animals were injected with breast cancer cells under the skin. Ten days later, when the tumors began to grow, treatment was started. To do this, the first targeting component was injected into the abdominal cavity of four mice, which "sat down" on the receptors of cancer cells. After the first component, which did not bind to the tumor, was naturally excreted from the animal's body, the second, cytotoxic, was injected. The two components were firmly "glued" exactly at the site of the tumor, thus delivering the medicine strictly to the right place. The procedure was repeated daily for ten days. As a control group, the scientists used four mice that were injected with placebo instead of drugs, and eight animals that received an incomplete set of components: either only the first or only the second of them.
Observations of the condition of mice and the size of their tumors lasted twenty-eight days from the beginning of treatment. It turned out that in animals that received a placebo or only one part of the drug, the tumors increased 3-5 times and formed metastases. On the contrary, in mice that received a complete two-component system, the size of neoplasms decreased by 71%, and metastases were not observed. At the same time, histological analysis of vital organs showed the absence of their damage, and hence general toxicity.
"There are only four systems in the world for pre-targeting a drug to a tumor. They are mainly designed for radiotherapy to reduce the radiation load on the patient's body, but each of them has its drawbacks. Among them, it is possible to note the undesirable activation of the immune response, the complexity and high cost of production. The components of the system developed by us — barnaza and barstar — do not have non-specific targets in the mammalian body, and therefore provide high selectivity of therapy. In addition, both barnase and barstar can be easily combined with any proteins that recognize any cancer markers using genetic engineering methods. As a result, such a "molecular glue" becomes a convenient, reliable and universal system for preliminary targeting of a variety of tumors and can form the basis for the development of new effective methods for combating malignant neoplasms," says Sergey Deev, project manager for the RNF grant, academician, Doctor of Biological Sciences, head of the Laboratory of Molecular Immunology at the Institute of Bioorganic Chemistry of the Russian Academy of Sciences.
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