Israeli development may enable a targeted attack on cancerous tumors through the sophisticated activation of several drugs at the same time
Dr. Doron Shabat from the School of Chemistry at Tel Aviv University deals with the design and preparation of chemical substances that work in biological systems. A few years ago Shabat became aware of a new approach in drug development, called healing Using a prodrug. In this approach, a chemical group is attached to the drug that blocks its biological activity. This chemical group can be removed, and thus the active drug is returned the biological
"The possibilities inherent in this field fascinated me," Shabat says. "Much research is devoted today to the design and creation of 'smart' drugs, which will only act against cancer cells. If we can build an effective prodrug that will be activated by a protein that is found and acts to an increased degree in cancer cells or in their environment and is missing or has little activity in healthy cells, we will be able to obtain a drug that will act in a way Selective on cancer cells".
"Since I'm a chemist, I don't have the tools to control the activity of the protein in the cancer cells. That's why I decided to focus on controlling the activity of the drug," says Shabat. "The simplest way is to block the activity of an existing anti-cancer drug using a molecule known to a protein found only in cancer cells. The blocked drug will indeed come into contact with all the cells of the body, but it will not work in healthy cells, while in cancer cells the protein will release the barrier and the drug will work."
The downside of the method is that it is often difficult to activate a sufficient amount of prodrugs to create a lethal dose of an active drug that can kill the cancer cells. For example, there may be a situation where the protein found in the cancer cell is able to activate only one drug unit in a given time unit, even though to kill the cancer cell two such units are needed and sometimes even more.
Shabat and the research group he leads were looking for a molecule to which many drug units can be attached and whose chemical components can be played with so that in some cases its activity is blocked and in other cases the barrier is removed and the drug is active. The choice fell on molecules called dendrimers. These are large artificial molecules that form a branched and symmetrical structure similar to a tree splitting into branches. A drug unit can be attached to the end of each branch, and in this way many drug units are attached to the dendrimer.
"The structure of the dendrimers fits exactly what we were looking for," says Shabat. "It is possible to block the activity of the dendrimer in a planned way so that the opening of the block is done with a protein - for example, a protein that is only found in cancer cells. Dendrimers are currently used to carry drugs to tumors cancerous, but so far they have been used to carry drugs that are activated individually. Our group has designed special dendrimers based on a self-destruction mechanism, which allow the release of a large number of drugs in the same time at the destination site.
"In the system we developed, the drug molecules are bound to the ends of the dendrimer and a chemical or biological switch is bound to its core. The release of the switch initiates a chain process, as a result of which the dendrimer breaks down into fragments and all the drugs are released from the ends. The action of the dendrimer resembles a chain reaction of several explosive charges, activated by a single switch." Since certain dendrimers are known to be able to enter the cell easily, they can serve as an excellent platform for carrying drugs into cells.
Shabat and his team built a system that binds up to eight markers simulating different drugs, which are released as soon as the switch is cut. In the first stage, the team of researchers checked whether the principle of operation works. When they added the activating protein to the dendrimer system they designed and applied it to cancer cells, a greater killing effect was obtained compared to a classical prodrug in which only one drug is released at a time. About a month ago, the results were published in the prestigious German chemistry journal "Angewandte Chemie" alongside the publication of similar results by a research group in the Netherlands. These systems, named "dendrimers with a self-destruct mechanism", were reviewed last week in the journal "Nature" and received rave reviews in other leading journals.
The next step in the research is to attach drugs to the dendrimer skeleton, create the switch that activates the dendrimer and connect it so that it can be removed under the unique conditions prevailing in living cells. Shabat and his group are already moving in this direction. They attached to the dendrimer skeleton two different anticancer drugs and created a switch that is activated by biological substances. When they activated the dendrimer they had built in cultures of cancer cells, the two drugs were released and began to work. The inhibition achieved in the growth and proliferation of the cancer cells was 50 times greater compared to cancer cells that received a mixture of the two prodrugs separately. The results of these experiments are now being published. "The ability to combine two different drugs in the same dendrimer unit and release them at the same time makes it possible to attack the cancer cell with two different mechanisms, thus increasing the intensity of the treatment and the killing effect," says Shabat. "In such a case, any drug can be used in a relatively small amount and thereby reduce the degree of immunity of the cancer cells to the drug."
The dendrimer systems developed by Shabat and his group are protected by an international patent, and Tel Aviv University's "Ramot" company handles their business promotion. Shabbat emphasizes that a lot of development of the systems is needed before it can be used for healing purposes.
Marit Sloin, Haaretz, voila!
