The transfer of chemotherapy drugs in the form of nanoparticles can help reduce the frequency of side effects thanks to the fact that the drugs are delivered directly to the tumor area
![The new nanoparticles consist of polymer chains (in blue) and three different drug molecules - doxorubicin in red, the small green particles symbolize the drug camptothecin and the larger green core the drug cis-platinum. [Courtesy of Jeremiah Johnson]](https://www.hayadan.org.il/images/content3/2014/04/TripleDrug-500x333.jpg)
The transfer of chemotherapy drugs in the form of nanoparticles can help reduce the frequency of side effects thanks to the fact that the drugs are delivered directly to the tumor area. In recent years, scientists have succeeded in developing nanoparticles capable of delivering one or two chemotherapy drugs, but it has been very difficult to design particles capable of carrying a larger number of drugs simultaneously.
Now, chemists from the Massachusetts Institute of Technology (MIT) have developed a new method for building such nanoparticles, into which it is easier to insert three or more drugs. The research findings were recently published in the scientific journal Journal of the American Chemical Society. "We believe this is the first example of a nanoparticle capable of carrying a precise number of three drugs and releasing them in response to three separate triggering mechanisms," said Jeremiah Johnson, professor of chemistry at MIT and lead author of the new paper.
These particles can be designed to deliver an even greater number of drugs, allowing researchers to develop new treatments that can eradicate cancer cells more effectively while avoiding the side effects associated with standard chemotherapy treatments. As part of the article, the researchers demonstrated that their new nanoparticles are able to eliminate ovarian cancer cells more effectively than particles carrying only one or two drugs, and after this step the researchers began to test these particles against tumors inside the uterus.
The researchers' new approach overcomes the limitations inherent in the two most common methods for preparing nanoparticles that carry drugs: the introduction of small drug molecules into the particles (encapsulation) and their chemical binding to the particle. When using these two methods, the reactions required to create the particles become more and more challenging with each additional type of drug. The combination of these two methods has shown some success, but it is still limited to only two drugs.
The researchers wanted to develop a new type of particle that could overcome these constraints, and that would be able to carry any number of different drugs. Instead of preparing the particle and then attaching the drug molecules to it, the researchers created building blocks that already contain the drug. These building blocks can be connected in a very defined structure, and thus the researchers can precisely control the ratio of drugs embedded in the particle.
Each of the building blocks consists of three components: the drug molecule, a linking unit that can be connected to other building blocks and a chain of polyethylene glycol (PEG) that prevents the array from breaking down inside the body. Hundreds of these building blocks can be connected using an approach that the researchers developed and which is called "brush first polymerization".
"This is a new way to build the particles from scratch," says the lead researcher. "If I want to make a particle that contains five different drugs, I simply take five suitable building blocks and connect them together into the particle. Basically, there is no limit to the number of different drugs that can be added, and the ratio of the drugs carried inside the particle depends only on how they are mixed at the beginning of the process."
For the purposes of this article, the researchers prepared particles containing three anticancer drugs (cis-platinum, doxorubicin, and camptothecin) that are commonly used individually or in combination to treat ovarian cancer. Each particle carries within it three drugs in a defined ratio that precisely corresponds to the maximum dose of each of the drugs separately, when each of the drugs has its own release mechanism: cis-platinum is released as soon as the particle enters the cell, since the bonds connecting it to the particle are broken upon exposure to glutathione, which functions as an antioxidant and which is found inside the cells; Camptothecin is also rapidly released once it meets cellular enzymes called esterases; The third drug, doxorubicin, was designed to be released only when exposed to ultraviolet radiation. After all three drugs are released from the particle, all that remains is the substance polyethylene glycol, which biodegrades easily in the body.
This approach "represents a new and sophisticated breakthrough for the release of multiple drugs through the inclusion of different drugs, through different chemical mechanisms, within a single system," says Professor Todd Emrick. The researchers are currently examining particles that carry four different drugs inside them, and they also plan to tag the particles with molecules that will appear on the cancer cells thanks to a reaction with specific proteins located on the surface of the cell. The researchers also believe that the ability to reliably produce large quantities of nanoparticles carrying several different drugs will enable practical testing of new treatments against cancer.
