Rabies virus and brain cancer

Maxim Rousseau, Polit.roo

Scientists intend to use the properties of the causative agent of a deadly disease – rabies – in the fight against brain tumors (Matt Blois, Science: How to stop brain cancer—with rabies). The rare ability of the rabies virus to penetrate the nervous system makes it a valuable assistant that can deliver nanoparticles intended for cancer therapy to the patient's brain and direct them directly to the tumor without damaging healthy cells. By reproducing the structure of the virus envelope, the researchers have already conducted a successful experiment on its use in laboratory mice.

As is often written in microbiology textbooks, rabies virus (Rabies lyssavirus) has the "shape of a rifle bullet", although if desired, it can be compared with lipstick. It really looks like a cylinder, one end of which is flat, and the second is conical or rounded. The length of such a cylinder is 75 – 180 nanometers, the diameter is about 75 nanometers. Inside the "bullet" contains the genetic material of the virus – a single DNA strand connected to a nucleoprotein. The outside is a protein shell. It is covered with small protrusions 5-10 nm long and 3 nm in diameter. This is glycoprotein G, which is responsible for the connection of the rabies virus with receptors on the cell surface and the penetration of viral RNA inside.

Many viruses have clear preferences for choosing the type of tissue in which cells they will multiply. The rabies virus settles in the nervous tissue. Once in the body, it quickly penetrates into the nerves closest to the insertion site and reaches the central nervous system through them. Once located in the brain, it begins to move along other nerves to the peripheral parts of the nervous system. The rate of spread of the virus through the nerves is approximately three millimeters per hour. It is its relatively slow progress that makes it possible to effectively use the rabies vaccine after infection. When the nerve cells of the brain are affected, all the clinical symptoms of rabies appear, which, if timely measures were not taken, leads to the death of the patient.

Rabies virus particles under an electron microscope.
Photo: Electron Microscopy Unit AAHL, CSIRO

The ability of the rabies virus to penetrate nerve cells and reach the central nervous system means that it does not need to overcome the so-called blood-brain barrier. This barrier is not a separate organ, but a system of cells from the inner surface of the blood capillaries of the brain and neuroglia cells, covering the entire blood supply system of the brain and configured so that only the necessary substances penetrate into the brain from the blood, and various microorganisms, toxins, and other potentially dangerous substances do not pass inside. The blood-brain barrier is necessary to protect the brain, but sometimes it becomes a serious obstacle in the treatment of diseases. Medications designed to fight brain tumors are also delayed by a barrier, so every time a drug is developed, this problem has to be solved.

To use the abilities of the rabies virus to solve this problem, scientists thought it was a very suitable idea. Already, there are methods in which a nanocapsule with a therapeutic drug is coated with the same glycoprotein G, which is located on the surface of the virus capsule and allows it to penetrate the central nervous system.

Now, scientists from the Songyungwan University in Seoul have taken the next step. Yu Seok Yong and his colleagues developed gold nanoparticles that were coated with surface proteins of the rabies virus. The size and shape of these particles corresponded to the size and shape of the virus. Compared with the previously used spherical and smaller nanoparticles, their surface area was larger, which facilitated the connection of glycoprotein with cell membranes.

In the experiment, nanoparticles were injected into the tail vein of four experimental mice that had brain tumors. As the authors of the work expected, nanoparticles quickly penetrated into the brain and accumulated in areas affected by tumors. Although they did not carry any chemical agent, the gold reacted to near-infrared laser radiation, warming up to about almost 50°C. Heating caused the death of tumor cells without harming other parts of the body. As a result, the size of the tumors was significantly reduced. The results of this experiment are described in the journal Advanced Materials (Lee et al., Rabies Virus-Inspired Silica-Coated Gold Nanorods as a Photothermal Therapeutic Platform for Treating Brain Tumors).

In another experiment, mice were injected with tumor cells into the lateral regions of the abdominal wall. After the introduction of gold nanoparticles with viral glycoprotein and irradiation with an infrared laser, the effect was again achieved. In two mice, the formed tumors disappeared, and in the rest they halved in size.

The new method is clearly promising, although not everything in it is clear yet. And most importantly, scientists are still unclear exactly how the nanoparticles used reach the tumor. Yoo Seok-yeon suggests that they are moving, like a rabies virus, through the nervous system. But not everyone is convinced of this. For example, Rachael Sirianni from the Barrow Neurological Institute in Phoenix notes that in the experiments of Yu Sek Yong, nanoparticles reached the brain much faster than the rabies virus did. It took only a few hours from the injection to the accumulation of nanoparticles in the tumor area. This raises the suspicion that at least the main part of the way they travel through the circulatory system. Sirianni does not deny the effectiveness of nanoparticles in suppressing tumors, but is not sure that researchers are able to control the distribution of all nanoparticles in the body. Some of them do reach the tumor, but it is possible that single nanoparticles remain in blood vessels, between cells, so that when they are heated by a laser, healthy cells will also be damaged.

Feng Chen of the Memorial Sloan Kettering Cancer Center in New York points to another problem. Nanoparticles can have toxic effects on the body. Usually particles of this size accumulate in the liver, and the excretory system spends a lot of time trying to cope with them. This, according to Chen, may complicate the admission of the method to human clinical trials and its approval by regulatory authorities.

But, according to Yu Seok-yong, such obstacles should not arise. The results of his experiments show that nanoparticles accumulate mainly in tumors and are able to compete with other methods of treatment in terms of the effectiveness of cancer cell damage and the preservation of healthy ones.

Portal "Eternal youth" http://vechnayamolodost.ru  13.02.2017