The fact that our immune system captures and destroys nanoparticles and the drugs they carry has been a problem in the field of nanomedicine for some time. But in the fight against cancer, researchers are trying to use this problem to their advantage.
Researchers around the world are striving to identify ways to use nanoparticles in the treatment of disease. Such particles are about 100 nanometers — one-thousandth of a millimeter — in diameter, and inside them researchers are injecting large numbers of even smaller drug molecules.
Optimism about this approach to the treatment of various types of cancer was extraordinary.
We observed that the walls of blood vessels in tumor tumors in mice have larger pores than the same vessels in healthy tissue. If we inject the nanoparticles into the blood, the holes make it easier for them to get out of the blood vessels and into the tumor..
Sjoerd Hak, researcher at the Norwegian Science Institute SINTEF
“Nanoparticles cannot escape in healthy tissues with intact blood vessels,” Hack tells Gemini.
Knowing this makes it easier to target the drugs where they are needed, and we can also limit the amount of drugs that reach the parts of the body that might cause harm.
However, nanomedicine faces a major challenge. Our immune system rejects small and unfamiliar foreign bodies.
Virus or drug?
“Nanoparticles are the same size as a virus and are made up of molecules that don’t normally belong in the blood naturally. This means the body can find them and remove them,” Hack explains.
As a result, the nanoparticles do not stay in the blood long enough to deliver an adequate drug dose to the target tumor.
“A lot of our research is focused on developing particles that can stay in the blood longer,” Hack says. “We’ve had some success, but drug uptake by tumor tissue is still limited. We’ve had a lot of great results in mice, but the effect in humans remains somewhat limited,” he says.
Like many other technologies with the prefix “nano-“, it will take some time for nanomedicine to live up to the expectations it created a decade or two ago.
“Relative to the scale of this field of research, very little progress has been made in terms of clinical treatment. But we will get there – I’m sure of it,” says Hack.
Meanwhile, he and his colleagues are testing an alternative route to tumors for nano-medicines. Instead of fighting the immune system, the new approach is to team up with it and play along.
Aggressive immune cells
It is very difficult to prevent nanoparticles from being consumed by immune cells. Such cells are specialists in searching for and removing foreign bodies. In addition, our knowledge of the role these cells play has greatly improved, and a number of new treatments have been developed in a field known as immunotherapy.
“We are trying to combine these two aspects as part of our research, and we are not alone,” says Hack. “There are a lot of researchers around the world who have realized this and are trying to exploit the interaction of immune cells,” he says.
“Our goal is to use the body’s own defense mechanisms to attack cancer. We don’t necessarily want to target cancer cells directly, but we want to create the right conditions for their growth and development,” explains Hack.
Targeting drugs directly to cancer cells is not the most important thing. The main focus here is what these drugs do when they interact with immune cells and the immune system.
What is happening in living tumors?
To achieve this, researchers need to learn more about what happens to nanoparticles and the drug molecules they carry. One of the methods they use is called intravital microscopy.
“Intravital microscopy involves taking films and pictures of living tumors in mice under a microscope,” Hack says. “This allows us to look at individual tumor cells and study the walls of blood vessels,” he explains.
Nanoparticles are too small to isolate, but by illuminating them by themselves, we can track their movement.
“They’re too small to see individually, even under a microscope, but we know where they are because we can detect their fluorescence,” Hack says.
“We see that the immune cells are moving and that they’re taking up a lot of fluorescent particles,” Hack says. “Inside the tumor, we can see cells that are very immobile and have taken up particles,” he explains.
“We see that some immune cells actually seem to be responsible, at least in part, for taking up the particles in the tumor. This can’t be seen using methods other than intravital microscopy,” Hack says.
Such information cannot be obtained using MRI or PET scanning methods.
“Intravital microscopy has given us a better mechanistic understanding of how these particles accumulate in the tumor,” Hack says.
Changing the behavior of immune cells
Researchers have shown that the particles can actually be taken up by immune cells inside the tumor. The next step is to identify the right medication and ensure that it has a therapeutic effect. The immune cells’ natural response is to try to destroy the nanoparticles, and they are well equipped to do so.
“Immune cells try to break down the particles,” Hack says. “They contain different enzymes and acids, as well as specific sites or compartments that send the material to be destroyed,” he says.
These immune cells are called by researchers phagocytes, from the Greek “eating cells. Hack and his colleagues are trying to manipulate these phagocytes to change their behavior.
“We are working with two different drugs encapsulated inside the nanoparticles and are now trying to see how they affect the immune cells,” Haq explains.
They target phagocytes because they can “switch sides” and work for the tumor rather than against it.
“We know that these cells play an important role in tumor growth and development. The tumor tricks them and works to their advantage,” Hack says.
“What we’re trying to do is control or turn off the functions of the cells that work for the tumor,” he says.
Promising test results in mice
In practice, this means that researchers are trying to increase the uptake of nanoparticles by immune cells. This is in stark contrast to what medical research has been trying to achieve for years. They are currently investigating how the process works in isolated human immune cells and in mice with breast cancer.
“A few weeks ago, we completed the first therapeutic experiments and the results are very exciting,” says Hack. “But there is still a lot of work to be done before any conclusions can be drawn. “It will take time to figure out exactly how we proceed and what concentrations and incubation times are best,” he explains.
“There’s a lot we need to figure out before we can say this technique works,” Hack says. “Maybe we’ll find that using the two drugs we’ve chosen won’t work at all. In this case, we may have to start from scratch again with new drugs,” he says.
A major hurdle in the process, not only for this project, but for the entire field of nanomedicine, is trying to persuade the drug-carrying particles to leave the compartments where cells have sent them for destruction.
“The molecules we’re using seem to escape,” Hack says. “Our first results confirm this, so I think we will succeed, although it is too early to say for sure,” he says.
Possibilities of innovative approaches
As with all medical research, many small steps must be taken before new treatments can be applied to patients. Sjoerd Haak sees the project as part of a much bigger picture.
“Certainly, it would be very interesting if we could find a treatment that works well enough to warrant further investigation of the same nano-drug that we are developing,” he says.
“But personally, I’m more interested in showing that we can achieve a therapeutic effect using this method, because it opens up a number of new therapeutic approaches,” says Hack.
Momo, J., etc. (2022) Intravital microscopy for real-time monitoring of drug delivery and nanobiological processes. Advanced reviews of drug delivery. doi.org/10.1016/j.addr.2022.114528.
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