Nanotechnology Combined with Ultrasound Advances Chemotherapy Treatment in Recent Lab Experiments

Many people diagnosed with cancer have been treated with chemotherapy,  have gone on to live healthy lives. However, chemotherapy does impact the body, the treatment attacks all the cells in the body, not just cancer cells.

The result kills healthy cells, which causes many patients to endure major side effects both during and after treatment.

Since existing treatments are not precisely targeted to cancer cells, just 0.01% of chemotherapy drugs actually reach the tumor and its diseased cells.

Last year, Sofie won the Researcher Grand Prix, a Norwegian science communication competition for PhD candidates. When she made her winning presentation about her research during the competition finals, she was involved in the testing of a new technique of cancer treatment on mice.

Now her research has demonstrated that the technique can cure cancer in mice.

Her paper titled, "Ultrasound Improves the Delivery and Therapeutic Effect of Nanoparticle-Stabilized Microbubbles in Breast Cancer Xenografts" has recently been published in the academic journal Ultrasound in Medicine and Biology.

I'm working on figuring out how we can deliver more of the chemotherapy drugs to the tumor and less to healthy cells.

Sofie Snipstad, who recently graduated from the Department of Physics at the Norwegian University of Science and Technology (NTNU).

Promising results

Snipstad's technique targets cancerous tumors with chemotherapy so that more of the drug enters the cancer cells while protecting healthy cells. The technique was tested in mice with an aggressive breast cancer type (triple negative).

Researchers conducted a number of laboratory experiments prior to conducting their tests with mice -- which were the first actual tests using this delivery technique for chemotherapy. Besides causing the tumors to fade during treatment, the cancer has not re-occurred in the trial animals.

This is an exciting technology that has shown very promising results. That the first results from our tests in mice are so good, and that the medicine does such a good job right from the start is very promising.

Snipstad

Here's how the treatment works

In this new technique, the chemotherapy medicine is no longer injected straight into the bloodstream, which causes it to reach both sick and healthy cells, instead the medicine is encapsulated in nanoparticles. When nanoparticles containing the cancer medicine are injected into the bloodstream, the nanoparticles are so large that they stay in the blood vessels in most types of healthy tissues. This prevents the chemotherapy from destroying healthy cells.

Blood vessels in the tumor, however, have porous walls, so that the nanoparticles with the chemotherapy can enter into the cancerous cells.

My research shows that this method allows us to supply 100 times more chemotherapy to the tumor compared to chemotherapy alone. That's good.

Snipstad

However, the nanoparticles can only make contact with cells that are nearest to the blood vessels that transport the drug-laden particles, she said. That means that cancer cells that are further from the blood vessels that supply the tumor do not receive the chemotherapy medicine.

For the treatment to be effective, it has to reach all parts of the tumor. So our nanoparticles need help to deliver the medicine.

Snipstad

Ultrasound is the key

The nanoparticles used by Snipstad and her research team were created at SINTEF in Trondheim. SINTEF is one of the largest independent research organizations in Europe. The particles are unique because they can form small bubbles. The nanoparticles can be found in the surface of the bubbles.

These bubbles are an essential part of the cancer treatment. Another important part is the use of ultrasound, which is Snipstad's area of research.

The bubbles that possess the chemotherapy-filled nanoparticles are injected into the bloodstream. Next, ultrasound is applied to the tumor. The ultrasound makes the bubbles to vibrate and finally burst, so that the nanoparticles are discharged. The vibrations also massage the blood vessels and tissues to make them more porous. This helps force the nanoparticles more into the cancerous tumor, instead of just reaching the cancer cells bordering the blood vessels.

By using ultrasound to transport the chemotherapy-laden nanoparticles into the tumors, our research on mice has shown that we can deliver about 250 times more of the drug to the tumor compared to just injecting chemotherapy into the bloodstream alone.

Three groups, three clear results

The mice were split into three groups:

• Group 1 did not receive any treatment, and the tumor continued to grow
• Group 2 received the treatment using drug-laden nanoparticles. The growth of the tumor stagnated after time, but the tumor did not fade away.
• Group 3 received the treatment using drug-laden nanoparticles, bubbles, and ultrasound. In this group, the tumor reduced in size and slowly disappeared. One hundred days after the treatment was stopped, the mice were still cancer-free.

Fooling cancer cells

For the treatment to be effective, we have to trick the cancer cells to take up the nanoparticles so that the chemotherapy reaches its target.

Snipstad

To examine this process, she has grown cancer cells and analyzed them under a microscope. Here, she noticed that the nanoparticles conceal the chemotherapy drug, allowing the cancer cells to take them up. But for the treatment to function well the nanoparticles have to discharge the cancer drug precisely when and where it is needed.

We can do that by changing the chemical composition of the nanoparticles so that we can tailor properties, including determining how quickly the nanoparticles break down. After the cell takes up the nanoparticle, the nanoparticle dissolves and releases the cancer drug inside the cell. That causes the cancer cell to stop dividing, and it will eventually shrink and die.

Close interdisciplinary cooperation

Snipstad is part of the research group headed by NTNU physics professor Catharina Davies. The group mostly works with nanoparticles.

The NTNU group works in partnership with SINTEF and St. Olavs Hospital in Trondheim. NTNU conducts the animal tests and examines the cancer cells. SINTEF has created the bubbles containing nanoparticles, which offers the research platform. The cancer clinic and ultrasound group at St. Olavs offer their clinical skills.

One of the things that I like about this project is that so many good people with different backgrounds are involved. Trondheim has a very good interdisciplinary environment, and this project needs all of these different disciplines for us to make progress.

Snipstad

No human trials anytime soon

While research results are very encouraging, it will still be some time before the technique can be applied on humans.

It can take from 10-20 years from the time a discovery is made in the lab until it can be used as a treatment. We've been working on this about six years, so we still have a lot to learn. We need to understand more about the mechanisms behind our success and we have to do much more work using microscopes to understand what is happening inside the tissues.

Snipstad

Snipstad said that the discovery also has researchers excited to try out the technique on other types of cancers, because each type of cancer is unique.

Possible treatment for brain cancer

This blend of nanoparticles, bubbles, and ultrasound also paves the way for possibility of treating brain diseases. The brain is safe-guarded by a special blood-brain barrier, which makes it hard to transport drugs to the brain for treatment. This barrier allows only substances that the brain requires to cross through the barrier, which means that for a number of brain diseases, there is no treatment whatsoever.

But there is hope. By using ultrasound and our bubbles we have managed to deliver nanoparticles and drugs to the brain. This may be promising for the treatment of cancer and other diseases in the brain.

Snipstad