Nanotech researcher working on precise cancer drug delivery

Nanotechnology is being used in a variety of fields and is revolutionising medicine. Kostevšek is one of the researchers exploring the technology's capabilities in cancer treatment.

Treatment targetting challenges

Working at Slovenia's foremost research centre, the Jožef Stefan Institute (IJS), Kostevšek is developing a precise targeting method that would deliver the drugs directly to cancer cells without damaging healthy tissue.

"The first obstacle comes up immediately after a drug is injected, as a variety of proteins and immune cells in the blood stream recognise the substance as a foreign body and remove it from the body," Kostevšek illustrated.

The active substances must first be "packaged" so that the immune system does not reject them and ensure that they stay in the blood stream long enough to reach the target tissue. The complex environment within the tumour is yet another challenge, preventing the active substances from entering the cells, one of them being endosomes, cell organelles that destroy anything unwanted in the cell.

Ineffective synthetic nanotech methods

A breakthrough in nanotech targetting happened back in the 1990s, Kostevšek said. Scientists managed to hide doxorubicin, a highly toxic drug, within a liposomal capsule made of polyethylene glycol, that prevented the nanoparticles from being removed from the blood stream.

But wider usage showed side effects, rendering the therapy ineffective. "Our group at the Nanostructure Materials Department of the Jožef Stefan Institute, wants to move away from anything synthetic and we are working on delivery systems using the body's own cells, erythrocytes," said Kostevšek.

Trojan horse to the tumour

The red blood cells are specialised to deliver oxygen to every cell in the body and ferry away carbon dioxide. Kostevšek's team is focusing on these cells for several reasons: "Firstly, they are the easiest of all to isolate from the body in large amounts, we only need a millilitre of blood. But the most important difference is that erythrocytes do not have a nucleus and a DNA, so there is no fear of transmitting the genetic material to another person."

Moreover, red blood cells are a natural delivery system within the body. They have a phospholipid membrane that is permeable to a number of substances and also allows the cells to change their size.

Kostevšek's team isolates the red blood cells and puts them in an artificial environment to subject them to osmotic shock and extract haemoglobin through the membrane pores. Once haemoglobin, which takes up most of the cell's volume, is removed, there is space for an active ingredient.

The substance is inserted through membrane pores and the cells are placed in a blood-like environment that allows the pores to close. The cells are then injected back into the body, which recognises them as erythrocytes, even though their contents are completely different, a veritable Trojan horse making its way to its target.

No side effects

Like any technology, nanotechnology has its downsides, which is why Kostevšek's team is trying to develop delivery methods that use the body's own cells. "There is no fear that the immune system will start attacking its own erythrocytes," said Kostevšek. "All erythrocytes carry certain markers that tell the immune cells that they must not be removed."

To differentiate between the healthy and target tissue, the cells use physiological characteristics and a variety of receptor molecules on the cell surface, which is used for active targetting of cancer tissue.

Researchers hope this approach will replace passive targetting, which is based on particle size and random cell absorption. Due to their increased nutrient demand, the membrane pores of cancer cells are larger than those of other cells. Nanoparticles of up to 700 nanometres can enter cancer cells, while healthy cells allow only particles smaller than ten nanometres.

"In active targetting, nanoparticles are bound with very specific receptor molecules that recognise the more pronounced molecules on the surface of cancer cells, like a key would open a lock. This means that the substances can only enter these cells. There are fewer side effects and a higher concentration of the drug in the tumour," Kostevšek said.

At the moment, the team is using type 0 erythrocytes, which are tolerated by all blood types, but in the future they hope that each patient would get personalised treatment using their own blood cells.

Coming home

While many Slovenian scientists leave to work abroad and might not return, Kostevšek came back despite a successful career abroad. After studying at the Ljubljana Faculty of Chemistry and Chemical Technology, she worked in several labs in Italy and the UK, earning the international Wüthrich International Young Star Award in 2019.

Nevertheless, she returned, telling the STA that work in Italy and the UK "is similar to Slovenia, but the quality of life is significantly better here, especially the work-life balance".