Featured Lendület Researcher: Péter Kele

Peter Kele first won a grant from the Momentum Programme in 2013, and then won the Advanced Grant category in 2024. His first Momentum proposal was for the development of fluorescent markers that can be introduced into the body in a biocompatible manner and then attach to specific molecules there.

Péter Kele

As a result of their research at the time, they were able to deliver these markers into cells without damaging them. This is important because labelling cells or structures within cells helps us to understand how they work. They have also managed to ensure that their markers only emit a fluorescent signal (which they can then detect) when the specific binding to the target molecule has actually occurred.

Every Jack has his Jill

“We deal with bioorthogonal chemistry – the prefix ‘bio’ refers to biocompatibility, and orthogonality refers to the high selectivity of reactions,” says Kele.

“We work with functional groups that are foreign to the organism, biologically and chemically inert, looking for their own partner, and when they find it – like Jack meeting his Jill – they bond with it.”

The research team developed photoresponsive compounds whose sensitivity to light could be switched off. Photoresponsivity refers to a molecule’s ability to react when excited by light. During the first Momentum grant, the main function of this photoresponsiveness was to make the marker molecule glow with a different color of light when excited by light. They managed to switch off this luminescence with bioorthogonal functional groups, so the marker molecules no longer glowed, or only glowed very weakly. Then, when the specific chemical reaction took place, that is, when the marker compound was combined with the biomolecule to be examined (e.g. a specific protein), their photoresponsiveness was restored, that is, their luminescence was switched on. Thus, only the specifically labelled protein was detected. The markers that were only physically attached to other biomolecules did not emit a signal (background fluorescence), since no chemical reaction occurred there.

Physical after chemical targeting

From a biological studies perspective, the red region of the spectrum is the most interesting, because red light penetrates tissues more effectively and less non-specific autofluorescence from the body’s own naturally fluorescent molecules is measured (that is, less noise). However, it is in this wavelength range that fluorescence is less effective at switching on and off. Therefore, the research team has spent the last ten years, including the previous Momentum grant period, working on structural solutions to efficiently switch off photoresponsivity in the red range. In the meantime, they have extended their scope of interest to other photoresponsive compounds that respond differently to light.

“Irradiation with light results in the breakdown of a bond in these compounds. The molecules that can do this are called photosensitive protecting groups, and are of interest to us because they can be used to temporarily switch off the activity of, for example, pharmaceutical compounds,” continued Kele.

“In our case, this activity mainly refers to the activity of different therapeutic agents. For example, with this method we can reduce the activity of certain chemotherapeutic agents by two to three orders of magnitude so that they can be used in larger quantities.

In other words, in theory, once the patient has received the chemotherapy drug blocked by photosensitive defence groups, the area to be treated (the tumour) can be irradiated with light. The photosensitive compounds then release the active ingredient, restoring its activity. Since light can be very well targeted, the treatment can be very site-specific. In other words, the effect of the agent can be limited to a very narrow area.

However, not all tumours can be localised, or they may be scattered over a larger area. In such cases, we do not benefit from the excellent targeting power of light, as we do not know where to shine it.

“In this project grant, we are therefore adding chemical targeting to the physical targeting of light. We are, so to speak, drawing a chemical crosshair on target cells, for example, tumour cells. This way, the bullet spray will only damage the cancer cells, while the healthy cells will remain bulletproof. And how do we do this? By transferring the knowledge we gained in the first Momentum grant, which we used to switch light sensitivity on and off, to the other type of photoresponsivity, that is, by turning off the bond-cleaving ability of the photosensitive protecting groups with a bioorthogonal functional group. The photosensitive protecting groups attached to the chemotherapeutic agent are then specifically linked to the target cells by covalent bonding, whereupon they regain their photoresponsiveness. Then, by illuminating the tissues, even over a larger area, the chemotherapeutic agent is activated only on the targeted cells and, in lucky cases, kills the tumour.”

“Magic bullet”

Targeted drug delivery is not a new idea, as Nobel Prize-winning German physician Paul Ehrlich developed the concept of the “magic bullet” over a century ago, borrowing the idea from Carl Maria von Weber’s opera The Marksman. In the opera, the magical hunter always hits the target with his bullet. “We don’t aim at all when we shoot (when we deliver the active ingredient), we shoot all over the place,

but the projectiles only do damage where it is needed.

It’s like shooting the whole battlefield, but only the enemy soldiers who are marked and thus lose their protection would die, while our own soldiers would not be harmed by the bullet spray,” says Kele, explaining the essence of the method. “Although cancer is the most important indication, this approach could also be used to specifically treat fungal or bacterial infections. In the same way, cancer cells that are spread over a large area and are difficult or impossible to localise can be selectively killed if we can effectively mark them and then use light to break down their protective group.”

According to the researcher, this is currently only a vision, and the aim of the Momentum research is to create the chemical toolbox for this approach. They are looking for solutions in which photoresponsiveness can be switched off and on as specifically as possible. In this way, they hope to ensure that photosensitivity is restored only inside or on the surface of cancer cells. They currently have two photosensitive compounds whose photoresponsiveness they have managed to modulate (turn on and off) using bioorthogonal functional groups. The next stage will be to test these compounds in a cellular environment to see if they can achieve the desired high degree of selectivity. If these experiments yield encouraging results, they will move on to in vivo mouse and rat experiments. This will raise another problem to be solved: how can they get the light to the tumour site?

Illuminating tumours on the surface of the skin is easy, but reaching deeper tissues is problematic. “There are several ways to do this, and here we will rely heavily on existing procedures that use light and are already used in clinical practice,” he continued. “One such treatment is photodynamic therapy, which involves the release of reactive oxygen species, but the important thing from our point of view is that we have a well-developed infrastructure for this therapy. We can use fibre optics to deliver light to the target area, but it’s not too far-fetched to surgically open up the surface to make the affected tissue accessible to the light.”

Kele said that this is a very competitive field of science, and new solutions for delivering light to the target are emerging every week. For example, a few months ago, an article appeared in Science about how food dye was applied to the skin of mice, and once the dye was absorbed, the refractive index of the skin became similar to the refractive index of the tissues, making the skin transparent to light in certain wavelength ranges.