Gold nanoparticles kill cancer, but not as previously thought

Gold particles as small as a billionth of a meter are deadly to cancer cells. This fact has long been known, as has a simple correlation: the smaller the nanoparticles used to fight cancer cells, the faster they die. However, a more interesting and complex picture of these interactions emerges from the latest research conducted at the Institute of Nuclear Physics of the Polish Academy of Sciences, using a new microscopic technique.

The gold nanoparticles used to fight cancer cells are smaller than others, which was previously thought. Scientists believed that the smaller nanoparticles would more easily penetrate inside cancer cells, where their presence would lead to metabolic disorders and, ultimately, cell death.

The reality, however, is more complex, as demonstrated by research conducted by scientists from the Institute of Nuclear Physics of the Polish Academy of Sciences (IFJ PAN) in Krakow, supported by theoretical analyses carried out at the University of Rzeszow (UR) and the Rzeszow University of Technology.

“Our institute runs a state-of-the-art medical and accelerator center for proton radiotherapy. So, when reports emerged a few years ago that gold nanoparticles could be good radiosensitizers and improve the efficacy of this type of therapy, we started to synthesize them ourselves and test their interaction with cancer cells. We quickly discovered that the toxicity of the nanoparticles was not always as expected,” explains Dr. Joanna Depciuch-Czarny (IFJ PAN), initiator of the research and first author of a paper discussing the results, published in the journal Little.

Nanoparticles can be produced using a variety of methods, resulting in particles of various sizes and shapes. Shortly after starting their own experiments with gold nanoparticles, physicists at IFJ PAN noticed that biology does not follow the popular rule that their toxicity is greater the smaller they are.

The 10-nanometer spherical nanoparticles produced in Krakow proved to be practically harmless to the studied glioma cell line. However, high mortality was observed in cells exposed to 200-nanometer nanoparticles, but with a star-shaped structure.

The elucidation of the stated contradiction became possible thanks to the use of the first holotomographic microscope in Poland, at the IFJ PAN.

A classic scanner scans the human body using X-rays and reconstructs its internal spatial structure section by section. In biology, a similar function is now provided by the holotomographic microscope. Here the cells are also scanned by a beam of radiation, but not high-energy radiation, but electromagnetic radiation. Its energy is chosen so that the photons do not disrupt cellular metabolism.

The result of the analysis is a set of holographic sections containing information on the distribution of refractive index changes. Since light refracts differently on the cytoplasm and on the cell membrane or nucleus, it is possible to reconstruct a three-dimensional image of the cell itself and its interior.

“Unlike other high-resolution microscopy techniques, holotomography does not require sample preparation or the introduction of foreign substances into the cells. The interactions of gold nanoparticles with cancer cells could therefore be observed directly in the incubator, where the latter were grown, in an undisturbed environment – and with nanometric resolution – from all sides simultaneously and practically in real time,” lists Dr. Depciuch-Czarny.

The unique characteristics of holotomography allowed physicists to determine the causes of the unexpected behavior of cancer cells in the presence of gold nanoparticles. A series of experiments was carried out on three cell lines: two gliomas and one from the colon. Among other things, it was observed that although the small spherical nanoparticles easily penetrated the cancer cells, the cancer cells regenerated and even began to divide again, despite the initial stress.

In the case of colon cancer cells, the gold nanoparticles were quickly expelled. The situation was different for large star-shaped nanoparticles. Their sharp tips punctured cell membranes, which likely led to increased oxidative stress inside the cells. When these cells were no longer able to repair the increasing damage, the mechanism of apoptosis, or programmed death, was triggered.

“We used the data from the Krakow experiments to build a theoretical model of the nanoparticle deposition process inside the cells studied. The end result is a differential equation into which properly processed parameters can be substituted – for now only describing the shape and size of the nanoparticles – to quickly determine how uptake of the analyzed particles by cancer cells will proceed over a period of time. of time,” explains Dr. Pawel Jakubczyk, professor at UR and co-author of the model.

He emphasizes: “Any scientist can already use our model at the design stage of their own research to instantly reduce the number of nanoparticle variants requiring experimental verification. »

The ability to easily reduce the number of potential experiments to be performed translates into reduced costs associated with purchasing cell lines and reagents, as well as a marked reduction in research time (it typically takes about two weeks to culture a commercially available cell line). In addition, the model can be used to design more targeted therapies than previously possible, in which nanoparticles will be particularly well taken up by selected cancer cells, while maintaining relatively low or no toxicity to healthy cells in other organs of the patient.

The group of scientists from Krakow-Rzeszow is already preparing to continue their research. New experiments should soon allow extending the model of interaction of nanoparticles with cancer cells to other parameters, such as the chemical composition of the particles or other types of tumors. Further plans also include supplementing the model with mathematical elements to optimize the effectiveness of phototherapy or proton therapy for the indicated combinations of nanoparticles and tumors.