Towards selective elimination of cancer cells using molecular cages

Chemotherapy saves the lives of cancer patients. However, these treatments are not free of side effects and other limitations, so there is a great deal of activity in the scientific community investigating possible ways to overcome these challenges.

A clear case is a recent study that has proposed the use of molecular “cages” (formed by pseudopeptides) to selectively eliminate cancer cells in acidic microenvironments.

The work is led by a scientific team from the Institute of Advanced Chemistry of Catalonia (IQAC), of the Spanish National Research Council (CSIC), in collaboration with the University of Burgos, and includes the participation of the Institute for Environmental Diagnosis and Water Studies (IDAEA, dependent on the CSIC), all of these institutions in Spain.

The team, led by Lucía Tapia of IQAC, carefully evaluated a large family of “cages” to understand how they operate.

This line of research and development can be of great help in the design of new ionophores (ion-transporting molecules) with potential therapeutic application in cancer treatment.

Challenges in the fight against cancer

Cancer chemotherapy faces two main challenges: the lack of selectivity, which produces unwanted side effects, and the emergence of chemoresistance, since cancer cells have the ability to generate resistance to the chemical agents used in chemotherapy, making treatments ineffective for some patients. On the other hand, one of the characteristics of cancer cells is that their metabolism generates an acidic pH in the environment of solid tumors. This confers special characteristics to these cells, making them more resistant and capable of migrating to other areas of the body (a process known as metastasis).

There is growing evidence of the potential of ionophores (ion-carrying molecules) as novel cancer chemotherapeutic agents. However, controlling their activity to limit their toxicity has been a difficult task so far. The use of molecular “cages” of this type that act selectively in the slightly acidic pH of the microenvironment of solid tumors is one way to overcome these obstacles.

Image of human lung adenocarcinoma cells like those used in the study. (Photo: IQAC / CSIC)

Molecular cages to destroy cancer cells

These “cages” derived from fluorine-substituted amino acids kill cancer cells at slightly acidic pH values ​​(below 7, which are the values ​​observed around tumors), but are harmless to the physiological pH of healthy tissues. “In a previous study, published in 2019, we designed a molecule with a three-dimensional cage-shaped structure that showed good selectivity for killing cancer cells in slightly acidic media,” explains Ignacio Alfonso, researcher at IQAC and co-author of the study. These cages had a fluorine atom in each of the three side chains and when they were in acidic media they encapsulated a chloride inside very efficiently. In addition, they were able to transport chloride through lipid bilayers, this transport also being more efficient when there was a pH gradient with an acidic environment, thus being more toxic for those cells that are in a slightly acidic pH such as the microenvironment of a solid tumor.

“In this work we wanted to go a little further and understand the mechanism of action of these molecules,” explains the IQAC researcher. “To do this, an exhaustive study was carried out with a large family of cages with different numbers of fluorine atoms in different positions to understand the capacity to capture chloride, the transport process and the toxicity at different pHs in cell cultures,” explains Alfonso.

The process has been studied in depth at the molecular level using state-of-the-art theoretical and experimental approaches (fluorescence, nuclear magnetic resonance and computational studies). The results show the effect of fluorine on these molecules and have therefore made it possible to understand the mechanism of action and identify a cage with even greater selectivity for killing cancer cells in acidic environments.

“These results will help to understand and improve the design of this type of ionophore with potential therapeutic application in cancer treatment,” concludes Roberto Quesada, researcher at the University of Burgos.

The study is titled “Tuning pH-dependent cytotoxicity in cancer cells by peripheral fluorine substitution on pseudopeptidic cages”. It has been published in the academic journal Cell Reports Physical Science. (Source: Ana Sotres / IQAC / CSIC)