New nanotechnological solution to stop tumor progression

Solid tumors are not simple agglomerations of malignant cells, but are enormously complex tissues inhabited by different cells that play a primary role in tumor progression. Throughout the development of a solid tumor, tumor cells are able to “hijack” cells from the immune system, making them work in favor of tumor progression, for example, by releasing cell growth stimulation factors, or inducing the construction of new blood vessels that supply nutrients to the growing malignant tissue.

Within this group of “kidnapped” cells, macrophages stand out. Macrophages are cells that incessantly patrol the body in search of pathogenic agents, such as bacteria or viruses, which they destroy by engulfing them. Once macrophages fall under the control of malignant cells, they act as if they were facing a wound, rather than a threat, in such a way that they begin to release growth factors and help vascularize the tissue, becoming what is known as tumor-associated macrophages, very valuable allies of tumor tissue.

On the other hand, as a tumor tissue grows, the amount of oxygen that reaches the tissue is increasingly less, since the speed of blood vessel production is not fast enough to adequately irrigate the entire tumor mass. This generates a hypoxic state that causes these tumor-associated macrophages to focus their efforts even more on helping the tissue grow and vascularize, causing a “call effect” that attracts more and more macrophages to the area. As an illustration of this effect, in many cases almost 50% of the tumor mass that is removed by surgery in certain solid tumors are macrophages that went to the area.

As if this were not bad enough, the presence of these macrophages prevents the action of other cells of the immune system, such as T lymphocytes or “natural killer cells”, which will also be attracted to the tumor, and which would have the capacity to attack. destroy malignant tissue if macrophages were not present. There are different drugs in the clinical setting with the capacity to destroy macrophages, but they generally have high toxicity and can give rise to serious side effects, since it would only be necessary to eliminate the macrophages associated with the tumor, not the rest of the macrophages that patrol the environment. organism, which are essential for the correct performance of the immune system.

A multidisciplinary team of scientists from the Polytechnic University of Madrid (UPM) and the Niño Jesús University Children’s Hospital in Madrid, both entities in Spain, has developed multitasking intelligent nanoparticles capable of selectively destroying tumor-associated macrophages.

This novel nanosystem can be loaded with different combinations of therapeutic agents and may be the first step in the development of personalized nanomedicines against various types of tumors.

These new nanoparticles, similar in size to many viruses (around 100 nanometers), are called protocells, and are made up of a silica core provided with thousands of small pores with the capacity to house combinations of drugs that are toxic to humans. macrophages, and combinations of enzymes capable of generating oxygen from the breakdown of glucose.

A) Scheme of protocells: silica core provided with porosity capable of housing combinations of therapeutic agents with a lipid bilayer coating and encapsulated enzymes. B) Electron microscopy image of the protocells. C) Fluorescence microscopy where the protocells (green) inside the macrophages, the released drugs that accumulate in the cell nucleus (red) and the outline of the cell membrane of the macrophages (white dotted line) are observed. (Images: UPM)

In order to increase the durability of the oxygen-generating enzymes, they were in turn coated with a thin polymeric envelope highly resistant to the conditions present in the organism. The surface of the protocells was provided with molecules of a synthetic derivative of mannose, which is a type of sugar that selectively binds to cellular receptors present on the surface of macrophages, especially macrophages associated with a tumor. In this way, when the protocells come into contact with the surface of the macrophages associated with the tumor, they act like tiny “Trojan horses” being quickly engulfed and then releasing the drugs safely inside the macrophages, causing the annihilation of the macrophages. these.

In parallel, the transported enzymes are also released in the internalization process in macrophages, acting as oxygen generators in the tissue.

These systems have been tested in cellular models under dynamic flow that simulate the conditions present in solid tumors, observing that the protocells are capable of selectively destroying macrophage populations using very low doses of nanoparticles, which the system has demonstrated its potential effectiveness as antitumor agent.

According to Alejandro Baeza, researcher at the UPM, “we are currently launching a study in an animal model of neuroblastoma, a type of very aggressive pediatric tumor, where we will study in a more exhaustive way the selectivity and safety of this new therapeutic agent.” . The researchers hope that the information obtained with these trials will allow their application in humans to be realized in the medium term.

The research project, thanks to which intelligent nanoparticles have been developed capable of destroying the cells of the immune system that help tumors to develop, has been carried out within a collaboration established for several years between the research groups of the Dr. Alejandro Baeza García, professor at the Polytechnic University of Madrid, and the team of Dr. Manuel Ramírez Orellana, from the Niño Jesús University Children’s Hospital in Madrid. For the biological assays, we have also had the collaboration of Dr. Diego Megías from the Carlos III Health Institute, in Spain. (Source: UPM)