To the rescue of a sick brain

The Lilly Foundation and The Conversation launch, for the third time, the first Dissemination Award on Medicine and Health with the aim of promoting and recognizing dissemination in health and medicine, encouraging the use of Spanish as a language for the transmission of scientific knowledge in general and health sciences in particular, as well as promoting the social dissemination of knowledge in the field. Spanish-speaking. Important recognition in which Inés Mármol, researchers at IIS Aragón, has been a finalist thanks to this article from The Conversation about nanotechnology or organ-on-chip models for the treatment of brain pathologies, a current research project being carried out in the Tissue MicroEnvironment (TME) lab group.

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Crowning the tops of hills and mountains, the memories of what once were contemplate the future of time and men: the castles. In the Middle Ages, its mission was to protect those who took shelter behind its walls. To achieve this, many were located in regions that were difficult to access, some were surrounded by a moat and all had thick walls to repel external attacks.

No effort was spared to protect the king and queen, the members of the court and those responsible for ensuring that the cream of the kingdom ate, drank and groomed themselves. Everyone found refuge behind its walls.

Well, in the same way, one of the most important organs in our body has its own medieval castle. Located in a high region, well protected from possible damage, the brain is responsible for the rest of the body functioning correctly while giving us those incredible qualities that make us human. Curiosity, empathy, creativity... all of this is born behind the walls of our castle.

The cell wall

While the skull and meninges protect the delicate brain structure from blows, a wall that is not made of bricks or cement safeguards it against more subtle attacks. This is the blood-brain barrier, the small blood vessels that supply the brain. These vessels are made up of cells called endothelial cells that join together in a very special way, leaving very little space between one cell and the next. Such tight junctions do not occur in the rest of the body's capillaries.

This makes it difficult for substances to pass into the brain tissue. Only a few privileged molecules, such as your nutrients, will be able to access it. Everything else, especially compounds that can cause harm, will be left out, since the brain's wall is as effective at repelling attacks as that of a medieval castle.

However, there is a key difference between the two: those who inhabited the castle could decide who they let in. For example, to harmless merchants. The blood-brain barrier does not know if something outside the body is safe. This is a problem when the brain becomes ill, since the vast majority of drugs cannot pass through it.

Therefore, Designing drugs to treat brain diseases, such as certain types of tumors or Alzheimer's, is a challenge. The drug must not only be effective, but also have a series of properties that guarantee that it can penetrate this defensive barrier.

Medicines on the bus

Suppose we have designed a compound to eliminate glioblastoma tumor cells, one of the most common and aggressive types of brain cancer. Our preliminary trials show that by putting the drug candidate in contact with these cells, it is able to destroy them.

Although we have something good on our hands, there is a drawback: its physical-chemical characteristics, such as its size or its charge, prevent it from crossing the blood-brain barrier. After years of hard work, will we have to rule out this potential drug?

In desperate situations like these, nanotechnology offers us a helping hand. After years of study in materials science on a tiny scale, strategies have been developed to “vehicle” drugs. That is, encapsulate compounds that, due to their characteristics, would have problems moving through the bloodstream or entering cells.

Nanomedicine, in addition, reduces side effects by directing the drug to the region of interest, preventing it from dispersing throughout the body and causing damage. On rebound, its effective dose will increase, so its therapeutic effect will be greater than when administered without vehicle.

In the specific case of nanomedicine applied to brain diseases, we can synthesize nanoparticles that are much more attractive to endothelial cells than the free drug. For example, we can coat them with molecules similar to others present on the outside of endothelial cells, such as receptors that allow the entry of nutrients. In this way we trick the endothelial cell into allowing the loaded nanoparticle to pass through.

The drugs will cross the blood-brain barrier, admiring the landscape from the comfort of a bus, like a group of tourists on a route through the castles of the Loire. Once they cross the wall, the drugs/tourists will abandon their nanoparticle/bus to carry out their function. Some will repair the damage and others will take photos or buy souvenirs.

A barrier in the palm of the hand

After designing this new nanomedicine, we will have to verify that it can cross the blood-brain barrier. Since we do not know its possible side effects, we will resort to experimental models instead of testing people.

Here another problem arises, since the available models have serious limitations. Those based on cells do not reproduce the complexity of the blood-brain barrier, while experimental animals show important differences compared to humans. And since we do not obtain the same results, many promising drugs in the preclinical phase are discarded when subsequently tested in humans. The so-called models organ-on-chip They were invented to overcome these limitations. They are an improvement on traditional cellular models that seek to reduce the need to use experimental animals, reducing ethical and economic costs. They allow cells to grow in three dimensions instead of two, mimic blood flow, or bring various types of cells into contact to create more realistic tissues. Thus, we create

Source: The Conversation.

Authorship: Inés Mármol. Postdoctoral researcher in Biomedicine. Health Research Institute of Aragon, University of Zaragoza.