CIC biomaGUNE designs a new contrast agent that detects cardiac fibrosis and slows its progression

The team led by Aitziber L. Cortajarena has demonstrated that the new magnetic resonance imaging contrast agent is safer for the heart than those commonly used

It consists of tiny clusters of iron atoms encapsulated within a custom-designed protein that targets diseased tissue and blocks the processes that trigger the disease

The Biomolecular Nanotechnology research group, led by Ikerbasque Professor Aitziber L. Cortajarena, has developed a new iron-based contrast agent for magnetic resonance imaging (MRI) that can be used for both diagnosis and treatment. In a study conducted on laboratory-engineered human cardiac tissue, the researchers demonstrated that the contrast agent accumulates in fibrotic tissue, that its MRI signal increases with the severity of the disease and that it also slows its progression.

The study, led by Cortajarena and carried out in collaboration with Ana Villar’s group at the Institute of Biomedicine and Biotechnology of Cantabria (IBBTEC, UC-CSIC), has been published in the prestigious scientific journal Advanced Functional Materials and paves the way for a potential alternative to gadolinium, the metal currently used in almost all contrast-enhanced MRI scans.

Cardiac fibrosis

Cardiac fibrosis is one of the main factors leading to heart failure, a condition that affects millions of people worldwide. There is currently no treatment specifically approved to halt the progression of this condition. When the heart suffers damage or sustained overload, for example following a heart attack or as a result of high blood pressure, it triggers a repair process similar to the healing of a wound on the skin. A process is activated that produces collagen to repair and strengthen the tissue. However, this process often fails to stop: collagen continues to accumulate, the heart becomes stiff and finds it increasingly difficult to fill with and pump blood.

MRI is currently one of the techniques used to diagnose fibrosis in the heart. In many cases, patients are given an intravenous contrast agent, almost always gadolinium-based, which is retained in damaged areas and makes them appear bright on the image. Although gadolinium works extremely well, it has several drawbacks. It is a metal that is foreign to the body: its use is restricted in people with kidney failure, and small amounts are known to remain deposited in various tissues for years. This is of particular concern for patients who require repeated MRI scans to monitor the progression of their disease, which is precisely the case with cardiac fibrosis.

Iron atoms encapsulated within a custom-designed protein

For this reason, researchers have been looking for years for iron-based contrast agents, since iron is an element that the human body is familiar with and knows how to store and eliminate. However, existing iron-based contrast agents have a drawback: rather than making the lesion brighter, they darken it, making it more difficult to distinguish in images. Several of them have even been withdrawn from the market. The group led by Cortajarena, Scientific Director of CIC biomaGUNE, has succeeded in “overcoming these problems by using custom-designed proteins”, explains CIC biomaGUNE researcher Lydia Martínez Parra, first author of the study.

According to Martínez, “the contrast agent consists of a specifically designed protein that surrounds and isolates tiny clusters of iron atoms measuring around 1.4 nanometres, approximately 50,000 times thinner than a human hair. It is also worth noting that this compound is safer for the body: it is stable, releases very little iron and has low toxicity to cells. Moreover, its production process is simple and sustainable, as it is manufactured in water, without toxic reagents or extreme conditions.”

In a laboratory-engineered fibrotic heart model

The CIC biomaGUNE group tested the effectiveness of the contrast agent in cardiac tissue produced using three-dimensional tissue engineering from patients’ heart cells, developed by Dr Ana Villar’s group (IBBTEC, UC-CSIC). These tissues reproduce some of the characteristics of cardiac fibrosis, such as collagen accumulation and increased tissue stiffness, and make it possible to evaluate new therapeutic strategies under conditions that are more representative than conventional cell cultures.

The research team found that the contrast agent preferentially targets and accumulates in fibrotic tissue, that the MRI signal increases with the severity of fibrosis and that it also slows its progression by reducing collagen production and deposition and preventing the tissue from becoming stiff. “In other words, in addition to indicating where the condition is located, this material exhibits antifibrotic activity in the models studied,” says Professor Cortajarena. “It is a ‘theranostic’ agent, providing both diagnosis and treatment in a single material.”

Martínez points out that “this new compound provides MRI contrast comparable to that obtained with gadolinium-based agents. Moreover, it retains this capability both at the magnetic field strengths routinely used in clinical practice and at the higher magnetic field strengths used in preclinical research.” The compound, consisting of iron atoms surrounded by the protein, makes the tissue appear bright on MRI scans.

The authors of the study emphasise that “there is still some way to go before this reaches patients. So far, this new contrast agent has been tested in cells and laboratory-engineered human tissue; the next step will be to study it with a view to its clinical use, examining how it is distributed and eliminated from the body and how it behaves in a real cardiac MRI scanner. Our aim is that, in the future, patients with cardiac fibrosis, including those who cannot receive gadolinium, will have access to a safer imaging test that can also form part of their treatment.”