San Sebastian. The Biomolecular Nanotechnology research group at CIC biomaGUNE, led by Ikerbasque research professor Aitziber L. Cortajarena, has developed a new iron-based contrast agent for magnetic resonance imaging that can be used for both diagnosis and treatment. In a study conducted on lab-grown human heart tissue, it was demonstrated that the contrast agent accumulates in the fibrotic tissue, that its signal intensity on the MRI image increases with disease severity, and that it slows disease 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), has been published in the prestigious scientific journal Advanced Functional Materials. It paves the way for a possible alternative to gadolinium, the metal currently used in almost all contrast-enhanced MRI scans.
Cardiac fibrosis is one of the main factors leading to heart failure, a disease affecting millions worldwide. Currently, there is no approved treatment specifically designed to slow this condition. When the heart is damaged or under sustained strain, a repair process begins, similar to skin healing. Collagen production is activated to repair and strengthen the tissue. However, this process often doesn't stop: collagen continues to accumulate, stiffening the heart and making it increasingly difficult to fill and pump blood properly.
One of the techniques currently used for diagnosing heart fibrosis is MRI. In many cases, an intravenous contrast agent, almost always based on gadolinium, is administered to the patient. This agent is retained in damaged areas, making them light up in the image. Although gadolinium works very well, it has drawbacks. It is a metal foreign to the body, its use is restricted in people with kidney failure, and small amounts may be retained in tissues for many years.
For years, researchers have sought to develop iron-based contrast agents. However, existing iron-based agents have a problem: instead of illuminating damaged areas, they darken them, making them difficult to distinguish in images. Many have even been withdrawn from the market. Cortajarena's group has managed to "overcome these problems by using designer proteins," explains Lydia Martínez Parra, lead author of the study and researcher at CIC biomaGUNE.
Martínez adds, "the contrast agent consists of a specially designed protein that encapsulates and isolates minute clusters of iron atoms measuring approximately 1.4 nanometers (about 50,000 times thinner than a hair). Furthermore, this compound is safer for the body, stable, releases very little iron, and has low toxicity to cells. It is also easy and sustainable to manufacture, produced in water without toxic reagents or extreme conditions."
The CIC biomaGUNE group tested the contrast agent's efficacy in cardiac tissue created with 3D tissue engineering using patient heart cells, developed by Ana Villar’s group (IBBTEC, UC-CSIC). These tissues replicate certain characteristics of cardiac fibrosis, such as collagen accumulation and increased tissue stiffness, allowing evaluation of new therapeutic strategies under more representative conditions than conventional cell cultures.
The research team has verified that the contrast agent moves towards and predominantly accumulates in fibrotic tissue, that the MRI signal increases with fibrosis severity, and that it slows progression by reducing collagen production and storage, preventing tissue stiffening. "In addition to indicating where the damage is, this material shows antifibrotic activity in the studied models," says research professor Cortajarena. It is a 'theranostic' agent offering diagnosis and treatment in the same material.
Martínez points out that "this new compound achieves a contrast in magnetic resonance imaging comparable to gadolinium-based agents. It maintains this capacity in both magnetic fields commonly used in clinical practice and stronger fields used in preclinical research." The compound formed by iron atoms encapsulated by the protein makes the tissue appear bright on MRI.
The study team states that "there is still a way to go to reach the patient. For now, this new contrast agent has been tested in cells and human tissue in the laboratory. The next step will be to study it for clinical practice, to see how it is distributed and eliminated from the body and how it behaves on a real cardiac scanner. Our goal is that, in the future, patients with cardiac fibrosis, including those who cannot receive gadolinium, can have a safer imaging test that also forms part of their treatment."
