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A radiotracer to identify and see cholesterol accumulated on vessel walls

A new peptide-based radiotracer has been designed to identify LDL-cholesterol retained and accumulated on the vascular wall of arteries, which can be seen in the very early stages of the disease. The CSIC and the Hospital de Sant Pau are leading this project, which recently was selected in the latest call for grants from the BBVA Foundation for Scientific Research Teams in Biomedicine.

Native LDL (top left) and LDL accumulated in the arterial intima (top right) have a different structure, as can be seen in the image, obtained by electron microscopy. The new radiatracer will allow to identify specifically the second one. Below, inflammation in the aortic intima (marked in red).Researchers from the Barcelona Biomedical Research Institute of the CSIC (IIBB-CSIC) and the IIB-SantPau are developing a molecular imaging tool to detect mechanisms that occur locally in the vascular wall and are associated with future acute cardiovascular events. Specifically, they are developing a radiotracer to allow visualization in an image of the cholesterol retained on the vascular wall of the arteries, a process that occurs in the very early stages of the disease. The tool, which will allow a better diagnosis, is an innovative approach, as there is nothing similar in the cardiovascular area nowadays.

The project is developed in close collaboration with cardiologists specializing in cardiac imaging and Nuclear Medicine at Sant Pau Hospital and Vall d'Hebron Hospital, and with experts in CIEMAT peptide radiolabeling. It is also one of the five projects that have just been selected by the BBVA Foundation in its latest call for aid for Biomedical research.

How to "see" the cholesterol accumulated in the vascular wall

Cardiovascular disease is the leading cause of death worldwide. Many current diagnostic strategies are based on assessing risk factors, but this is not enough to establish a differential and early diagnosis.

An alternative option are molecular imaging techniques, which allow to "see" what is happening inside the body. Since a risk factor is the cholesterol accumulated on the vascular wall, a form of early diagnosis would be, precisely, to be able to detect as soon as possible this accumulation of cholesterol and the related mechanisms.

This is the goal of the PlaqueCHOL project (acronym for Translational Molecular Imaging for Detection of Cholesterol Entrapment in the Vasculature with 68Ga-labeled LRP1-derived Peptides), which is coordinated by Dr. Vicenta Llorente Cortés, a CSIC scientist at the IIBB-CSIC and the IIB-SantPau.

To do this, the team will design a new peptide-based radiotracer, to detect cholesterol on vascular walls by positron emission tomography coupled to computed tomography (PET / CT). The team led by Vicenta Llorente will design the radiotracer from a peptide that "recognizes" cholesterol, which afterwards will be tagged to be used in nuclear medicine.

Identifies only the LDL cholesterol retained on the vascular wall

The radiotracer will specifically recognize the low-density lipoproteins - LDL - that are retained within what is known as the ‘arterial intima’, a space occupied by the extracellular matrix between the endothelium and the middle layer of the vessel wall.

 “The LDL retained here is different from the circulating native LDL, since in the intima the LDL undergoes a whole series of modifications that make it recognizable by the radiotracer. There is currently significant evidences to support the idea that the modified LDL in the intima is much more closely associated with cardiovascular risk than circulating LDL. ”

From the IIBB-CSIC we provide this molecule that will be tagged, says Vicenta Llorente, but the final design of the radiotracer involves more important steps such as the conjugation of the peptide with a bifunctional chelating agent and the binding of the chelating agent to the radioisotope. "All these steps can only be done in collaboration with the CIEMAT, a center specialized in radioactive labeling, and with clinicians who are experts in the use of radioisotopes in clinical practice," she adds.

The new radiotracer will be applied in the same way as other radiolabeled compounds (usually intravenously), it will be active for about 40 minutes and will be excreted by the renal route, according to the previous pharmacokinetic studies.

The development will make it possible to know in advance which patients have higher cardiovascular risk, facilitating their inclusion in prevention strategies.

Technique translation into clinical practice

In addition, the translational nature of the project, in which collaborate research centers specialized in peptide radiolabeling such as the Center for Energy, Environmental and Technological Research (CIEMAT) and hospital units specialized in cardiac imaging and nuclear medicine at SantPau Hospital and Vall d’Hebron Hospital will facilitate the translation of the results of the preclinical in vivo model into clinical practice.

Atherosclerosis is a disease that progresses throughout life. And actually people have an increasingly longer life expectancy. In such a scenario, this new technology, cheaper than current ones and with greater capacity to detect atherosclerosis in early (subclinical) stages, can be crucial to improve management, clinical decision-making and medical care, allowing also a sustainable use of healthcare resources.