Project

Back to overview

Non-invasive ultrasound molecular imaging of atherosclerosis: development of clinically translatable tracers for targeting of Vascular Cell Adhesion Molecule 1

English title Non-invasive ultrasound molecular imaging of atherosclerosis: development of clinically translatable tracers for targeting of Vascular Cell Adhesion Molecule 1
Applicant Kaufmann Beat
Number 169905
Funding scheme Project funding (Div. I-III)
Research institution Klinik für Kardiologie Bereich Medizin Universitätsspital Basel
Institution of higher education University of Basel - BS
Main discipline Cardiovascular Research
Start/End 01.04.2017 - 31.03.2020
Approved amount 363'513.00
Show all

Keywords (5)

Molecular imaging; Plaque imaging; Ultrasound; Small animal models; Echocardiography

Lay Summary (German)

Lead
Nicht-invasive ultraschallgestützte bildgebende Diagnostik der Atherosklerose: Entwicklung klinisch anwendbarer Kontrastmittel zur Darstellung des Gefässentzündungsmarkers Vaskuläres Zelladhäsionsmolekül 1
Lay summary

Die Atherosklerose ist eine entzündliche Erkrankung der Gefässwände. Die Atherosklerose entwickelt sich schleichend über Jahrzehnte bis es schliesslich zu klinischen Ereignissen wie zum Beispiel einem Herzinfarkt oder einem Hirnschlag kommt. Um das Risiko einer Person abzuschätzen, in der Zukunft ein derartiges Ereignis zu erleiden, können aktuell lediglich bekannte klinische Risikofaktoren wie Bluthochdruck, erhöhte Blutfette, Zuckerkrankheit, Rauchen, sowie eine familiäre Veranlagung herangezogen werden. Eine Risikoabschätzung mit diesen Faktoren alleine ist ungenau. Entsprechend gibt es Bestrebungen, die Entzündung der Gefässwand bildgebend darzustellen, um so die Entstehung der Atherosklerose früh zu detektieren. Zu diesem Zweck sind in den letzten Jahren Ultraschallkontrastmittel, sogenannte Mikrobläschen, entwickelt worden. Diese tragen auf ihrer Oberfläche Antikörper, welche das vaskuläre Zellasdhäsionsmolekül 1 detektieren. Das vaskuläre Zelladhäsionsmolekül 1 wird bei einer entzündlichen Veränderung der Gefässwand vermehrt produziert. Im vorliegenden Projekt werden wir diese zielgerichteten Ultraschallkontrastmittel weiterentwickeln, sodas eine klinische Anwendung dieser Methode möglich werden wird. Dazu werden wir neuartige Bindungsmoleküle, welche gegen das vaskuläre Zelladhäsionsmolekül 1 gerichtet sind, verwenden und diese neuartigen Ultraschallkontrastmittel im Tiermodell sowie auch an menschlichem Gewebe testen.

Direct link to Lay Summary Last update: 16.10.2016

Responsible applicant and co-applicants

Employees

Associated projects

Number Title Start Funding scheme
123819 Contrast enhanced ultrasound molecular imaging of vascular inflammation in atherosclerosis: development of methods for early detection of cardiovascular risk and assessment of the effect of targeted therapies 01.04.2009 Ambizione
149718 Non-invasive ultrasound molecular imaging of myocarditis and autoimmune myocardial inflammation 01.04.2014 Project funding (Div. I-III)

Abstract

Risk assessment for atherosclerotis relies on established clinical risk factors. This approach places a large proportion of individuals in an intermediate risk category, where the value of interventions to reduce the risk for events is uncertain. Therefore, tools to better assess the risk in these patients are needed. It is generally thought that noninvasive imaging of molecular events associated with atherosclerotic disease may serve this purpose. Previous studies have shown that contrast enhanced ultrasound (CEU) molecular imaging using microbubble contrast agents directed against vascular cell adhesion molecule 1 (VCAM-1), which is involved in inflammatory processes in atherosclerosis, is feasible in murine disease models. However, the ultrasound contrast agents used in these studies are not suitable for clinical translation, and there is a need for the development of microbubbles employing (a) clinically translatable strategies for conjugation of targeting moieties, and (b) targeting ligands that can readily be used in the clinical field. Nanobodies are small antibody fragments (10-15kDa) derived from heavy-chain-only antibodies. They are attractive for applications in molecular imaging, as they are highly specific, non-immunogenic and thus offer the potential for clinical translation. Likewise, Designed Ankyrin Repeat Proteins (DARPins) are potential candidates for clinical ultrasound molecular imaging given their easy production and selection, high affinity and low immunogenicity.The overall aim of this application will therefore be to develop and validate novel VCAM-1 targeted microbubbles with clinically translatable binders coupled to the microbubble surface using maleimide covalent bonding. Preliminary data from our laboratory show that a VCAM-1 targeted nanobody can be conjugated to microbubbles using maleimide bonding. Preliminary in vitro and in vivo experiments show that maleimide microbubbles carrying a VCAM-1 targeted nanobody specifically attach to VCAM-1 under flow conditions, and to the aortic endothelium of mice with advanced atherosclerosis. Thus, we propose the following three study aims:Specific aim 1. To test whether CEU molecular imaging with two novel microbubbles carrying either nanobodies or DARPins targeting VCAM-1 can detect vascular inflammation in advanced atherosclerosis. CEU molecular imaging will be performed in 40 weeks old mice with established atherosclerosis and control animals. Specific aim 2. To test whether CEU molecular imaging with two novel microbubbles carrying either nanobodies or DARPins targeting VCAM-1 can detect vascular inflammation in early atherosclerosis. CEU molecular imaging will be performed in 10 weeks old mice with early atherosclerotic plaques and control animals.Specific aim 3: To test whether CEU molecular imaging with two novel microbubbles carrying either nanobodies or DARPins targeting VCAM-1 can detect vascular inflammation in human endarterectomy specimens. CEU molecular imaging will be performed on perfused human thrombendarterectomy specimens with VCAM-1 targeted and control microbubbles.Significance. Better noninvasive imaging tools for risk stratification in large patient populations with an intermediate risk for atherosclerotic complications are a clinical need. CEU molecular imaging can detect vascular inflammation even at very early stages of atherosclerosis, and could possibly contribute to risk stratification. However, the approaches that have been used in these studies are not readily translatable into the clinical practice. In this proposal, we will address these issues and will design targeted microbubbles that will be ready for clinical translation.
-