Multi-targeted 1H/19F MRI unmasks specific danger patterns for emerging cardiovascular disorders

Abstract

Prediction of the transition from stable to acute coronary syndromes driven by vascular inflammation, thrombosis with subsequent microembolization, and vessel occlusion leading to irreversible myocardial damage is still an unsolved problem. Here, we introduce a multi-targeted and multi-color nanotracer platform technology that simultaneously visualizes evolving danger patterns in the development of progressive coronary inflammation and atherothrombosis prior to spontaneous myocardial infarction in mice. Individual ligand-equipped perfluorocarbon nanoemulsions are used as targeting agents and are differentiated by their specific spectral signatures via implementation of multi chemical shift selective 19F MRI. Thereby, we are able to identify areas at high risk of and predictive for consecutive development of myocardial infarction, at a time when no conventional parameter indicates any imminent danger. The principle of this multi-targeted approach can easily be adapted to monitor also a variety of other disease entities and constitutes a technology with disease-predictive potential.

Modulation of mTOR Signaling in Cardiovascular Disease to Target Acute and Chronic Inflammation

“…Endothelial dysfunction is considered the beginning point for atherosclerotic plaques, involving decreased nitric oxide levels, increased oxidative stress, and pro-inflammatory signaling ( 30 , 31 ). Early inflammation in the vessels occur after exposure to high lipoprotein levels within several days ( 32 ). Lipoprotein particle uptake and phagocytosis [e.g., oxidized Low Density Lipoprotein (LDL)] triggers the formation of “fatty streaks” that develop over time toward advanced plaques composed of a necrotic lipid core covered by a fibrous cap ( 33 ).…”

Nanobiotechnology approaches for cardiovascular diseases: site-specific targeting of drugs and nanoparticles for atherothrombosis

“…The choice of perfluorocarbon is interesting because it was previously used as blood substitute and may thus allow a smooth transition into their clinical use. These perfluorocarbon NPs are currently used as 19-Fluorine MRI contrast [ 116 , 117 ] and ultrasound contrast agents [ 118 ], therefore moving forward, these could potentially be used in theranostic approaches.…”

A Toolbox to Investigate the Impact of Impaired Oxygen Delivery in Experimental Disease Models

“…Over the past years, our group has established a platform for the active targeting of PFCs and we were able to functionalize PFCs with specific targeting ligands and to use this technology to visualize thrombi ( 180 – 182 ), activated platelets ( 183 ), cells expressing synthetic receptors ( 184 ) or specific progenitor cells of the heart ( 185 ). Moreover, we recently implemented a 19 F-imaging technology, which enables the simultaneous detection of PFCs with distinct 19 F spectra and combined this with the simultaneous visualization of factor XIIIa-activity, fibrin and monocytes/macrophages ( 186 ). We exposed mice that express a hypomorphic mutant form of apolipoprotein E and also lack the scavenger receptor class B type I to a high fat/high cholesterol diet that leads to a thromboinflammatory phenotype with plaque ruptures and subsequent myocardial infarction ( 187 ).…”

“…We exposed mice that express a hypomorphic mutant form of apolipoprotein E and also lack the scavenger receptor class B type I to a high fat/high cholesterol diet that leads to a thromboinflammatory phenotype with plaque ruptures and subsequent myocardial infarction ( 187 ). Using this multitargeted approach, it was possible to identify high-risk areas at very early time points and importantly the 19 F signal was predictive for consecutive development of myocardial infarction ( 186 ).…”