Assessment of Albumin ECM Accumulation and Inflammation as Novel In Vivo Diagnostic Targets for Multi-Target MR Imaging

Abstract

Atherosclerosis is a progressive inflammatory vascular disease characterized by endothelial dysfunction and plaque burden. Extracellular matrix (ECM)-associated plasma proteins play an important role in disease development. Our magnetic resonance imaging (MRI) study investigates the feasibility of using two different molecular MRI probes for the simultaneous assessment of ECM-associated intraplaque albumin deposits caused by endothelial damage and progressive inflammation in atherosclerosis. Male apolipoprotein E-deficient (ApoE-/-)-mice were fed a high-fat diet (HFD) for 2 or 4 months. Another ApoE-/--group was treated with pravastatin and received a HFD for 4 months. T1- and T2*-weighted MRI was performed before and after albumin-specific MRI probe (gadofosveset) administration and a macrophage-specific contrast agent (ferumoxytol). Thereafter, laser ablation inductively coupled plasma mass spectrometry and histology were performed. With advancing atherosclerosis, albumin-based MRI signal enhancement and ferumoxytol-induced signal loss areas in T2*-weighted MRI increased. Significant correlations between contrast-to-noise-ratio (CNR) post-gadofosveset and albumin stain (R2 = 0.78, p < 0.05), and signal loss areas in T2*-weighted MRI with Perls’ Prussian blue stain (R2 = 0.83, p < 0.05) were observed. No interference of ferumoxytol with gadofosveset enhancement was detectable. Pravastatin led to decreased inflammation and intraplaque albumin. Multi-target MRI combining ferumoxytol and gadofosveset is a promising method to improve diagnosis and treatment monitoring in atherosclerosis.

Iron Oxide Nanoparticles for Visualization of Prostate Cancer in MRI

“…Thus, it can be said that macrophages are able to take up ferumoxytol. We have already been able to show this in other diseases [ 21 , 22 , 23 ]. Some publications indicate that tumor-associated macrophages (TAMs) are able to take up administered nanoparticles [ 24 , 25 ].…”

“…Ferumoxytol is not only used in imaging techniques for tumor diseases but may also have applications in cardiovascular diseases [ 21 , 22 , 44 ] and the central nervous system [ 15 ]. Different studies have investigated the molecular properties of cardiovascular disease with a combined approach using iron-oxide nanoparticles and a gadolinium-based contrast agent [ 21 , 22 , 44 ]. A limitation that needs to be considered regarding ferumoxytol is that it is not prostate tumor specific or even tumor specific.…”

Advanced EPI-X4 Derivatives Covalently Bind Human Serum Albumin Resulting in Prolonged Plasma Stability

“…It would be highly interesting to study whether the design of EPI-X4 derivatives containing thiol-reactive linkers may allow albumin binding after systemic administration of the peptide. The circulating albumin preferentially accumulates in tumors [ 31 ] or inflamed tissues [ 32 , 33 ], delivering optimized EPI-X4 molecules to the sites where they are therapeutically required.…”