Abstract
Inflammation drives the degradation of atherosclerotic plaque, yet there are no non-invasive techniques available for imaging overall inflammation in atherosclerotic plaques, especially in the coronary arteries. To address this, we have developed a clinically relevant system to image overall inflammatory cell burden in plaque. Here, we describe a targeted contrast agent (THI0567-targeted liposomal-Gd) that is suitable for magnetic resonance (MR) imaging and binds with high affinity and selectivity to the integrin α4β1(very late antigen-4, VLA-4), a key integrin involved in recruiting inflammatory cells to atherosclerotic plaques. This liposomal contrast agent has a high T1 relaxivity (~2 × 105 mM−1s−1 on a particle basis) resulting in the ability to image liposomes at a clinically relevant MR field strength. We were able to visualize atherosclerotic plaques in various regions of the aorta in atherosclerosis-prone ApoE−/− mice on a 1 Tesla small animal MRI scanner. These enhanced signals corresponded to the accumulation of monocyte/macrophages in the subendothelial layer of atherosclerotic plaques in vivo, whereas non-targeted liposomal nanoparticles did not demonstrate comparable signal enhancement. An inflammatory cell-targeted method that has the specificity and sensitivity to measure the inflammatory burden of a plaque could be used to noninvasively identify patients at risk of an acute ischemic event.
Highlights
Recruitment and accumulation of leukocytes at inflammatory sites[9,10,11]
Integrin α4β1 binds the counter-receptor VCAM-1 on activated endothelial cells; this binding recruits monocytes/macrophages and T cells to atherosclerotic plaques[9,10,11]
The targeted liposomal Gd contrast agents used in our study enable imaging of relevant cell types within atherosclerotic plaques at clinically relevant field strengths
Summary
Recruitment and accumulation of leukocytes at inflammatory sites[9,10,11]. Monocytes/macrophages and lymphocytes make up about half of the cellular components of atherosclerotic plaques[12]; neutrophils are present in lower numbers[13]. The aim of this work was to develop a targeted MR imaging agent that would enable imaging of inflammatory cell burden in atherosclerotic plaques using a system that would have broad clinical applicability. To this end, we have incorporated a novel non-peptidic small molecule integrin α4β1 antagonist into a liposomal Gd contrast agent. The targeted liposomal Gd contrast agents used in our study enable imaging of relevant cell types within atherosclerotic plaques at clinically relevant field strengths. These unique features of our approach should facilitate translation to clinical development
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