title: MRI of inducible P-selectin expression in human activated platelets involved in the early stages of atherosclerosis.
abstract: The noninvasive imaging of atherosclerotic plaques at an early stage of atherogenesis remains a major challenge for the evaluation of the pathologic state of patients at high risk of acute coronary syndromes. Recent studies have emphasized the importance of platelet-endothelial cell interactions in atherosclerosis-prone arteries at early stages, and the prominent role of P-selectin in the initial loose contact between platelets and diseased vessel walls. A specific MR contrast agent was developed here for the targeting, with high affinity, of P-selectin expressed in large amounts on activated platelets and endothelial cells. For this purpose, PEGylated dextran/iron oxide nanoparticles [PEG, poly(ethylene glycol)], named versatile ultrasmall superparamagnetic iron oxide (VUSPIO) particles, labeled with rhodamine were coupled to an anti-human P-selectin antibody (VH10). Flow cytometry and microscopy experiments on human activated platelets were highly correlated with MRI (performed at 4.7 and 0.2 T), with a 50% signal decrease in T(2) and T(1) values corresponding to the strong labeling of activated vs resting platelets. The number of 1000 VH10-VUSPIO nanoparticles attained per activated platelet appeared to be optimal for the detection of hypo- and hyper-signals in the platelet pellet on T(2) - and T(1) -weighted MRI. Furthermore, in vivo imaging of atherosclerotic plaques in ApoE mice at 4.7 T showed a spatial resolution adapted to the imaging of intimal thickening and a hypo-signal at 4.7 T, as a result of the accumulation of VH10-VUSPIO nanoparticles in the plaque. Our work provides support for the further assessment of the use of VH10-VUSPIO nanoparticles as a promising imaging modality able to identify the early stages of atherosclerosis with regard to the pertinence of both the target and the antibody-conjugated contrast agent used.
authors.affiliation: CNRS, Université de Bordeaux, CRMSB, Bordeaux, France.
authors.forename: Marie-Josée
authors.initials: MJ
authors.lastname: Jacobin-Valat
authors.forename: Kamel
authors.initials: K
authors.lastname: Deramchia
authors.forename: Stéphane
authors.initials: S
authors.lastname: Mornet
authors.forename: Christoph E
authors.initials: CE
authors.lastname: Hagemeyer
authors.forename: Stéphane
authors.initials: S
authors.lastname: Bonetto
authors.forename: Rémy
authors.initials: R
authors.lastname: Robert
authors.forename: Marc
authors.initials: M
authors.lastname: Biran
authors.forename: Philippe
authors.initials: P
authors.lastname: Massot
authors.forename: Sylvain
authors.initials: S
authors.lastname: Miraux
authors.forename: Stéphane
authors.initials: S
authors.lastname: Sanchez
authors.forename: Anne-Karine
authors.initials: AK
authors.lastname: Bouzier-Sore
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Franconi
authors.forename: Etienne
authors.initials: E
authors.lastname: Duguet
authors.forename: Gisèle
authors.initials: G
authors.lastname: Clofent-Sanchez
mesh_terms: D000818:Animals; D000906:Antibodies / Q000378:metabolism; D001011:Aorta / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency; D050197:Atherosclerosis / Q000097:blood* / Q000175:diagnosis*; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism*; D003911:Dextrans / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D005434:Flow Cytometry; D006801:Humans; D008279:Magnetic Resonance Imaging / Q000379:methods*; D058185:Magnetite Nanoparticles; D051379:Mice; D008807:Mice, Inbred BALB C; D018613:Microscopy, Confocal; D019007:P-Selectin / Q000097:blood*; D015539:Platelet Activation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D018179:Receptors, Thrombin / Q000378:metabolism; D013917:Thrombin / Q000494:pharmacology
chemical_list: D000906:Antibodies; D001057:Apolipoproteins E; D003911:Dextrans; D058185:Magnetite Nanoparticles; D019007:P-Selectin; D018179:Receptors, Thrombin; C546937:SELP protein, human; C097921:ferumoxtran-10; D013917:Thrombin