title: Localization to atherosclerotic plaque and biodistribution of biochemically derivatized superparamagnetic iron oxide nanoparticles (SPIONs) contrast particles for magnetic resonance imaging (MRI).
abstract: Annexin V recognizes apoptotic cells by specific molecular interaction with phosphatidyl serine, a lipid that is normally sequestered in the inner leaflet of the cell membrane, but is translocated to the outer leaflet in apoptotic cells, such as foam cells of atherosclerotic plaque. Annexin V could potentially deliver carried materials (such as superparamagnetic contrast agents for magnetic resonance imaging) to sites containing apoptotic cells, such as high grade atherosclerotic lesions, so we administered biochemically-derivatized (annexin V) superparmagnetic iron oxide particles (SPIONs) parenterally to two related rabbit models of human atherosclerosis. We observe development of negative magnetic resonance imaging (MRI) contrast in atheromatous lesions and but not in healthy artery. Vascular targeting by annexin V SPIONs is atheroma-specific (i.e., does not occur in healthy control rabbits) and requires active annexin V decorating the SPION surface. Targeted SPIONs produce negative contrast at doses that are 2,000-fold lower than reported for non-specific atheroma uptake of untargeted superparamagnetic nanoparticles in plaque in the same animal model. Occlusive and mural plaques are differentiable. While most of the dose accumulates in liver, spleen, kidneys and bladder, annexin V SPIONs also partition rapidly and deeply into early apoptotic foamy macrophages in plaque. Contrast in plaque decays within 2 months, allowing MRI images to be replicated with a subsequent, identical dose of annexin V SPIONs. Thus, biologically targeted superparamagnetic contrast agents can contribute to non-invasive evaluation of cardiovascular lesions by simultaneously extracting morphological and biochemical data from them.
authors.affiliation: Department of Biomedical Engineering, Ohio State University, 1080 Carmack Road, Columbus, OH 43210, USA.
authors.forename: Bryan R
authors.initials: BR
authors.lastname: Smith
authors.forename: Johannes
authors.initials: J
authors.lastname: Heverhagen
authors.forename: Michael
authors.initials: M
authors.lastname: Knopp
authors.forename: Petra
authors.initials: P
authors.lastname: Schmalbrock
authors.forename: John
authors.initials: J
authors.lastname: Shapiro
authors.forename: Masashi
authors.initials: M
authors.lastname: Shiomi
authors.forename: Nicanor I
authors.initials: NI
authors.lastname: Moldovan
authors.forename: Mauro
authors.initials: M
authors.lastname: Ferrari
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Lee
mesh_terms: D000818:Animals; D017304:Annexin A5 / Q000378:metabolism; D001012:Aorta, Abdominal / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D050197:Atherosclerosis / Q000175:diagnosis* / Q000378:metabolism* / Q000473:pathology; D003287:Contrast Media; D003911:Dextrans; D004195:Disease Models, Animal; D052203:Ferrosoferric Oxide; D006801:Humans; D007501:Iron / Q000378:metabolism* / Q000493:pharmacokinetics; D008279:Magnetic Resonance Imaging; D058185:Magnetite Nanoparticles; D053768:Metal Nanoparticles / Q000737:chemistry*; D010087:Oxides / Q000378:metabolism* / Q000493:pharmacokinetics; D010316:Particle Size; D011817:Rabbits; D013670:Sodium Pertechnetate Tc 99m / Q000493:pharmacokinetics; D014018:Tissue Distribution; D015899:Tomography, Emission-Computed, Single-Photon; D014057:Tomography, X-Ray Computed
chemical_list: D017304:Annexin A5; D003287:Contrast Media; D003911:Dextrans; D058185:Magnetite Nanoparticles; D010087:Oxides; D013670:Sodium Pertechnetate Tc 99m; D007501:Iron; C065507:ferumoxides; D052203:Ferrosoferric Oxide