In Vivo Targeting of Inflammation-Associated Myeloid-Related Protein 8/14 Via Gadolinium Immunonanoparticles

    Authors

    A. Maiseyeu; M. A. Badgeley; T. Kampfrath; G. Mihai; J. A. Deiuliis; C. Q. Liu; Q. H. Sun; S. Parthasarathy; D. I. Simon; K. Croce;S. Rajagopalan

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    Abbreviated Journal Title

    Arterioscler. Thromb. Vasc. Biol.

    Keywords

    atherosclerosis; imaging agents; macrophages; magnetic resonance imaging; SCAVENGER RECEPTOR CD36; MACROPHAGE FOAM CELL; ENDOTHELIAL-CELLS; APOPTOTIC CELLS; VASCULAR INJURY; PHOSPHATIDYLSERINE LIPOSOMES; OXIDIZED; PHOSPHOLIPIDS; CARDIOVASCULAR EVENTS; BIOLOGICAL RESPONSE; INTEGRIN; MAC-1; Hematology; Peripheral Vascular Disease

    Abstract

    Objective-Myeloid-related protein (Mrp) 8/14 complex (is a highly expressed extracellularly secreted protein, implicated in atherosclerosis. In this study, we evaluated the feasibility of targeting Mrp in vivo through synthetic immuno-nanoprobes. Methods and Results-Anti-Mrp-14 and nonspecific IgG-conjugated gadolinium nanoprobes (aMrp-) were synthesized and characterized. Pharmacokinetics and vascular targeting via MRI of the formulations were assessed in vivo in high fat-fed apolipoprotein E deficient (ApoE(-/-)), ApoE(-/-)/Mrp14(-/-) (double knockout) and chow-fed wild-type (C57BL/6) mice. Bone marrow-derived myeloid progenitor cells were isolated from both ApoE(-/-) and double knockout mice, differentiated to macrophages, and were treated with LPS, with or without Mrp8, Mrp14, or Mrp8/14; conditioned media was used for in vitro studies. Mrp-activated cells secreted significant amounts of proinflammatory cytokines, which was abolished by pretreatment with aMrp-NP. We show in vitro that aMrp-NP binds endothelial cells previously treated with conditioned media containing Mrp8/14. MRI following intravenous delivery of aMrp-NP revealed prolonged and substantial delineation of plaque in ApoE(-/-) but not double knockout or wild-type animals. Nonspecific IgG-conjugated gadolinium nanoprobe-injected animals in all groups did not show vessel wall enhancement. Flow-cytometric analysis of aortic digesta revealed that aMrp-NP present in Ly-6G (1), CD11b (1), CD11c (1), and CD31 (1) cells in ApoE(-/-) but not in double knockout animals. Conclusion-Targeted imaging with aMrp-NP demonstrates enhancement of plaque with binding to inflammatory cells and reduction in inflammation. This strategy has promise as a theranostic approach for atherosclerosis. (Arterioscler Thromb Vasc Biol. 2012; 32: 962-970.)

    Journal Title

    Arteriosclerosis Thrombosis and Vascular Biology

    Volume

    32

    Issue/Number

    4

    Publication Date

    1-1-2012

    Document Type

    Article

    Language

    English

    First Page

    962

    Last Page

    U258

    WOS Identifier

    WOS:000301672300020

    ISSN

    1079-5642

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