In vivo targeting of inflammation-associated myeloid-related protein 8/14 via gadolinium immunonanoparticles.
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.


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(+), CD11b(+), CD11c(+), and CD31(+) cells in ApoE(-/-) but not in double knockout animals.


CONCLUSIONS
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.
Davis Heart & Lung Research Institute, The Ohio State University College of Medicine, Columbus, USA.
Andrei
A
Maiseyeu
Marcus A
MA
Badgeley
Thomas
T
Kampfrath
Georgeta
G
Mihai
Jeffrey A
JA
Deiuliis
Cuiqing
C
Liu
Qinghua
Q
Sun
Sampath
S
Parthasarathy
Daniel I
DI
Simon
Kevin
K
Croce
Sanjay
S
Rajagopalan
D000418:Albumins / Q000737:chemistry / Q000493:pharmacokinetics*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology; D000906:Antibodies / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D040501:Calgranulin A / Q000276:immunology* / Q000378:metabolism; D040502:Calgranulin B / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D002478:Cells, Cultured; D003287:Contrast Media / Q000737:chemistry / Q000493:pharmacokinetics*; D017077:Culture Media, Conditioned / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005240:Feasibility Studies; D005434:Flow Cytometry; D019786:Gadolinium DTPA / Q000737:chemistry / Q000493:pharmacokinetics*; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism; D006801:Humans; D018796:Immunoconjugates / Q000737:chemistry / Q000493:pharmacokinetics*; D007249:Inflammation / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D018836:Inflammation Mediators / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D008279:Magnetic Resonance Imaging; D008297:Male; D053768:Metal Nanoparticles; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D023461:Myeloid Progenitor Cells / Q000378:metabolism; D014018:Tissue Distribution
D000418:Albumins; D000893:Anti-Inflammatory Agents; D000906:Antibodies; D001057:Apolipoproteins E; D040501:Calgranulin A; D040502:Calgranulin B; D003287:Contrast Media; D017077:Culture Media, Conditioned; D016207:Cytokines; D018796:Immunoconjugates; D018836:Inflammation Mediators; C086145:S100a8 protein, mouse; C058946:albumin-(gadolinium-DTPA); D019786:Gadolinium DTPA