Targeted molecular probes for imaging atherosclerotic lesions with magnetic resonance using antibodies that recognize oxidation-specific epitopes.
BACKGROUND
Oxidized low-density lipoprotein plays a key role in the initiation, progression, and destabilization of atherosclerotic plaques and is present in macrophages and the lipid pool. The aim of this study was to assess the feasibility of magnetic resonance imaging of atherosclerotic lesions in mice using micelles containing gadolinium and murine (MDA2 and E06) or human (IK17) antibodies that bind unique oxidation-specific epitopes.


RESULTS
MDA2 micelles, E06 micelles, IK17 micelles, nonspecific IgG micelles, and untargeted micelles (no antibody) were prepared and characterized with respect to pharmacokinetics and biodistribution in wild-type and atherosclerotic apolipoprotein E-deficient (apoE(-/-)) mice. Magnetic resonance imaging was performed at 9.4 T over a 96-hour time interval after the administration of 0.075-mmol Gd/kg micelles. MDA2, E06, and IK17 micelles exhibited a longer plasma half-life than IgG or untargeted micelles in apoE(-/-) but not wild-type mice. In apoE(-/-) mice, MDA2 and IK17 micelles showed maximal arterial wall uptake at 72 hours and E06 micelles at 96 hours, manifested by 125% to 231% enhancement in magnetic resonance signal compared with adjacent muscle. Confocal microscopy revealed that MDA2, IK17, and E06 micelles accumulated within atherosclerotic lesions and specifically within macrophages. Intravenous injection of free MDA2 before imaging with MDA2 micelles resulted in significantly diminished magnetic resonance signal enhancement. IgG micelles and untargeted micelles showed minimal enhancement in apoE(-/-) mice. There was no significant signal enhancement with all micelles in wild-type mice.


CONCLUSIONS
Magnetic resonance imaging with micelles containing gadolinium and oxidation-specific antibodies demonstrates specific targeting and excellent image quality of oxidation-rich atherosclerotic lesions.
Imaging Science Laboratory, Department of Radiology, Mount Sinai School of Medicine, New York, NY 10029, USA.
Karen C
KC
Briley-Saebo
Peter X
PX
Shaw
Willem J M
WJ
Mulder
Seung-Hyuk
SH
Choi
Esad
E
Vucic
Juan Gilberto S
JG
Aguinaldo
Joseph L
JL
Witztum
Valentin
V
Fuster
Sotirios
S
Tsimikas
Zahi A
ZA
Fayad
D000818:Animals; D000906:Antibodies / Q000008:administration & dosage / Q000737:chemistry; D000918:Antibody Specificity; D001012:Aorta, Abdominal / Q000378:metabolism / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency; D050197:Atherosclerosis / Q000175:diagnosis* / Q000276:immunology; D003287:Contrast Media / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D003432:Cross-Linking Reagents / Q000737:chemistry; D004195:Disease Models, Animal; D000939:Epitopes / Q000276:immunology*; D005240:Feasibility Studies; D005682:Gadolinium / Q000737:chemistry / Q000493:pharmacokinetics; D006801:Humans; D008077:Lipoproteins, LDL / Q000276:immunology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008279:Magnetic Resonance Imaging / Q000379:methods*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008823:Micelles; D015335:Molecular Probes / Q000737:chemistry / Q000493:pharmacokinetics; D010084:Oxidation-Reduction; D010743:Phospholipids / Q000276:immunology; D013864:Thioglycolates / Q000737:chemistry; D014018:Tissue Distribution
D000906:Antibodies; D001057:Apolipoproteins E; D003287:Contrast Media; D003432:Cross-Linking Reagents; D000939:Epitopes; D008077:Lipoproteins, LDL; D008823:Micelles; D015335:Molecular Probes; D010743:Phospholipids; D013864:Thioglycolates; C099252:oxidized low density lipoprotein; D005682:Gadolinium