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Anti-malondialdehyde-modified low-density lipoprotein MDA2 murine monoclonal antibody manganese-micelles

MDA2-Mn micelles
, PhD
National for Biotechnology Information, NLM, NIH, Bethesda, MD
Corresponding author.

Created: ; Last Update: August 27, 2012.

Chemical name:Anti-malondialdehyde-modified low-density lipoprotein MDA2 murine monoclonal antibody manganese-micelles
Abbreviated name:MDA2-Mn micelles
Agent category:Antibody
Target:Malondialdehyde-modified low-density lipoprotein (MDA-LDL)
Target category:Antigen
Method of detection:Magnetic resonance imaging (MRI)
Source of signal/contrast:Gadolinium, Gd
  • Checkbox In vitro
  • Checkbox Rodents
Click on protein, nucleotide (RefSeq), and gene for more information about apolipoprotein B.



Magnetic resonance imaging (MRI) maps information about tissues spatially and functionally. Protons (hydrogen nuclei) are widely used in imaging because of their abundance in water molecules. Water comprises ~80% of most soft tissue. The contrast of proton MRI depends primarily on the density of the nucleus (proton spins), the relaxation times of the nuclear magnetization (T1, longitudinal; T2, transverse), the magnetic environment of the tissues, and the blood flow to the tissues. However, insufficient contrast between normal and diseased tissues requires the development of contrast agents. Most contrast agents affect the T1 and T2 relaxation times of the surrounding nuclei, mainly the protons of water. T2* is the spin–spin relaxation time composed of variations from molecular interactions and intrinsic magnetic heterogeneities of tissues in the magnetic field (1). Cross-linked iron oxide nanoparticles and other iron oxide formulations affect T2 primarily and lead to decreased signals. On the other hand, paramagnetic T1 agents, such as gadolinium (Gd3+) and manganese (Mn2+), accelerate T1 relaxation and lead to brighter contrast images.

Apolipoprotein E (apoE) is essential for the normal catabolism of triglyceride-rich lipoprotein chylomicrons (lipoprotein particles) (2). Oxidation of low-density lipoprotein (LDL) generates a number of highly reactive short chain-length aldehydic fragments of oxidized fatty acids capable of conjugating with lysine residues of apoliprotein B and other proteins. Oxidized LDL (OxLDL) is present in atherosclerotic lesions and is essential for the formation of foam cells in atherosclerotic plaques. During atherogenic conditions, deposition of lipids and extracellular matrix proteins on the endothelial cell surfaces of the aorta leads to the development of atherosclerotic plaques (3), which may erode and rupture. MDA2 is a murine monoclonal antibody to malondialdehyde-lysine epitopes of OxLDL and other oxidatively modified proteins, but not to normal LDL (4). The antibody-OxLDL complexes are taken up by macrophages and foam cells in the atherosclerotic plaques. Briley-Saebo et al. (5) demonstrated the accumulation of MDA2 micelles containing Gd (MDA2-Gd micelles) in macrophages of atherosclerotic lesions in apoE-deficient (apoE–/–) mice using MRI. However, Gd may lead to renal toxicity in patients. In another study, Briley-Saebo et al. (6) demonstrated that MDA2-Mn micelles exhibited sensitive and robust in vivo detection of atherosclerotic lesions in apoE–/– mice using MRI.



1,2-Distearoyl-sn-glycer-3-phosphoethanolamine-n-methoxy(polyethylene glycol-2000) ammonium salt (PEG-DSPE), Mn-DTPA-bis(stearyl-amid), and PEG-maleimide-DSPE were dissolved at a molar ratio of 49:50:1 in a chloroform:methanol solution with rhodamine added as a fluorescent label (6). The solvents were removed under heat and vacuum until a thin film was formed. The film was hydrated in a HEPES buffer (pH 7.0), and the sample was incubated at 65°C until micelles formed. MDA2 was modified with S-acetylthioglycolic acid N-hydroxysuccinimide ester and then covalently linked to the surface of the MDA2-Mn micelles. MDA2-Mn micelles have a hydrated diameter of 22 ± 2 nm with an r1 value of 9.3 nM–1s–1 at 60 MHz and 40ºC. The number of Mn molecules and the number of MDA2 monoclonal antibodies per MDA2-Mn micelle were not reported.

In Vitro Studies: Testing in Cells and Tissues


125I-MDA2 has been shown to bind specifically to human MDA-LDL but not to normal human LDL, high-density lipoprotein, very low-density lipoprotein, or bovine serum albumin (7). Confocal microscopy analysis showed that the highest accumulation of MDA2-Mn micelles in macrophages was obtained when both the macrophages and the MDA2-Mn micelles were pretreated with MDA-LDL; this accumulation was higher than with pretreatment of either one alone (5). The intracellular r1 value for MDA2-Mn micelles after incubation with J744a.1 macrophages (pretreated with MDA-LDL) was 45 ± 5 nM–1s–1, whereas the intracellular r1 value was not detectable in the macrophages incubated with untargeted Mn micelles (6).

Animal Studies



Briley-Saebo et al. (6) performed ex vivo biodistribution studies of MDA2-Mn micelles in 11-month-old apoE–/– mice that were fed a high-fat, high-cholesterol diet at 6 weeks of age. Animals were injected with either 0.05 mmol Mn/kg MDA2-Mn micelles (n = 3 mice/group) or non-targeted Mn micelles (n = 3 mice/group). As a comparison, MDA2-Gd and non-targeted micelles (0.075 mmol Gd/kg) were also injected. The accumulation of Mn/Gd was determined as a percentage of injected dose (% ID) at 1, 2, 3, 4, and 7 d after injection. The blood half-life was 16.4 h for MDA2-Mn micelles and 3.4 h for non-targeted Mn micelles, whereas the blood half-life was 14.3 h for MDA2-Gd micelles and 1.5 h for non-targeted Gd micelles. Liver and kidney uptake of Mn peaked at 48 h with ~10% ID and 1% ID, respectively, and the liver and kidney accumulation levels of Gd were 40% ID and 2% ID, respectively. The atherosclerotic aorta showed 0.50%, 0.27%, and 0.12% ID of MDA2-Mn micelles at 24, 48, and 96 h, respectively. On the other hand, MDA2-Gd micelles exhibited accumulation values of 0.20%, 0.30%, and 0.22% ID Gd at 24, 48, and 96 h, respectively. Little Mn was detected in the aorta after injection of non-targeted Mn micelles. Sequential T1-weighted MRI images (9.4 T) showed that MDA2-Mn micelles caused increased atherosclerotic arterial vessel wall enhancement at 24–96 h after injection. The mean enhancement was 60%, 140%, 70%, 45%, and 10% at 1, 2, 3, 4, and 7 d, respectively. A similar enhancement was also observed with a human single-chain Fv antibody fragment IK17 targeted to MDA-like epitopes (IK17-Mn-micelles). On the other hand, MDA2-Gd micelles exhibited a gradual enhancement over time (50% at 1 d, 80% at 2 d, and 120% at 3 d and 4 d) with maximal enhancement (~150%) at 7 d. In contrast, non-targeted Mn micelles caused minimal signal enhancement of ~20% at these time points. Co-injection of excess MDA2 reduced the enhancement with MDA2-Mn micelles by >90% in the aorta at 48–96 h. Confocal microscopy revealed that MDA2 localized primarily with intraplaque foam cells/macrophages in atherosclerotic lesions of the arterial wall. Briley-Saebo et al. concluded that no significant difference in the MR efficacy was observed between the MDA2-Mn and MDA2-Gd micelles at the optimal imaging time points after injection (2 d vs.7 d, respectively).

Other Non-Primate Mammals


No publication is currently available.

Non-Human Primates


No publication is currently available.

Human Studies


No publication is currently available.

NIH Support

R21 HL091399


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Tsimikas S., Palinski W., Halpern S.E., Yeung D.W., Curtiss L.K., Witztum J.L. Radiolabeled MDA2, an oxidation-specific, monoclonal antibody, identifies native atherosclerotic lesions in vivo. J Nucl Cardiol. 1999;6(1 Pt 1):41–53. [PubMed: 10070840]


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