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Anti-malondialdehyde-modified low-density lipoprotein MDA2 monoclonal antibody gadolinium-labeled micelles

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

Created: ; Last Update: October 22, 2009.

Chemical name:Anti-malondialdehyde-modified low-density lipoprotein MDA2 monoclonal antibody gadolinium-labeled micelles
Abbreviated name:MDA2 micelles
Synonym:
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
Activation:No
Studies:
  • Checkbox In vitro
  • Checkbox Rodents
Click on protein, nucleotide (RefSeq), and gene for more information about apolipoprotein B.

Background

[PubMed]

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 is present in atherosclerotic lesions and is essential for formation of foam cells in atherosclerotic plaques. During atherogenic conditions, depositions of lipids and extracellular matrix proteins on the endothelial cell surfaces of the aorta and cells lead to the development of atherosclerotic plaques (3), which may erode and rupture. MDA2 is a murine monoclonal antibody to malondialdehyde-lysine epitopes of MDA-LDL and other oxidatively modified proteins but not to normal LDL (4). Briley-Saebo et al. (5) studied magnetic resonance imaging of atherosclerotic lesions in mice using micelles containing Gd and MDA2.

Synthesis

[PubMed]

1,2-Distearoyl-sn-glycer-3-phosphoethanolamine-n-methoxy(polyethylene glycol-2000) ammonium salt (PEG-DSPE), Gd-DTPA-bis(stearyl-amid), and PEG-malamide-DSPE were dissolved at a molar ratio of 49:50:1 in a chloroform:methanol solution with rhodamine added as a fluorescent label (5). 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 Gd micelles. Gd-MDA2 micelles have a hydrated diameter of 22 ± 2 nm with an r1 value of 9.3 nM-1s -1 at 60 MHz and 40ºC. Neither the number of Gd molecules nor MDA2 monoclonal antibodies per micelle was reported.

In Vitro Studies: Testing in Cells and Tissues

[PubMed]

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 (6). Confocal microscopy analysis showed that the highest accumulation of MDA2 micelles in macrophages was obtained when both the macrophages and MDA2 micelles were pretreated with MDA-LDL than either one alone (5). The Gd contents were 0.3 µg/ml for macrophages and MDA2 micelles with no pre-exposure, 0.5 µg/ml for macrophages pretreated with MDA-LDL, 11 µg/ml for MDA2 micelles pretreated with MDA-LDL, and 15 µg/ml for both macrophages and MDA2 micelles pretreated with MDA-LDL, respectively. The enhanced uptake as in the latter two cases may be due to uptake of MDA-LDL MDA2 micelle complexes by macrophages.

Animal Studies

Rodents

[PubMed]

Briley-Saebo et al. (5) performed ex vivo biodistribution studies of MDA2 micelles in 11-month-old apoE-/- knockout mice that were fed a high-fat, high-cholesterol diet for 6 weeks. Animals were injected with either 0.075 mmol Gd/kg MDA2 micelles (n = 8 mice) or IgG micelles (n = 3 mice). The accumulation of Gd was determined as percent of injected dose (% ID) at 24, 48, and 96 h after injection. The blood half-life was 14.3 h for MDA2 micelles and 1.4 h for IgG micelles, whereas the blood half-life was ~1.5 h for both micelles in the wild-type mice. Liver, spleen, and kidney uptake peaked at 48 h with 38% ID, 6% ID, and 2% ID of Gd, respectively. Accumulation was <0.4% ID in the heart and lung. The abdominal lymph nodes showed 10, 80, and 37 µg/g Gd at 24, 48, and 96 h, respectively. The atherosclerotic aorta showed 0.30, 0.48, and 0.12% ID at 24, 48, and 96 h, respectively. No Gd was detected in the aorta after injection of either the untargeted or IgG micelles. Sequential T1-weighted MRI images (9.4 T) showed that MDA2 micelles caused increased atherosclerotic arterial vessel wall enhancement at 24–72 h after injection. The mean enhancement was 60%, 90%, and 125% at 24, 48, and 72 h, respectively. In contrast, IgG and untargeted micelles caused minimal signal enhancement. The liver showed enhancement of 33% with MDA2 micelles at the three time points. Pretreatment with excess MDA2 reduced the enhancement to 20% in the aorta and -8% in the liver at 72 h. Confocal microscopy revealed that MDA2 colocalized primarily with CD68 staining (macrophages) in the arterial wall.

Other Non-Primate Mammals

[PubMed]

No publication is currently available.

Non-Human Primates

[PubMed]

No publication is currently available.

Human Studies

[PubMed]

No publication is currently available.

NIH Support

R01 HL071021, R01 HL078667

References

1.
Wang Y.X., Hussain S.M., Krestin G.P. Superparamagnetic iron oxide contrast agents: physicochemical characteristics and applications in MR imaging. Eur Radiol. 2001;11(11):2319–31. [PubMed: 11702180]
2.
Eichner J.E., Dunn S.T., Perveen G., Thompson D.M., Stewart K.E., Stroehla B.C. Apolipoprotein E polymorphism and cardiovascular disease: a HuGE review. Am J Epidemiol. 2002;155(6):487–95. [PubMed: 11882522]
3.
Libby P., Ridker P.M., Maseri A. Inflammation and atherosclerosis. Circulation. 2002;105(9):1135–43. [PubMed: 11877368]
4.
Palinski W., Yla-Herttuala S., Rosenfeld M.E., Butler S.W., Socher S.A., Parthasarathy S., Curtiss L.K., Witztum J.L. Antisera and monoclonal antibodies specific for epitopes generated during oxidative modification of low density lipoprotein. Arteriosclerosis. 1990;10(3):325–35. [PubMed: 1693068]
5.
Briley-Saebo K.C., Shaw P.X., Mulder W.J., Choi S.H., Vucic E., Aguinaldo J.G., Witztum J.L., Fuster V., Tsimikas S., Fayad Z.A. Targeted molecular probes for imaging atherosclerotic lesions with magnetic resonance using antibodies that recognize oxidation-specific epitopes. Circulation. 2008;117(25):3206–15. [PMC free article: PMC4492476] [PubMed: 18541740]
6.
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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