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. 2012:7:3751-68.
doi: 10.2147/IJN.S33139. Epub 2012 Jul 17.

Recombinant high-density lipoprotein nanoparticles containing gadolinium-labeled cholesterol for morphologic and functional magnetic resonance imaging of the liver

Mengjie Rui  1 , Wei Guo, Qian Ding, Xiaohui Wei, Jianrong Xu, Yuhong Xu
Affiliations

Recombinant high-density lipoprotein nanoparticles containing gadolinium-labeled cholesterol for morphologic and functional magnetic resonance imaging of the liver

Mengjie Rui et al. Int J Nanomedicine. 2012.

Abstract

Background: Natural high-density lipoproteins (HDL) possess important physiological functions to the transport of cholesterol from the peripheral tissues to the liver for metabolic degradation and excretion in the bile.

Methods and results: In this work, we took advantage of this pathway and prepared two different gadolinium (Gd)-DTPA-labeled cholesterol-containing recombinant HDL nanoparticles (Gd-chol-HDL) and Gd-(chol)(2)-HDL as liver-specific magnetic resonance imaging (MRI) contrast agents. The reconstituted HDL nanoparticles had structural similarity to native HDL, and could be taken up by HepG2 cells via interaction with HDL receptors in vitro. In vivo MRI studies in rats after intravenous injections of 10 μmol gadolinium per kg of recombinant HDL nanoparticles indicated that both nanoparticles could provide signal enhancement in the liver and related organs. However, different T(1)-weighted image details suggested that they participated in different cholesterol metabolism and excretion pathways in the liver.

Conclusion: Such information could be highly useful to differentiate functional changes as well as anatomic differences in the liver. These cholesterol-derived contrast agents and their recombinant HDL preparations may warrant further development as a new class of contrast agents for MRI of the liver and related organs.

Keywords: apolipoprotein; contrast agent; gadolinium; high-density lipoprotein; liver; magnetic resonance imaging.

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Figures

Figure 1
Figure 1
High-density lipoprotein nanoparticles incorporated with cholesterol-based gadolinium complexes. Abbreviations: Gd, gadolinium; DTPA, diethylenetriamine penta-acetic acid; DMPC, 1,2-dimyristoyl-sn-glycero-3-phosphocholine.
Figure 2
Figure 2
Electron micrographs of negatively stained Gd-chol-HDL (A and B) and Gd-(chol)2-HDL (C and D). Notes: Both samples were stained with 1% sodium phosphotungstate. White arrows indicate that the morphology of Gd-chol-HDL and Gd-(chol)2-HDL are discoidal nanoparticles. Original magnifications: (A and C) 30,000×, bar = 100 nm; (B and D) 60,000×, bar = 50 nm. Abbreviations: Gd, gadolinium; chol, cholesterol; HDL, high-density lipoprotein; DTPA, diethylenetriamine penta-acetic acid.
Figure 3
Figure 3
(A) In vitro T1-weighted magnetic resonance images of Gd-chol-HDL, Gd-(chol)2-HDL, and Gd-DTPA in Tris buffers (3T, repetition time/echo time = 10,000/7.6 msec). The gadolinium concentration of each tube was 0.6, 0.3, 0.15, 0.08, 0.04, and 0.02 mM (from left to right), respectively. (B) Longitudinal relaxation rates (1/T1) of Gd-chol-HDL, Gd-(chol)2-HDL, and Gd-DTPA in Tris buffer with respect to gadolinium concentration. Abbreviations: Gd, gadolinium; chol, cholesterol; HDL, high-density lipoprotein; DTPA, diethylenetriamine penta-acetic acid.
Figure 4
Figure 4
Cell viability of HepG2 cells after incubation with Gd-chol-HDL, Gd-(chol)2-HDL, and Gd-DTPA for 8 hours. Note: Data represent the mean ± standard deviation (n = 5). Abbreviations: Gd, gadolinium; chol, cholesterol; HDL, high-density lipoprotein; DTPA, diethylenetriamine penta-acetic acid.
Figure 5
Figure 5
(A) Gadolinium uptake curves of Gd-chol-HDL and Gd-(chol)2-HDL in HepG2 cells at a gadolinium ion concentration of 10 μM. (B) Competitive inhibition effect of two different apoA-I concentrations of native HDL on uptake of Gd-chol-HDL in HepG2 cells after incubation for 8 hours. Notes: Bars represent the mean ± standard deviation (n = 3). **P < 0.005, significantly different from the value of Gd-chol-HDL. Abbreviations: Gd, gadolinium; chol, cholesterol; HDL, high-density lipoprotein.
Figure 6
Figure 6
Representative in vivo MRI images of Sprague-Dawley rat liver injected with gadolinium-labeled reconstituted HDL. MRI images were obtained at different time points after injection of 10 μmol/kg (A) Gd-chol-HDL or (B) Gd-(chol)2-HDL. The five measured ROI used for the time courses in (A) and (B) are shown in the preinjection images. ROI1–3 and ROI4–5 were 6 mm and 2 mm in diameter, respectively. (C) Intensity enhancement of liver and the surrounding duodenum in vivo after injection of Gd-chol-HDL (n = 3) or Gd-(chol)2-HDL (n = 3). Note: Bars represent the mean ± standard deviation (n = 3). Abbreviations: Gd, gadolinium; chol, cholesterol; MRI, magnetic resonance imaging; HDL, high-density lipoprotein; ROI, region of interest.
Figure 7
Figure 7
Possible uptake mechanism of Gd-chol-HDL and Gd-(chol)2-HDL nanoparticles. After intravenous injection, discoidal Gd-chol-HDL and Gd-(chol)2-HDL nanoparticles were taken up by the liver through several pathways. The cholesterol-based complexes could be taken up by mediation of SR-BI. In addition, holoparticle uptake by hepatocytes is mediated by the ectopic β-chain of ATP synthase and P2Y13 receptors. Gd-DTPA-cholesterol may be converted into bile acids and retained in the liver for a relatively long period of time. The bile acids are then excreted into bile. However, Gd-DTPA-(cholesterol)2 may not be a suitable substrate for enzymes that catalyze the conversion of cholesterol into bile acid. Thus Gd-DTPA-(cholesterol)2 may be excreted into bile directly via the biliary sterol secretion pathway. Abbreviations: DTPA, diethylenetriamine penta-acetic acid; Gd, gadolinium; chol, cholesterol; MRI, magnetic resonance imaging; HDL, high-density lipoprotein; SR-BI, scavenger receptor class B type I.
Scheme 1
Scheme 1
Route of synthesis for Gd-DTPA-cholesterol and Gd-DTPA-(cholesterol)2. Abbreviations: Gd, gadolinium; DTPA, diethylenetriamine penta-acetic acid.
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