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Molecular Imaging and Contrast Agent Database (MICAD) [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2004-2013.

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Molecular Imaging and Contrast Agent Database (MICAD) [Internet].

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Gd@C82 Fullerenol

Gd@C82(OH)40
, PhD
National Center for Biotechnology Information, NLM, NIH, Bethesda, MD, vog.hin.mln.ibcn@dacim

Created: ; Last Update: December 1, 2008.

Chemical name:Gd@C82 Fullerenol
Abbreviated name:Gd@C82(OH)40
Synonym:Gd-fullerenol
Agent category:Cage molecule
Target:
Target category:Retention
Method of detection:Magnetic resonance imaging (MRI)
Source of signal/contrast:Gadolinium
Activation:No
Studies:
  • Checkbox In vitro
  • Checkbox Rodents
No structure is currently available in PubChem.

Background

[PubMed]

Fullerenes, also known as buckyballs, are spheroidal carbon cages with a molecular formula of C2n (n = 30–41) and a diameter of ~1 nm (1). The high chemical stability of fullerenes can resist any potential metabolic cage-opening process and hence prevents them from degradation in various biological conditions (2). Fullerenes contain hollow interiors that can hold atoms or ions as payloads for various biomedical applications (1). For example, Gd atoms or the trimetallic nitride Gd3N can be trapped inside the cage to form endohedral metallofullerenes denoted as Gd@C2n or Gd3N@C2n, where the “@” symbol refers to the encapsulated nature of the Gd or Gd3N. For the Gd@C2n, the encapsulation of electropositive Gd atom leads to the transfer of electrons from the Gd atom to the electronegative fullerene cage, resulting in a zwitterion [Gd3+@C823-]. For Gd3N@C2n, each Gd atom shares one electron with the N atom and donates the other two electrons to the C80 cage that is in Ih-symmetry to produce a zwitterion [Gd3N6+@C806-] (3, 4). These endohedral metallofullerenes thus lead to the generation of a novel type of contrast agent for magnetic resonance imaging (MRI), which possesses a high biological safety in that the carbon cage completely prevents the release of toxic Gd3+ ions into surrounding tissues (5, 6). The surface of fullerenes can be functionalized with a variety of groups or specific ligands; i.e., the addition of hydroxyls or polyethylene glycols (PEG) substantially increases their aqueous solubility (7).

Gd-Fullerenols (Gd@C82(OH)40) are water-soluble Gd endohedral metallofullerenes used with in vivo MRI (8). The encapsulation of Gd has three electrons transferred to the C82 fullerene cage, resulting in zwitterions [Gd3+@C82(OH)403-] in which seven unpaired electrons are located on the 4f-orbital of gadolinium ion and one unpaired electron is located on the fullerene cage. These unpaired electrons contribute to the paramagnetic moment of Gd@C82(OH)40. Nevertheless, the encapsulation of the Gd ion inside the carbon cage prevents direct coordination and exchange of water to Gd3+. The relaxation enhancement of Gd@C82(OH)40 is therefore quite different from the classic inner-sphere mechanism in conventional Gd chelates such as Gd-DTPA but depends on its paramagnetic moment and intermolecular aggregation effect (1). The aggregation leads to an increase in the rotational correlation time and alterations in the water exchange kinetics, which both influence the resultant relaxivity.

Synthesis

[PubMed]

Mikawa et al. reported the preparation of Gd@C82(OH)n in two steps (8). Initially, Gd@C82 was obtained by arc-vaporization of 0.8% Gd/graphite rods under helium atmosphere (50 Torr), followed by extraction with carbon disulfide and then purification with high-performance liquid chromatography. The purified Gd@C82 was dissolved in toluene and reacted with 50% aqueous NaOH solution in the presence of 15-crown-5 as a catalyst at room temperature to produce brownish Gd@C82(OH)n. The average number of hydroxyl groups (n) was found to be ~40, yielding a molecular formula of Gd@C82(OH)40 (one Gd atom per fulluerene). The charge state of encapsulated gadolinium atom was found to be trivalent (Gd3+) using a Gd M4,5-edge electron energy loss spectroscopy.

In Vitro Studies: Testing in Cells and Tissues

[PubMed]

The proton relaxivity of Gd@C82(OH)40 was measured in aqueous solutions with various magnetic fields. The T1 relaxivity (R1) was 67 mM-1s-1 at 0.47 T, 81 mM-1s-1 at 1.0 T, and 31 mM-1s-1 at 4.7 T. The T2 relaxivity (R2) was 79 mM-1s-1 at 0.47 T, 108 mM-1s-1 at 1.0 T, and 131 mM-1s-1 at 4.7 T. Compared to the 3.9 mM-1s-1 (R1) and 6.2 mM-1s-1 (R2) of Gd-DTPA at 1.0 T, the relaxivity of Gd@C82(OH)40 (R1 or R2) was increased ~20-fold. In addition, the relaxivity of Gd@C82(OH)40 appeared to be significantly influenced by the pH and ionic strength in the solution; i.e., a bell shape profile was observed for T1 relaxivity in the pH range of 3–8, and T1 relaxivity was lower in a 1.0 M aqueous NaCl solution than in water (61 mM-1s-1versus 67 mM-1s-1).

Anderson et al. used Gd@C82(OH)40 to label human cervical carcinoma cells (HeLa) and human mesenchymal stem cells (MSCs) (9). Cells were incubated for 10 h with 0.5 μmol Gd/ml Gd@C82(OH)40 in the presence of the transfection agent protamine sulfate. The labeled cells exhibited ~100% labeling efficiency and viability with cellular Gd content of 1.19 × 10-10 mg per cell (7.5 × 10-13 mmol Gd per cell). The cellular proliferation was evaluated with 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay; the MTT ratio was 74–78% for day 2 through day 6 and ~100% by day 9. The internalized Gd@C82(OH)40 nanoparticles were found with electron microscopy to be aggregated within the endosomes in cytoplasm. In addition, the labeled MSCs demonstrated normal adipogenic, chondrogenic, and osteogenic differentiation compared with the unlabeled control cells. The relaxation enhancement efficiency was examined ex vivo in the labeled HeLa cells with a 7-T MR imager. An increase of ~200% in the signal intensity was observed in the T1-weighted images compared to unlabeled cells.

Animal Studies

Rodents

[PubMed]

Mikawa et al. examined the biodistribution of Gd@C82(OH)40 in mice with in vivo MRI, followed by Gd assay with inductively coupled plasma-atomic emission spectrometry (ICP-AES) (8). CDF1 mice (n = 3, 8 wks old, ~20 g) were injected intravenously with Gd@C82(OH)40 at a dose of 5 μmol Gd/kg (compared to the typical dose of 100 μmol Gd/kg for Gd-DTPA). T1-Weighted images were collected with a 4.7-T imager before injection and at 30 min, 1 h, and 24 h after injection. Strong signal enhancement was observed in the lung, liver, spleen, and kidney. The Gd content in these organs was quantified with ICP-AES: ~60 μg Gd/g tissue in the lung, ~8 μg Gd/g tissue in the liver, ~5 μg Gd/g tissue in the spleen, and ~3 μg Gd/g tissue in the blood at 30 min; ~25 μg Gd/g tissue in the lung, ~10 μg Gd/g tissue in the liver, ~8 μg Gd/g tissue in the spleen, and <2 μg Gd/g tissue in the blood at 1 h; <1 μg Gd/g tissue in the lung, ~9 μg Gd/g tissue in the liver, ~12 μg Gd/g tissue in the spleen, and fell into background in the blood at 24 h. These results demonstrated that Gd@C82(OH)40 was readily trapped in the reticuloendothelial system.

Anderson et al. examined the relaxation enhancement efficiency of Gd@C82(OH)40-labeled cells in vivo with MRI (9). Rats were injected intramuscularly with 3 × 106 Gd@C82(OH)40-labeled MSCs in the thigh and imaged with a 7-T imager. A 33% increase in imaging contrast versus muscle was observed in the T1-weighted images. As a comparison, a rat was injected intramuscularly with 4 × 106 Gd@C82(OH)40-labeled MSCs (~1.19×10-10 mg Gd per cell or 7.5× 10-13 mmol Gd per cell) in the thigh and imaged at 1.5 T. These labeled cells demonstrated an 83% increase in signal intensity compared to the muscle in the T1-weighted images.

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

NIH intramural Research Program.

References

1.
Bolskar R.D. Gadofullerene MRI contrast agents. Nanomed. 2008;3(2):201–13. [PubMed: 18373426]
2.
Fatouros P.P. , Corwin F.D. , Chen Z.J. , Broaddus W.C. , Tatum J.L. , Kettenmann B. , Ge Z. , Gibson H.W. , Russ J.L. , Leonard A.P. , Duchamp J.C. , Dorn H.C. In vitro and in vivo imaging studies of a new endohedral metallofullerene nanoparticle. Radiology. 2006;240(3):756–64. [PubMed: 16837672]
3.
Aihara J. Kinetic stability of metabllofullerenes as predicted by bond resonance enery model. Phys. Chem. Chem. Phys. 2001;3:1427.
4.
Ge Z. , Duchamp J.C. , Cai T. , Gibson H.W. , Dorn H.C. Purification of endohedral trimetallic nitride fullerenes in a single, facile step. J Am Chem Soc. 2005;127(46):16292–8. [PubMed: 16287323]
5.
Lu J. , Sabirianov R.F. , Mei W.N. , Gao Y. , Duan C.G. , Zeng X. Structural and magnetic properties of Gd3N@C80. J Phys Chem B. 2006;110(47):23637–40. [PubMed: 17125320]
6.
Krause M. , Dunsch L. Gadolinium nitride Gd3N in carbon cages: the influence of cluster size and bond strength. Angew Chem Int Ed Engl. 2005;44(10):1557–60. [PubMed: 15674866]
7.
MacFarland D.K. , Walker K.L. , Lenk R.P. , Wilson S.R. , Kumar K. , Kepley C.L. , Garbow J.R. Hydrochalarones: a novel endohedral metallofullerene platform for enhancing magnetic resonance imaging contrast. J Med Chem. 2008;51(13):3681–3. [PMC free article: PMC2630425] [PubMed: 18558670]
8.
Mikawa M. , Kato H. , Okumura M. , Narazaki M. , Kanazawa Y. , Miwa N. , Shinohara H. Paramagnetic water-soluble metallofullerenes having the highest relaxivity for MRI contrast agents. Bioconjug Chem. 2001;12(4):510–4. [PubMed: 11459454]
9.
Anderson S.A. , Lee K.K. , Frank J.A. Gadolinium-fullerenol as a paramagnetic contrast agent for cellular imaging. Invest Radiol. 2006;41(3):332–8. [PubMed: 16481917]

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