Tri-gadolinium nitride PEGylated-hydroxylated endohedral metallofullerene

[Gd₃N@C₈₀[DiPEG₅₀₀₀(OH)_x]]

Background

[PubMed]

Fullerenes, also known as buckyballs, are spheroidal carbon cages with a molecular formula of C_2n (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@C_2n or Gd₃N@C_2n, where the “@” symbol refers to the encapsulated nature of the Gd or Gd₃N. For the Gd@C_2n, 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⁺@C₈₂^3-]. For Gd₃N@C_2n, each Gd atom shares one electron with the N atom and donates the other two electrons to the C80 cage that is in I_h-symmetry to produce a zwitterion [Gd₃N⁶⁺@C₈₀^6-] (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).

The tri-gadolinium nitride PEGylated-hydroxylated endohedral metallofullerene (Gd₃N@C₈₀[DiPEG₅₀₀₀(OH)_x]) is a PEG₅₀₀₀-functionalized trimetallic nitride endohedral metallofullerene for in vivo MRI (2). The encapsulation of three Gd ions inside the carbon cage prevents direct coordination and exchange of water to Gd³⁺. The relaxation enhancement of Gd₃N@C₈₀[DiPEG₅₀₀₀(OH)_x] is therefore quite different from the classic inner-sphere mechanism in conventional Gd chelates such as Gd-DOTA (1). Depending on the symmetry of Gd₃N (pyramidal) and the C₈₀ cage (icosahedral), Gd₃N@C₈₀[DiPEG₅₀₀₀(OH)_x] can possess a permanent dipolar moment to induce an increase of T₁ relaxivity as much as 30 times more than that of Gd-DOTA (2).

Synthesis

[PubMed]

Fatouros et al. described the preparation of Gd₃N@C₈₀[DiPEG₅₀₀₀(OH)_x] in two steps (2). Initially, Gd₃N@C₈₀ was obtained by arc-vaporization of graphite rods packed with Gd₂O₃, Fe_xN, and graphite powder in a Krätschmer-Huffman (K-H) electric-arc generator in a N₂/He atmosphere (3). The obtained soot was mixed with CBr₄ in toluene under sonication, and the resulting mixture was reacted with PEG malonate (Mw ~10,000) and 1,8-diazabicyclo[5.4.0]-undec-7-ene for 20 h under nitrogen atmosphere at room temperature (2). The produced Gd₃N@C₈₀[DiPEG₅₀₀₀(OH)_x] was purified with silica gel column chromatography and the gadolinium content was measured with the inductively coupled plasma optical emission spectroscopy (ICP-OES).

In Vitro Studies: Testing in Cells and Tissues

[PubMed]

The T₁/T₂ relaxivity of Gd₃N@C₈₀[DiPEG₅₀₀₀(OH)_x] appeared to be dependent on concentration (2). In the low concentration range of 0.0016–0.0126 mM, the T₁ relaxivity was 102 mM^-1s^-1 at 0.35 T, 143 mM^-1s^-1 at 2.4 T, and 32 mM^-1s^-1 at 9.4 T, and the corresponding T₂ relaxivity values were 144 mM^-1s^-1, 222 mM^-1s^-1, and 137 mM^-1s^-1, respectively. A nonlinear relaxivity pattern was found over the concentration range of 0.0016–0.202 mM at 2.4 T. Compared to conventional MRI contrast agents such as Gd-DOTA, which has a T₁ relaxivity value of 3.84 mM^-1s^-1 at 0.47 T, the T¹ relaxivity of Gd₃N@C₈₀[DiPEG₅₀₀₀(OH)_x] increased ~30-fold per fullerene molecule or ~10-fold per Gd ion.

Animal Studies

Human Studies

[PubMed]

No publication is currently available.