Gadolinium-based metallic fullerene water-soluble nitrene derivative as well as preparation method and application thereof

Abstract

The invention discloses a gadolinium-based metallic fullerene water-soluble nitrene derivative as well as a preparation method and application thereof. The gadolinium-based metallic fullerene water-soluble nitrene derivative is prepared by carrying out nitrene reaction on paramagnetic gadolinium-based metallic fullerene GdaNb@C2n and nitrine N3(CH2)mNH2 or N3(CH2)m-1COOH, and the structural general formula of the nitrene derivative is as shown as follow: GdaNb@C2n[N(CH2)mNH2]x or GdaNb@C2n[N(CH2)m-1COOM]x, wherein a is equal to 1-3, b is equal to 0-3, n is equal to 30-45, m is equal to 2-6, xis equal to 8-30, and M is H, NH4, Na or K. The invention provides the method for preparing the gadolinium-based metallic fullerene water-soluble nitrene derivative through nitrene reaction. The gadolinium-based metallic fullerene water-soluble nitrene derivative has good water solubility, also shows good paramagnetic properties and can serve as a magnetic resonance imaging contrast agent, when the nitrene derivative is used for MRI (magnetic resonance imaging), the contrast enhancement effect is very remarkable, and the nitrene derivative has an important application prospect in the aspect ofmedical diagnosis and treatment, especially in the aspect of diagnosis and treatment guided by MRI images.

Description

technical field

[0001] The invention belongs to the field of carbon nanomaterials, and relates to a class of paramagnetic gadolinium-based metal fullerene water-soluble nitrene derivatives and a preparation method and application thereof. The gadolinium-based metal fullerene water-soluble nitrene derivatives can be used as Magnetic resonance imaging (MRI) contrast agents. Background technique

[0002] have a high longitudinal relaxation rate (R 1 ), paramagnetic metallofullerenes with low biotoxicity T 1 Type MRI contrast agents have been developed for nearly 20 years. Among them, gadolinium-based metal fullerene MRI contrast agents as molecular imaging probes are most commonly reported in the literature. These MRI probes are Gd@C modified by hydroxylation, amination, Bingel-Hirsch or Prato reactions in one or more steps. 60 、Gd@C 82 、Sc x Gd 3-x N@C 80 、Gd 3 N@C 80 、Gd 3 N@C 84 derivative. Among these derivatives, Gd@C 82 (OH) 40 Labeling cells as molecular p...

Examples

Embodiment 1

[0049] Example 1: Preparation of Gd@C 82 With the water-soluble derivative of azidopropionic acid Gd@C 82 (NCH 2 COOH) 22

[0050] 10mg Gd@C 82 with liquid N 3 CH 2 CH 2 COOH was sequentially fed into the three-necked reaction flask according to the stoichiometric ratio of 1:500, protected by nitrogen, and stirred; first, the temperature was slowly raised to 60°C at a heating rate of 2°C / min, kept for 1 hour, and then raised to 120°C at a heating rate of 0.5°C / min ℃, keep warm for 48 hours, stop heating; add ethyl acetate to wash and filter, the residue is extracted repeatedly with deionized water until it is colorless, the extract is filtered and dried to obtain a solidified crude product; redissolve in deionized water, use MW= Dialysis with 3500 dialysis bags, membrane filtration, and freeze-drying to obtain pure paramagnetic Gd@C 82 A solid product of a water-soluble derivative of polyalanine.

[0051] Such as figure 1 As shown, the ion peak at m / z 1142 in MALDI-T...

Embodiment 2

[0054] Example 2: Preparation of Gd@C 82 With the water-soluble derivative of azidoacetic acid Gd@C 82 (NCH 2 COOH) 24

[0055] 10mg Gd@C 82 with liquid N 3 CH 2 COOH is sequentially fed into the three-necked reaction flask, protected by nitrogen, and stirred; first, the temperature is slowly raised to 80°C at a heating rate of 2°C / min, and kept for 2 hours, and then raised to 120°C at a heating rate of 0.5°C / min, kept for 48 hours, and the heating is stopped. Add ether for washing, and all the other conditions are the same as in Example 1 of the present invention. Get pure paramagnetic Gd@C 82 Solid product of polyglycine water-soluble derivatives. Thermogravimetric analysis characterized its average molecular formula as Gd@C 82 (NCH 2 COOH) 24 .

Embodiment 3

[0056] Example 3: Preparation of Gd@C 82 The water-soluble derivative Gd@C with azidoethylamine 82 (NCH 2 CH 2 NH 2 ) 20

[0057] 10mg Gd@C 82 with liquid N 3 CH 2 CH 2 NH 2 Feed into the three-necked reaction flask in sequence, under nitrogen protection, and stir; first, slowly raise the temperature to 60°C at a heating rate of 2°C / min, keep it for 2 hours, then raise it to 125°C at a heating rate of 0.5°C / min, keep it for 48 hours, and stop heating Add ethyl acetate to wash; All the other conditions are the same as Example 1 of the present invention. Get pure paramagnetic Gd@C 82 Polyethylenediamine water-soluble derivative Gd@C 82 (NCH 2 CH 2 NH 2 ) 20 solid products.

[0058] Such as Figure 4 As shown, the infrared spectrum is at 3385cm -1 The strong absorption peak at is attributed to N-H stretching vibration, 1388cm -1 The absorption peak is attributed to NH bending vibration, 1037cm -1 Belonging to C-NH 2 Stretching vibration at 2935, 2850cm -1 T...

technical field

[0001] The invention belongs to the field of carbon nanomaterials, and relates to a class of paramagnetic gadolinium-based metal fullerene water-soluble nitrene derivatives and a preparation method and application thereof. The gadolinium-based metal fullerene water-soluble nitrene derivatives can be used as Magnetic resonance imaging (MRI) contrast agents. Background technique

[0002] have a high longitudinal relaxation rate (R 1 ), paramagnetic metallofullerenes with low biotoxicity T 1 Type MRI contrast agents have been developed for nearly 20 years. Among them, gadolinium-based metal fullerene MRI contrast agents as molecular imaging probes are most commonly reported in the literature. These MRI probes are Gd@C modified by hydroxylation, amination, Bingel-Hirsch or Prato reactions in one or more steps. 60 、Gd@C 82 、Sc x Gd 3-x N@C 80 、Gd 3 N@C 80 、Gd 3 N@C 84 derivative. Among these derivatives, Gd@C 82 (OH) 40 Labeling cells as molecular p...

Examples

Embodiment 1

[0049] Example 1: Preparation of Gd@C 82 With the water-soluble derivative of azidopropionic acid Gd@C 82 (NCH 2 COOH) 22

[0050] 10mg Gd@C 82 with liquid N 3 CH 2 CH 2 COOH was sequentially fed into the three-necked reaction flask according to the stoichiometric ratio of 1:500, protected by nitrogen, and stirred; first, the temperature was slowly raised to 60°C at a heating rate of 2°C / min, kept for 1 hour, and then raised to 120°C at a heating rate of 0.5°C / min ℃, keep warm for 48 hours, stop heating; add ethyl acetate to wash and filter, the residue is extracted repeatedly with deionized water until it is colorless, the extract is filtered and dried to obtain a solidified crude product; redissolve in deionized water, use MW= Dialysis with 3500 dialysis bags, membrane filtration, and freeze-drying to obtain pure paramagnetic Gd@C 82 A solid product of a water-soluble derivative of polyalanine.

[0051] Such as figure 1 As shown, the ion peak at m / z 1142 in MALDI-T...

Embodiment 2

[0054] Example 2: Preparation of Gd@C 82 With the water-soluble derivative of azidoacetic acid Gd@C 82 (NCH 2 COOH) 24

[0055] 10mg Gd@C 82 with liquid N 3 CH 2 COOH is sequentially fed into the three-necked reaction flask, protected by nitrogen, and stirred; first, the temperature is slowly raised to 80°C at a heating rate of 2°C / min, and kept for 2 hours, and then raised to 120°C at a heating rate of 0.5°C / min, kept for 48 hours, and the heating is stopped. Add ether for washing, and all the other conditions are the same as in Example 1 of the present invention. Get pure paramagnetic Gd@C 82 Solid product of polyglycine water-soluble derivatives. Thermogravimetric analysis characterized its average molecular formula as Gd@C 82 (NCH 2 COOH) 24 .

Embodiment 3

[0056] Example 3: Preparation of Gd@C 82 The water-soluble derivative Gd@C with azidoethylamine 82 (NCH 2 CH 2 NH 2 ) 20

[0057] 10mg Gd@C 82 with liquid N 3 CH 2 CH 2 NH 2 Feed into the three-necked reaction flask in sequence, under nitrogen protection, and stir; first, slowly raise the temperature to 60°C at a heating rate of 2°C / min, keep it for 2 hours, then raise it to 125°C at a heating rate of 0.5°C / min, keep it for 48 hours, and stop heating Add ethyl acetate to wash; All the other conditions are the same as Example 1 of the present invention. Get pure paramagnetic Gd@C 82 Polyethylenediamine water-soluble derivative Gd@C 82 (NCH 2 CH 2 NH 2 ) 20 solid products.

[0058] Such as Figure 4 As shown, the infrared spectrum is at 3385cm -1 The strong absorption peak at is attributed to N-H stretching vibration, 1388cm -1 The absorption peak is attributed to NH bending vibration, 1037cm -1 Belonging to C-NH 2 Stretching vibration at 2935, 2850cm -1 T...

Images