# US 12,214,057 B2 · Graphene quantum dots-gadolinium ion chelate as magnetic resonance imaging contrast agent and preparation method thereof

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- Number: US 12,214,057 B2
- Document ID: US12214057B2
- Status: Granted
- Kind: B2
- Application number: 17/422,211
- Filed: 2019-03-05
- Published: 2022-03-10
- Granted: 2025-02-04
- Earliest claimed: 2019-01-31
- Assignees: Anhui University
- Applicants: Anhui University
- Inventors: Hong Bi; Dong Wang
- Web page: https://patentgrep.com/patent/US12214057B2

## CPC

- A61K 49/0002: {General or multifunctional contrast agents, e.g. chelated agents}
- A61K 49/0019: {characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules}
- A61K 49/085: {conjugated systems}
- C01B 32/15: Nano-sized carbon materials
- C01B 32/182: Graphene
- C01B 32/198: Graphene oxide
- C09K 11/025: {non-luminescent particle coatings or suspension media}
- C09K 11/65: containing carbon (in organic compounds C09K11/06)
- B82Y 5/00: Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
- B82Y 20/00: Nanooptics, e.g. quantum optics or photonic crystals
- B82Y 25/00: Nanomagnetism, e.g. magnetoimpedance, anisotropic magnetoresistance, giant magnetoresistance or tunneling magnetoresistance
- B82Y 30/00: Nanotechnology for materials or surface science, e.g. nanocomposites
- B82Y 40/00: Manufacture or treatment of nanostructures
- C01P 2004/04: obtained by TEM, STEM, STM or AFM
- C01P 2004/64: Nanometer sized, i.e. from 1-100 nanometer
- C01P 2004/80: Particles consisting of a mixture of two or more inorganic phases
- C01P 2006/60: Optical properties, e.g. expressed in CIELAB-values
- C01P 2006/82: water content
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- C01B: NON-METALLIC ELEMENTS; COMPOUNDS THEREOF; {METALLOIDS OR COMPOUNDS THEREOF NOT COVERED BY SUBCLASS C01C}
- C09K: MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
- B82Y: SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- C01P: INDEXING SCHEME RELATING TO STRUCTURAL AND PHYSICAL ASPECTS OF SOLID INORGANIC COMPOUNDS

## Abstract

A graphene quantum dots-gadolinium ion chelate (Gd@GQDs) nanomaterial with hydrophilic groups on the surface has a preparation method that includes: preparing graphene oxide by using a Hummers method; subsequently, subjecting the graphene oxide to heating, oxidation, and purification to obtain pure graphene quantum dots; and finally, chelating the graphene quantum dots with Gd3+ to form stable Gd@GQDs. The Gd@GQDs is easily dispersed in water, phosphate buffered solution (PBS), biological medium and other aqueous system, has good biocompatibility and low cytotoxicity, shows an excellent T1-weighted contrast performance in a 1.5-Tesla magnetic resonance testing system, and has a relaxation rate r1 as high as 72 mM−1s−1, the value of r1 being 20 times higher than that of the current commercial T1-weighted magnetic resonance imaging contrast agent Gd-DTPA.

## Claims

### Claim 1

A method for preparing the graphene quantum dots-gadolinium ion chelate, comprising the following steps:
1) Preparing graphene oxide by using a Hummers method;
2) Weighing and dissolving the graphene oxide in deionized water to obtain a first solution, performing an ultrasonic treatment on the first solution, and then adding a predetermined amount of a strong oxidant for being fully dissolved to obtain a second solution, wherein the strong oxidant is a mixture of at least one of potassium persulfate, hydrogen peroxide, and hypochloric acid;
3) Adding 400-1,000 μL of a basic compound to the second solution to obtain a resulting solution, and then refluxing the resulting solution for 7-12 h at 70-120° C.;
4) After the resulting solution is refluxed, performing a purification and a drying on the resulting solution to obtain the graphene quantum dots;
5) Preparing the graphene quantum dots into a third solution with a predetermined concentration, wherein the graphene quantum dots are pure, and then adding a predetermined amount of a gadolinium chloride solution to perform a chelation reaction under predetermined conditions to obtain a solution after the chelation reaction; and
6) Performing a purification and a drying on the solution after the chelation reaction to obtain the graphene quantum dots-gadolinium ion chelate.

### Claim 2 (depends on 1)

The method according to claim 1, wherein
an ultrasonic power in step 2) is 500-800 W.

### Claim 3 (depends on 1)

The method according to claim 1, wherein
in step 2), a mass ratio of the graphene oxide to the strong oxidant is (1-3):(1,000-3,000); and
a mass ratio of the graphene oxide to the deionized water is (1-3):(1,000-3,000).

### Claim 4 (depends on 1)

The method according to claim 1, wherein
the basic compound in step 3) is a mixture of at least one of potassium hydroxide, sodium hydroxide, ammonia, hydrazine hydrate, ethylenediamine, and hydroxylamine.

### Claim 5 (depends on 1)

The method according to claim 1, wherein
each of the purification in step 4) and the purification in step 6) is at least one selected from the group consisting of suction filtration, chromatography, dialysis, filtration, extraction, distillation, and fractionation;
each of the drying in step 4) and the drying in step 6) is at least one selected from the group consisting of vacuum drying, freeze drying, and high temperature drying.

### Claim 6 (depends on 1)

The method according to claim 1, wherein
in step 5), the predetermined concentration of the third solution prepared by the graphene quantum dots is 0.05-0.4 mg·mL−1; and
a concentration of the gadolinium chloride solution is 0.1-0.5 mmol·L−1.

### Claim 7 (depends on 1)

The method according to claim 1, wherein
the chelation reaction in step 5) is performed by one selected from the group consisting of water bath heating, hydrothermal reaction, solution dialysis, and room temperature treatment.

### Claim 8 (depends on 1)

A method of preparing a medical imaging contrast agent, further comprising: using the graphene quantum dots-gadolinium ion chelate prepared by the method according to claim 1.

### Claim 9 (depends on 8)

The method according to claim 8, wherein
the medical imaging contrast agent comprises a magnetic resonance imaging contrast agent and a fluorescent imaging agent.

### Claim 10 (depends on 8)

The method according to claim 8, wherein
an ultrasonic power in step 2) is 500-800 W.

### Claim 11 (depends on 8)

The method according to claim 8, wherein
in step 2), a mass ratio of the graphene oxide to the strong oxidant is (1-3):(1,000-3,000); and
a mass ratio of the graphene oxide to the deionized water is (1-3):(1,000-3,000).

### Claim 12 (depends on 8)

The method according to claim 8, wherein
the basic compound in step 3) is a mixture of at least one of potassium hydroxide, sodium hydroxide, ammonia, hydrazine hydrate, ethylenediamine, and hydroxylamine.

### Claim 13 (depends on 8)

The method according to claim 8, wherein
each of the purification in step 4) and the purification in step 6) is at least one selected from the group consisting of suction filtration, chromatography, dialysis, filtration, extraction, distillation, and fractionation;
each of the drying in step 4) and the drying in step 6) is at least one selected from the group consisting of vacuum drying, freeze drying, and high temperature drying.

### Claim 14 (depends on 8)

The method according to claim 8, wherein
in step 5), the predetermined concentration of the third solution prepared by the graphene quantum dots is 0.05-0.4 mg· mL−1; and
a concentration of the gadolinium chloride solution is 0.1-0.5 mmol·L−1.

### Claim 15 (depends on 8)

The method according to claim 8, wherein
the chelation reaction in step 5) is performed by one selected from the group consisting of water bath heating, hydrothermal reaction, solution dialysis, and room temperature treatment.