Preparation method of superfine gadolinium oxide T1-MRI contrast agent
By preparing citric acid-modified ultrafine gadolinium oxide nanoparticles (Gd2O3-CA), the problems of water dispersibility and biocompatibility of gadolinium oxide nanoparticles were solved, achieving high relaxation rate and rapid clearance, thus enhancing the clinical application potential of MRI contrast agents.
Patent Information
- Application Number
- CN202610313481.4
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2026-03-16
- Publication Date
- 2026-04-14
AI Technical Summary
Existing gadolinium oxide nanoparticles have poor water dispersibility, low biocompatibility, and are not easily cleared by the kidneys, which limits their potential for clinical translation.
Hydrophobic gadolinium oxide nanoparticles Gd2O3-OA with surface oleic acid stable were prepared by high-temperature thermal decomposition. They were then reacted with gallic acid to obtain Gd2O3-GA, and then reacted with citric acid under alkaline conditions to prepare citric acid modified ultrafine gadolinium oxide nanoparticles Gd2O3-CA.
The prepared Gd2O3-CA nanoparticles have uniform particle size, good water dispersibility, and higher longitudinal relaxation rate. They can be rapidly metabolized by the kidneys, reducing the risk of gadolinium ion deposition and improving MRI imaging results.
Smart Images
Figure CN121846316A_ABST
Abstract
Description
Technical Field
[0001] This invention relates to the field of medical contrast agent technology, and more specifically, to a method for preparing an ultrafine gadolinium oxide T1-MRI contrast agent. Background Technology
[0002] Magnetic resonance imaging (MRI) is an important medical imaging diagnostic technique. T1-weighted imaging often utilizes gadolinium-based contrast agents (GBCAs) to enhance tissue contrast. Currently, commonly used small-molecule gadolinium chelate contrast agents (such as Gd-DTPA) have safety risks, including low relaxation rate, short in vivo retention time, and a tendency to induce renal systemic fibrosis (NSF) and gadolinium ion deposition in tissues such as the brain.
[0003] In recent years, gadolinium oxide nanoparticles have been regarded as candidate materials for next-generation MRI contrast agents due to their high gadolinium ion loading and tunable surface properties. However, most existing gadolinium oxide nanoparticles are modified with hydrophobic ligands, resulting in poor water dispersibility, low biocompatibility, and difficulty in rapid renal clearance, which limits their clinical translation potential.
[0004] Therefore, it is of great significance to develop a new contrast agent with higher relaxation rate, good stability and rapid clearance. Summary of the Invention
[0005] The purpose of this invention is to overcome the shortcomings of the existing technology and to propose a method for preparing an ultrafine gadolinium oxide T1-MRI contrast agent.
[0006] To address the aforementioned technical problems, the present invention adopts the following technical solution:
[0007] A method for preparing an ultrafine gadolinium oxide T1-MRI contrast agent includes the following steps:
[0008] S1: Hydrophobic gadolinium oxide nanoparticles (Gd2O3-OA) with surface oleic acid stabilized were prepared by high-temperature thermal decomposition method;
[0009] S2: Gd2O3-OA was reacted with gallic acid to obtain Gd2O3-GA nanoparticles;
[0010] S3: Gd2O3-GA was reacted with citric acid under alkaline conditions to obtain citric acid-modified ultrafine gadolinium oxide nanoparticles Gd2O3-CA.
[0011] Further, step S1 specifically involves: using a high-temperature thermal decomposition method, Gd(acac)3, oleic acid and oleylamine are used as raw materials for reaction. After the reaction is completed, the mixture is washed three times with ethanol / cyclohexane to obtain hydrophobic gadolinium oxide nanoparticles Gd2O3-OA with oleic acid surface stability. These nanoparticles are dispersed in cyclohexane and stored in a sealed container at 4°C.
[0012] Furthermore, the molar ratio of Gd(acac)3, oleic acid and oleylamine is 1:8-20:40-60;
[0013] Furthermore, the reaction conditions for the reaction using Gd(acac)3, oleic acid and oleylamine as raw materials are as follows: first heat to 100-150℃ and hold for 1-3 h, then heat to 280-320℃ and reflux for 3-8 h, and finally cool to room temperature after the reaction is completed.
[0014] Further, step S2 specifically involves dissolving gallic acid in a first organic solvent, adding Gd2O3-CA, stirring the mixture at room temperature for 5–24 hours, precipitating the mixture with ethanol and washing it three times after the reaction is complete to obtain gallic acid-modified gadolinium oxide nanoparticles Gd2O3-GA.
[0015] Furthermore, the first organic solvent is selected from N,N-dimethylformamide (DMF), dichloromethane (DCM), tetrahydrofuran (THF), or a mixture thereof; the molar ratio of Gd2O3-OA to gallic acid is 1:3 to 20.
[0016] Further, step S3 specifically involves: dispersing Gd₂O₃-GA in a second organic solvent, mixing it with an aqueous citric acid solution at pH 10–13, reacting at 0–60°C for 24–96 hours, collecting the lower layer, adding a small amount of ethanol to precipitate, and then washing twice with a small amount of ethanol / water to remove unreacted citric acid, obtaining citric acid-modified ultrafine gadolinium oxide nanoparticles Gd₂O₃-CA. Finally, it is dispersed in water and stored at 4°C.
[0017] Furthermore, the molar ratio of Gd2O3-GA to citric acid is 1:5 to 20, and the volume ratio of water to the second organic solvent is 1:1 to 3.
[0018] Furthermore, the second organic solvent is selected from ethanol, dimethyl sulfoxide (DMSO), N,N-dimethylformamide (DMF), tetrahydrofuran (THF), or a mixture thereof.
[0019] Compared with the prior art, the advantages of this invention are:
[0020] The Gd₂O₃-CA nanoparticles prepared by this method are uniform in size and ultrafine, exhibiting good water dispersibility and stability. These nanoparticles possess a higher longitudinal relaxation rate and superior in vivo imaging performance, while also being rapidly eliminated through renal metabolism, reducing the risk of gadolinium ion deposition. Attached Figure Description
[0021] Figure 1 Transmission electron microscopy image of the Gd2O3-CA nanoparticles prepared in this invention;
[0022] Figure 2 The infrared spectrum of the Gd2O3-CA nanoparticles prepared in this invention;
[0023] Figure 3 The T1 relaxation rate fitting diagram is shown for the Gd2O3-CA nanoparticles prepared in this invention.
[0024] Figure 4 Enhanced MRI images of the liver and kidneys of mice after injection of the Gd2O3-CA nanoparticles of this invention. Detailed Implementation
[0025] The technical solutions of the present invention will be clearly and completely described below with reference to the accompanying drawings of the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. All other embodiments obtained by those skilled in the art based on the embodiments of the present invention without creative effort are within the scope of protection of the present invention.
[0026] I. Synthesis of Gd2O3-OA:
[0027] Using 40 mmol oleylamine as a solvent, 1 mmol of Gd(acac)3 and 10 mmol of oleic acid were added and stirred until homogeneous. The mixture was heated to 120 °C and held at that temperature for 1 h, then further heated to 280 °C and refluxed at this temperature for 6 h. After the reaction was completed, the mixture was cooled to room temperature, and the product was mixed with anhydrous ethanol and washed three times by precipitation-centrifugation to obtain the Gd2O3-OA product. This product was dispersed in cyclohexane (1 mmol / 10 ml, Gd) and stored in a sealed container at 4 °C.
[0028] 2. Gd2O3-GA synthesis:
[0029] Gallic acid (10 mmol, 1701.2 mg) was weighed and dissolved in 40 ml of tetrahydrofuran (THF) under slow stirring. 1 mmol of Gd₂O₃-OA dispersion was added to the above solution, and the mixture was stirred at room temperature for 24 h. After the reaction was complete, ethanol was added to precipitate the product, which was then separated by centrifugation and washed three times with ethanol to obtain Gd₂O₃-GA nanoparticles.
[0030] III. Gd2O3-CA Synthesis:
[0031] 1 mmol of Gd₂O₃-GA was dispersed in 50 mL of THF. Separately, 10 mmol (1921.2 mg) of citric acid was dissolved in water, and the pH was adjusted to 13 with NaOH solution. The citric acid aqueous solution was mixed with the Gd₂O₃-GA THF solution, maintaining a water to THF volume ratio of 1:1. The mixture was reacted at 50 °C for 72 h. After the reaction, the mixture was allowed to stand, and the lower layer was collected. A small amount of ethanol was added to precipitate the precipitate, followed by washing twice with a small amount of ethanol / water mixture to remove unreacted citric acid, ultimately yielding citric acid-modified ultrafine gadolinium oxide nanoparticles (Gd₂O₃-CA). These nanoparticles were dispersed in water and stored at 4 °C.
[0032] IV. Characterization and Effects:
[0033] Transmission electron microscopy (TEM) revealed that the Gd₂O₃-CA nanoparticles prepared in this embodiment had a particle size of approximately 6 nm, exhibiting uniform morphology and distribution (see [link to TEM]). Figure 1 The FT-IR spectrum is shown at ~1600 cm⁻¹. -1 and ~1400 cm -1 The presence of a carboxylate characteristic peak confirms successful modification with citric acid (see...). Figure 2 Relaxation performance tests show that, measured under a 3.0 T magnetic field, its longitudinal relaxation rate r1 is approximately 8.322 mM. -1 s -1 Furthermore, the r2 / r1 ratio is approximately 1.2, demonstrating excellent T1 contrast imaging potential (see...). Figure 3 ).
[0034] Animal experimental MRI images ( Figure 4 Studies have confirmed that these nanoparticles can effectively enhance the imaging contrast of mouse liver and kidneys. Due to their ultra-fine particle size, these particles can be rapidly eliminated through kidney metabolism, demonstrating promising biosafety prospects.
[0035] The above description is merely a preferred embodiment of the present invention; however, the scope of protection of the present invention is not limited thereto. Any equivalent substitutions or modifications made by those skilled in the art within the scope of the technology disclosed in the present invention, based on the technical solution and its improved concepts, should be covered within the scope of protection of the present invention.
Claims
1. A method for preparing an ultrafine gadolinium oxide T1-MRI contrast agent, characterized in that: Includes the following steps: S1: Hydrophobic gadolinium oxide nanoparticles (Gd2O3-OA) with surface oleic acid stabilized were prepared by high-temperature thermal decomposition method; S2: Gd2O3-OA was reacted with gallic acid to obtain Gd2O3-GA nanoparticles; S3: Gd2O3-GA was reacted with citric acid under alkaline conditions to obtain citric acid-modified ultrafine gadolinium oxide nanoparticles Gd2O3-CA.
2. The method for preparing an ultrafine gadolinium oxide T1-MRI contrast agent according to claim 1, characterized in that: Step S1 specifically involves using a high-temperature thermal decomposition method to react Gd(acac)3, oleic acid, and oleylamine as raw materials. After the reaction is completed, the mixture is washed with ethanol / cyclohexane to obtain hydrophobic gadolinium oxide nanoparticles Gd2O3-OA with oleic acid surface stability.
3. The method for preparing an ultrafine gadolinium oxide T1-MRI contrast agent according to claim 2, characterized in that: The molar ratio of Gd(acac)3, oleic acid and oleylamine is 1:8-20:40-60.
4. The method for preparing an ultrafine gadolinium oxide T1-MRI contrast agent according to claim 2, characterized in that: The reaction conditions for the reaction using Gd(acac)3, oleic acid and oleylamine as raw materials are as follows: first heat to 100-150℃ and hold for 1-3 h, then heat to 280-320℃ and reflux for 3-8 h, and finally cool to room temperature after the reaction is completed.
5. The method for preparing an ultrafine gadolinium oxide T1-MRI contrast agent according to claim 1, characterized in that: Step S2 is as follows: Gallic acid is dissolved in the first organic solvent, Gd2O3-CA is added, and the mixture is stirred at room temperature for 5 to 24 hours. After the reaction is completed, the mixture is precipitated with ethanol and washed to obtain gallic acid-modified gadolinium oxide nanoparticles Gd2O3-GA.
6. The method for preparing an ultrafine gadolinium oxide T1-MRI contrast agent according to claim 5, characterized in that: The first organic solvent is selected from DMF, DCM, THF or a mixture thereof; the molar ratio of Gd2O3-OA to gallic acid is 1:3 to 20.
7. The method for preparing an ultrafine gadolinium oxide T1-MRI contrast agent according to claim 1, characterized in that: Step S3 is as follows: Gd2O3-GA is dispersed in a second organic solvent and mixed with an aqueous solution of citric acid with a pH of 10-13. The mixture is reacted at 0-60°C for 24-96 hours. The lower layer contents are collected, a small amount of ethanol is added to precipitate the mixture, and then it is washed with a small amount of ethanol / water to remove unreacted citric acid, thereby obtaining citric acid-modified ultrafine gadolinium oxide nanoparticles Gd2O3-CA.
8. The method for preparing an ultrafine gadolinium oxide T1-MRI contrast agent according to claim 7, characterized in that: The molar ratio of Gd2O3-GA to citric acid is 1:5 to 20, and the volume ratio of water to the second organic solvent is 1:1 to 3.
9. The method for preparing an ultrafine gadolinium oxide T1-MRI contrast agent according to claim 7, characterized in that: The second organic solvent is selected from ethanol, DMSO, DMF, THF or a mixture thereof.