CN101845112B - Preparation method of high-flexibility nuclear magnetic resonance imaging contrast agents based on high molecular nanometer particles - Google Patents

Abstract

The invention relates to a nuclear magnetic resonance imaging contrast agent, in particular to a method for preparing a high-sensitivity nuclear magnetic resonance imaging contrast agent based on polymer nanoparticles by miniemulsion polymerization. The complex of 1,4,7,10-tetraazacyclododecane with long-chain alkanes and gadolinium (referred to as Gd-DOTA) or the complex of diethylenetriaminepentaacetic acid and gadolinium (referred to as Gd-DTPA ) and polymer monomers are prepared by miniemulsion polymerization; the Gd-DOTA derivatives with long-chain alkanes (Gd-DOTA derivatives for short) and the Gd-DTPA derivatives with long-chain alkanes (Gd- for short) DTPA derivatives) have the structures of formula 1 and formula 2 respectively,

Formula 1 Formula 2 wherein the value of n is 8-24.

Description

A preparation method of a high-sensitivity nuclear magnetic resonance imaging contrast agent based on polymer nanoparticles

technical field

The invention relates to a nuclear magnetic resonance imaging contrast agent, in particular to a method for preparing a high-sensitivity nuclear magnetic resonance imaging contrast agent based on polymer nanoparticles by miniemulsion polymerization.

Background technique

Magnetic resonance imaging (MRI) technology has received unprecedented attention and application in the field of modern medical diagnosis. It can provide people with high-quality three-dimensional soft tissue imaging pictures under the condition of avoiding ion radiation. It is the main technology for disease diagnosis in the field of modern medicine. one. The signal intensity obtained by MRI mainly depends on the hydrogen nucleus density and the relaxation rate of water protons at the examination site, and the difference in hydrogen nucleus density and relaxation time between different tissues in the human body, between normal tissues and diseased tissues in the same tissue It is the main basis for MRI technology to distinguish between different tissues of the human body and whether the same tissue is diseased or not. However, since there is a certain overlap between the relaxation times of normal tissue and diseased tissue, more than 35% of MRI clinically need to inject MRI contrast agent to improve the imaging quality.

The paramagnetic metal complex contrast agents currently used in clinical practice mainly include: Gd-DOTA (Dotarem, Dotalin), Gd-HP-DO3A (ProHance, Proxians), Gd-BT-DO3A (Gadovist), Gd -DTPA (Magnevist, Magnevist), Gd-DTPA-BMA (Omniscan, Omniscan), Gd-DTPA-BMEA (Mallinckrodt), Gd-BOPTA (MultihHance, Modus), Gd-EOB-DTPA (Primovist) and MS -325 (Vasovist) and others. Although these small-molecule MRI contrast agents are stable, low-toxic and have good imaging effects, due to the low relaxation rate, more contrast agents need to be injected each time, which increases some potential safety hazards, and these The excretion rate of contrast agent molecules in the human body is fast, and it is easy to penetrate from the blood vessels to the cytoplasm, which is not conducive to blood vessel imaging. Although studies have shown that combining small molecule contrast agents with dendrimers through certain chemical constructions can greatly increase their relaxation rate and prolong their circulation time in blood (J Biol Inorg Chem (2007) 12: 406-420 ), but its application is restricted by the difficulties in the synthesis and purification of dendrimers. Studies have also found that small molecule contrast agents with long-chain alkanes exist in a micellar state in a higher concentration of aqueous solution (J Biol Inorg Chem (2002) 7: 757-769), and the contrast agents at this time also have higher However, because micelles cannot exist stably at low concentrations, this directly leads to their inability to be applied clinically. Therefore, it is very necessary to prepare a magnetic resonance imaging contrast agent with a suitably long residence time in the human body and a relatively high relaxation rate and stability.

Contents of the invention

The purpose of the present invention is to use the mechanism of miniemulsion polymerization to prepare a polymer nanosphere loaded with a gadolinium-containing complex on the surface. The polymer nanosphere can be used as a contrast agent for nuclear magnetic resonance imaging. High performance, stable performance, controllable molecular weight and in vivo residence time, etc.

The complexes formed by DOTA and DTPA and gadolinium have high thermodynamic and kinetic stability, so they are often used as ligands of gadolinium ions in clinical practice. DOTA and DTPA and Gd-DOTA and Gd-DTPA all have good water solubility. When a long alkane chain is drawn on a nitrogen atom in DOTA or DTPA, the entire molecule has a hydrophilic and lipophilic amphiphilic property, so it can be made Used as a surfactant. When these surfactants carry out miniemulsion polymerization with some oily macromolecular monomers, they rely on the hydrophobic-hydrophobic interaction between long alkane chains and macromolecules to make them loaded on the surface of macromolecular nanospheres. Since the polymer nanosphere has a large molecular weight, the rotation rate of the entire sphere can be reduced, and the rotation-related time τ _R of each molecule can be increased, thereby increasing its relaxation rate. In addition, the excretion rate in the human body can be adjusted by controlling the molecular weight of the polymer. In order to improve the stability of the emulsion after polymerization, the present invention uses a mixed surfactant, that is, derivatives of Gd-DOTA or Gd-DTPA are used together with some commercially available surfactants with biocompatibility, and experiments have proved that the emulsions are more stable.

A preparation method of a high-sensitivity nuclear magnetic resonance imaging contrast agent based on polymer nanoparticles, which is a complex of 1,4,7,10-tetraazacyclododecane and gadolinium with long-chain alkanes (referred to as Gd-DOTA) or the complex of diethylenetriaminepentaacetic acid and gadolinium (Gd-DTPA for short) and macromolecular monomers are prepared by miniemulsion polymerization; -DOTA derivatives) and Gd-DTPA derivatives (abbreviated as Gd-DTPA derivatives) with long-chain alkane have structures of formula 1 and formula 2 respectively,

Formula 1 Formula 2

Wherein the value of n is 8-24.

In yet another solution, the preparation method of the contrast agent of the present invention is prepared by performing miniemulsion polymerization with polymer monomers on DOTA or DTPA derivatives with long alkane chains, and then coordinating with gadolinium. The DOTA derivatives with long-chain alkanes (DOTA derivatives for short) and the DTPA derivatives with long-chain alkanes (DTPA derivatives for short) have the structures of formula 3 and formula 4 respectively:

Formula 3 Formula 4

Wherein the value of n is 8-24.

The polymer monomer used in the polymerization is styrene, divinylbenzene, methyl methacrylate, ethyl methacrylate, tert-butyl methacrylate, methyl acrylate, ethyl acrylate, butyl acrylate, acrylic acid One or more of tert-butyl ester and acrylamide.

The surfactant used in the miniemulsion polymerization is a mixture of Gd-DOTA derivatives or Gd-DTPA derivatives and other surfactants, or a mixture of DOTA derivatives or DTPA derivatives and other surfactants.

The other surfactants mentioned are Tween 20, Tween 40, Tween 60, Tween 80, Span 20, Span 40, Span 60, Span 80, polyvinyl alcohol, gum arabic, polycyclo Any one or more of ethylene oxide-polypropylene oxide-polyethylene oxide (referred to as PEG-PPG-PEG) triblock copolymers.

The whole preparation process has two schemes, one of which includes the following steps:

(1) Preparation of Gd-DOTA and Gd-DTPA derivatives (J. Org. Chem. 1999, 64, 2683-2689; Synlett, 2006, 17, 2815-2817).

((2), miniemulsion polymerization: take by weighing 10 mg-2000 mg of Gd-DOTA or Gd-DTPA derivatives and 5 mg-2000 mg of other surfactants, add 5 ml-500 ml of deionized water, stir until completely dissolved, then add 100mg-5000mg of polymer monomer, hexadecyl alcohol and azobisisobutyronitrile mixture, stir for 10-60 minutes, then ultrasonic for 5-20 minutes, after nitrogen gas for 10-30 minutes, quickly Raise the temperature to 60-90°C, react for 5-10 hours, cool and filter to obtain a stable polymer emulsion.

(3) Dialysis to remove small molecules: put the polymerized emulsion into a water-based dialysis bag (the highest permeation molecular weight is about 3000), dialyze in deionized water for 3-6 days with stirring, and the obtained emulsion can be used for testing.

(4) Determination of relaxation rate: The relaxation rate and imaging effect were measured with Siemens Trio 3T magnetic resonance imaging equipment. First, the contrast agent emulsion was diluted into solutions of several different concentrations, placed in a 1.5 ml centrifuge tube, and placed in a 1.5 ml centrifuge tube. The 3T magnetic resonance imager adopts the inversion recovery method for imaging operation, and the transverse relaxation time (T ₁ ) of each concentration solution can be calculated through the brightness of the image, and then through the formula:

cr ₁ +1/T _W ＝1/T ₁

T ₁ at each concentration is calculated (where c is the gadolinium content, T _W is the transverse relaxation time of water molecules), and finally the relaxation rate r ₁ of the contrast agent is obtained by computer fitting. Wherein the content of gadolinium is measured by full-spectrum direct-reading plasma emission spectrometry (ICP-AES).

The second includes the following steps:

(1) Preparation of DOTA and DTPA derivatives (J. Org. Chem. 1999, 64, 2683-2689; Synlett, 2006, 17, 2815-2817).

(2), miniemulsion polymerization: Weigh 10 mg-2000 mg of DOTA or DTPA derivatives and 5 mg-2000 mg of other surfactants, add 5 ml-500 ml of deionized water, stir until completely dissolved, and then add 100mg-5000mg mixture of macromolecular monomer, cetyl alcohol and azobisisobutyronitrile, stirred for 10-40 minutes, then ultrasonicated for 5-20 minutes, and then heated to 60-90°C after 10-30 minutes of nitrogen gas , react for 5 to 10 hours, cool and filter to obtain a stable polymer emulsion.

(3) Coordination with gadolinium: Take a certain amount of emulsion after polymerization, adjust the pH to 5-9 with hydrochloric acid and sodium hydroxide, then slowly add aqueous solution of gadolinium chloride dropwise, and after the dropwise addition, put it at 20-50°C React for 24 hours.

(4) Dialysis to remove small molecules: Put the complexed emulsion into a water-based dialysis bag (the highest permeation molecular weight is about 3000), and dialyze in deionized water for 3 to 6 days with stirring to remove excess gadolinium ions and other For small molecular weight substances, the resulting emulsion can be used for testing.

(5) Determination of relaxation rate: The relaxation rate and imaging effect were measured with Siemens Trio 3T magnetic resonance imaging equipment. First, the contrast agent emulsion was diluted into solutions of different concentrations, placed in a 1.5 ml centrifuge tube, and placed in a 1.5 ml centrifuge tube. The 3T magnetic resonance imager adopts the inversion recovery method for imaging operation, and the transverse relaxation time (T ₁ ) of each concentration solution can be calculated through the brightness of the image, and then through the formula:

cr ₁ +1/T _W ＝1/T ₁

T ₁ at each concentration is calculated (where c is the gadolinium content, T _W is the transverse relaxation time of water molecules), and finally the relaxation rate r ₁ of the contrast agent is obtained by computer fitting. Wherein the content of gadolinium is measured by full-spectrum direct-reading plasma emission spectrometry (ICP-AES).

Observed by TEM, the diameter of the polymer-carrier contrast agent obtained by miniemulsion polymerization is between 20 and 50 nanometers, showing good uniformity and stability. Magnetic resonance imaging experiments show that the relaxation rate of Gd-DOTA series of contrast agents with polymer as the carrier is 11.1mMS ^-1 , which is almost twice as high as the clinical application value (4.2mMS ^-1 ); Gd-DTPA series The relaxation rate of the contrast agent with polymer as the carrier is 6.6mMS ^-1 , which is more than 50% higher than the clinical application value (4.3mMS ^-1 ).

Description of drawings

Fig. 1 is a TEM image of a polymer nuclear magnetic resonance imaging contrast agent obtained by miniemulsion polymerization according to Example 3.

Fig. 2 is a SEM image of the polymer nuclear magnetic resonance imaging contrast agent obtained by miniemulsion polymerization according to Example 3.

Fig. 3 is a diagram showing the variation of the reciprocal of the transverse relaxation time (T ₁ ) of the polymer nuclear magnetic resonance imaging contrast agent obtained according to Example 3 with the concentration of gadolinium.

FIG. 4 is a diagram showing the variation of the imaging effect of the polymer nuclear magnetic resonance imaging contrast agent with the concentration of gadolinium obtained according to Example 3. FIG.

Fig. 5 is a TEM image of the polymer nuclear magnetic resonance imaging contrast agent obtained by miniemulsion polymerization according to Example 10.

Fig. 6 is a SEM image of the polymer nuclear magnetic resonance imaging contrast agent obtained by miniemulsion polymerization according to Example 10.

Fig. 7 is a diagram showing the variation of the reciprocal of the transverse relaxation time (T ₁ ) of the polymer nuclear magnetic resonance imaging contrast agent obtained according to Example 10 with the concentration of gadolinium.

FIG. 8 is a diagram showing the variation of the imaging effect of the polymer nuclear magnetic resonance imaging contrast agent obtained according to Example 10 with the concentration of gadolinium.

Detailed ways

The present invention will be described in further detail below in conjunction with specific embodiments.

Example 1

Preparation of DOTA derivatives: 10g of triethylenetetramine and 10g of 40% aqueous solution of glyoxal in acetonitrile, reacted in ice bath for 2 hours, then added 4-10 ml of dibromoethane and 40g of potassium carbonate, 60 React at ~80°C for 24 hours, cool and filter, dissolve with a small amount of dichloromethane and precipitate with n-hexane, spin the solution to dryness, and purify through the column, and react the obtained product with 1.5 equivalents of hexadecane iodide in toluene at 60°C After 4 to 6 days, remove the solvent, wash with ether, add 10 equivalents of hydroxylamine hydrochloride, reflux in ethanol for 2 hours, remove the solvent, add aqueous sodium hydroxide solution, extract three times with chloroform, remove chloroform, add hydrochloric acid to precipitate, and precipitate Recrystallize in ethanol, alkalization, extraction, and drying. The resulting product is reacted with bromoacetic acid in an aqueous solution at 40-100°C for 4-10 hours, and the pH is kept between 8 and 11. After the reaction, the pH is adjusted to neutral. After cooling and standing, a white solid precipitates out, which is the derivative of DOTA (Formula 3).

Example 2

Preparation of Gd-DOTA derivatives: Dissolve 200mg of DOTA derivatives in 5ml of water, adjust the pH to 5-8, add 1.2 equivalents of gadolinium chloride, react at 20-100°C for 24 hours, and then adjust the pH to 9 or so, filter with a microporous membrane, pass through an ion exchange resin, and remove the solvent water to obtain a derivative with Gd-DOTA (Formula 1).

Example 3

Weigh a certain amount of Gd-DOTA and Tween 60 according to the molar ratio of 1:2 to 4:1, add 5 to 20 ml of deionized water, add 0.1 to 0.4 g of styrene, 0.1 to 0.2 g of Divinylbenzene, 2-20 mg of cetyl alcohol, 2-20 mg of AIBN, 60-90 ° C under the protection of nitrogen, reacted for 6-10 hours, filtered and dialyzed for 3-6 days, the obtained emulsion was uniformly dispersed, and the latex particles The diameter is 20-50 nanometers (as shown in Figure 1), and solutions with different concentrations are prepared, and the relaxation rate is measured by a magnetic resonance imaging instrument. The transverse relaxation time has a good linear relationship with the concentration of gadolinium ions (as shown in Figure 2). The calculated transverse relaxation rate r ₁ =8.9mMS ^-1 , as the concentration of gadolinium ions decreases, the brightness of the imaging also shows a downward trend (as shown in Figure 3 ).

Example 4

Weigh a certain amount of Gd-DOTA and Tween 80 according to the molar ratio of 1:2 to 4:1, add 5 to 20 ml of deionized water, add 0.1 to 0.4 g of styrene, 0.1 to 0.2 g of Divinylbenzene, 2-20 mg of cetyl alcohol, 2-20 mg of AIBN, 60-90 ° C under the protection of nitrogen, reacted for 6-10 hours, filtered and dialyzed for 3-6 days, the obtained emulsion was uniformly dispersed, and the latex particle The diameter is 20-100 nanometers, and solutions _with different concentrations are prepared, and the relaxation rate is measured by a magnetic resonance imaging instrument. The transverse relaxation time has a good linear relationship with the concentration of gadolinium ions. 11mMS ^-1 , as the concentration of gadolinium ions decreases, the brightness of the imaging also shows a downward trend.

Example 5

Weigh a certain amount of Gd-DOTA and polyvinyl alcohol according to the molar ratio of 1:2 to 4:1, add 5 to 20 ml of deionized water, add 0.1 to 0.4 g of styrene, 0.1 to 0.2 g of Divinylbenzene, 2-20mg of cetyl alcohol, 2-20mg of AIBN, react under nitrogen protection at 60-90°C for 6-10 hours, filter and dialyze for 3-6 days to obtain a stable and uniform translucent emulsion, test performance Close to Example 1.

Example 6

Weigh a certain amount of Gd-DOTA and PEG-PPG-PEG according to the molar weight of 1:2~4:1, add 5~20 ml of deionized water, add 0.1~0.4g of styrene, 0.1~0.2 g of divinylbenzene, 2-20 mg of cetyl alcohol, 2-20 mg of AIBN, react under nitrogen protection at 60-90°C for 6-10 hours, filter and dialyze for 3-6 days to obtain a stable and uniform translucent emulsion. Test performance is close to Example 1.

Example 7

Weigh a certain amount of Gd-DOTA and Tween 60 according to the molar ratio of 1:2 to 4:1, add 5 to 20 ml of deionized water, add 0.1 to 0.4 g of methyl methacrylate, 0.1 to 20 ml of deionized water after completely dissolving 0.2g of divinylbenzene, 4-20mg of acrylamide, 2-20mg of cetyl alcohol, 2-20mg of AIBN, react under nitrogen protection at 60-90℃ for 6-10 hours, filter and dialyze for 3- After 6 days, a uniform and stable emulsion was obtained, and the test performance was close to that of Example 1.

Example 8

Preparation of DTPA derivatives: 10 g of diethylenetriamine and 3 g of hexadecane bromide were reacted in ethanol at 90° C. for 6 hours, and stirring was continued for 15 to 20 hours after stopping heating. The solvent was removed by rotary evaporation, and the light yellow crude product obtained was extracted with dichloromethane and saturated sodium chloride. The lower organic phase was removed, the solvent was removed by rotary evaporation, and dried in vacuum. The resulting solid was reacted with an aqueous solution of bromoacetic acid in tetrahydrofuran at 90°C for 6 hours, while sodium hydroxide solution was added dropwise to keep the pH between 8 and 12. Add HCl to adjust the pH to about 1-3, remove the solvent by rotary evaporation, wash the solid with ice ethanol, filter with suction, re-dissolve the solid in water (pH=8), add HCl to adjust the pH to about 1-3, stand still, and have a white color The solid precipitated out is the DTPA derivative (Formula 4).

Example 9

Preparation of Gd-DTPA derivatives: Dissolve 200mg of DTPA derivatives in 5ml of water, adjust the pH to 5-8, add 1.2 equivalents of gadolinium chloride, react at 20-100°C for 24 hours, and then adjust the pH to 9 or so, filter with a microporous membrane, pass through an ion exchange resin, and remove the solvent water to obtain a derivative with Gd-DTPA (Formula 2).

Example 10

Weigh a certain amount of Gd-DTPA and Tween 60 according to the molar weight of 1:2~5:1, add 5~20 ml of deionized water, add 0.1~0.4g of styrene, 0.01~0.02g of Divinylbenzene, 2-20 mg of cetyl alcohol, 2-20 mg of AIBN, react under nitrogen protection at 40-100°C for 6-10 hours, filter and dialyze for 3-6 days, the obtained emulsion is uniformly dispersed, and prepared with different concentrations solution, the relaxation rate was measured using a magnetic resonance imaging instrument, and the transverse relaxation time had a good linear relationship with the concentration of gadolinium ions (as shown in Figure 2). The final calculated transverse relaxation rate r ₁ =6～9mM ^-1 S ^{- 1} .

Example 11

Weigh a certain amount of Gd-DTPA and Tween 80 according to the molar weight of 1:2~5:1, add 5~20 ml of deionized water, add 0.1~0.4g of styrene, 0.01~0.02g of Divinylbenzene, 2-20 mg of cetyl alcohol, 2-20 mg of AIBN, reacted for 6-10 hours under nitrogen protection at 40-100 ° C, filtered and dialyzed for 3-6 days, the obtained emulsion was uniformly dispersed, and the test performance was consistent with Example 10 is similar.

Example 12

Weigh a certain amount of Gd-DTPA gum arabic according to the molar weight of 1:2~5:1, add 5~20 ml of deionized water, add 0.1~0.4g of styrene and 0.01~0.02g of diethylene after completely dissolving Benzene, 2-20 mg of cetyl alcohol, 2-20 mg of AIBN, reacted under nitrogen protection at 40-100 ° C for 6-10 hours, filtered and dialyzed for 3-6 days, the obtained emulsion was uniformly dispersed, and the test performance was the same as that of the examples 10 is close.

Example 13

Weigh a certain amount of Gd-DTPA and polyvinyl alcohol according to the molar weight of 1:2~5:1, add 5~20 ml of deionized water, add 0.1~0.4g of methyl methacrylate, 0.01~ 0.02g of divinylbenzene, 4-20mg of acrylamide, 2-20mg of cetyl alcohol, 2-20mg of AIBN, react under nitrogen protection at 40-100°C for 6-10 hours, filter and dialyze for 3- After 6 days, the obtained emulsion was uniformly dispersed, and the test performance was similar to that of Example 10.

Example 14

Weigh a certain amount of Gd-DTPA and Tween 60 according to the molar weight of 1:2~5:1, add 5~20 ml of deionized water, add 0.1~0.4g of methyl methacrylate, 0.01~ 0.02g of divinylbenzene, 4-20mg of acrylamide, 2-20mg of cetyl alcohol, 2-20mg of AIBN, react under nitrogen protection at 40-100°C for 6-10 hours, filter and dialyze for 3- After 6 days, the obtained emulsion was uniformly dispersed, and the test performance was similar to that of Example 10.

Claims (4)

1. A method for preparing a high-sensitivity nuclear magnetic resonance imaging contrast agent based on macromolecular nanoparticles, characterized in that Gd-DOTA or Gd-DTPA has derivatives of long-chain alkane and macromolecular monomers for miniemulsion polymerization Preparation; the Gd-DOTA derivatives or Gd-DTPA derivatives have the structures of formula 1 and formula 2 respectively:

Formula 1 Formula 2 Wherein the value of n is 8-24; The polymer monomer used in the polymerization is one or more of styrene, divinylbenzene, methyl methacrylate, methyl acrylate, ethyl acrylate, butyl acrylate, methacrylic acid, and acrylamide; The surfactant used in the miniemulsion polymerization is a mixture of Gd-DOTA derivatives shown in Formula 1 or Gd-DTPA derivatives shown in Formula 2 and other surfactants; The other surfactants mentioned are soil temperature 20, soil temperature 40, soil temperature 60, soil temperature 80, Span 20, Span 40, Span 60, Span 80, polyvinyl alcohol, gum arabic, polyethylene Any one or more of diol-polypropylene oxide-polyethylene glycol (referred to as PEG-PPG-PEG) triblock copolymers. 2. A method for preparing a high-sensitivity nuclear magnetic resonance imaging contrast agent based on macromolecular nanoparticles, characterized in that DOTA or DTPA derivatives with long alkane chains carry out miniemulsion polymerization with macromolecular monomers and then with gadolinium Coordination preparation; the DOTA derivatives or DTPA derivatives have the structures of formula 3 and formula 4 respectively:

Formula 3 Formula 4 Wherein the value of n is 8-24; The polymer monomer used in the polymerization is one or more of styrene, divinylbenzene, methyl methacrylate, methyl acrylate, ethyl acrylate, butyl acrylate, methacrylic acid, and acrylamide; The surfactant used in the miniemulsion polymerization is a mixture of Gd-DOTA derivatives shown in Formula 1 or Gd-DTPA derivatives shown in Formula 2 and other surfactants; The other surfactants mentioned are soil temperature 20, soil temperature 40, soil temperature 60, soil temperature 80, Span 20, Span 40, Span 60, Span 80, polyvinyl alcohol, gum arabic, polyethylene Any one or more of diol-polypropylene oxide-polyethylene glycol (referred to as PEG-PPG-PEG) triblock copolymers. 3. The preparation method of contrast agent according to claim 1, is characterized in that, comprises the following steps: (1), preparation of Gd-DOTA or Gd-DTPA derivatives; (2), miniemulsion polymerization: take by weighing 10 milligrams-2 grams of Gd-DOTA or Gd-DTPA derivatives and 5 milligrams-2 grams of other surfactants, add 5 milliliters-500 milliliters of deionized water, stir until Dissolve completely, then add 100mg-5g of polymer monomer, hexadecanol and azobisisobutyronitrile mixture, stir for 10-60 minutes, then ultrasonic for 5-20 minutes, and then heat up rapidly after 10-30 minutes of nitrogen gas to 60-90°C, react for 5-10 hours, cool and filter to obtain a stable polymer emulsion; (3), dialysis to remove small molecules: put the polymerized emulsion into an aqueous dialysis bag with a maximum molecular weight of 3000, Dialyzed in deionized water for 3 to 6 days under stirring, the obtained emulsion is a high-sensitivity nuclear magnetic resonance imaging contrast agent based on polymer nanoparticles. 4. The preparation method of contrast agent according to claim 2, is characterized in that, comprises the following steps: (1), preparation of DOTA or DTPA derivatives; (2), miniemulsion polymerization: Weigh 10 mg-2 g of DOTA or DTPA derivatives and 5 mg-2 g of other surfactants, add 5 ml-500 ml of deionized water, stir until completely dissolved, then add 100mg-5g mixture of polymer monomer, cetyl alcohol and azobisisobutyronitrile, stirred for 10-40 minutes, then ultrasonicated for 5-20 minutes, after 10-30 minutes of nitrogen gas, the temperature was rapidly raised to 60-90°C , react for 5-10 hours, cool and filter to obtain a stable polymer emulsion; (3) Coordination with gadolinium: take 2ml-50ml of the emulsion after polymerization, adjust the pH to 5-9 with hydrochloric acid and sodium hydroxide, then slowly add aqueous solution of gadolinium chloride dropwise, after the dropwise addition, 20-9 React at 50°C for 24 hours; (4) Dialysis to remove small molecules: put the coordinated emulsion into an aqueous dialysis bag with a maximum molecular weight of 3000, and dialyze in deionized water for 3 to 6 days with stirring to remove excess (uncoordinated) gadolinium Ions and other small molecular weight substances, the resulting emulsion is a high-sensitivity nuclear magnetic resonance imaging contrast agent based on polymer nanoparticles.

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