Method for converting oil-soluble nanoparticles into water-soluble nanoparticles

Abstract

The invention provides a method for converting oil-soluble nano-particles into water-soluble nano-particles, which comprises the following steps: mixing an oil-soluble nano-particle dispersion liquid and a nitrite tetrafluoroborate solution, and carrying out ligand exchange reaction to obtain the water-soluble nano-particles, a solvent in the nitrous tetrafluoroborate solution comprises N, N-dimethylformamide. According to the method, nitrous tetrafluoroborate is used for replacing a long alkane ligand on the surface of an oil-soluble nano-particle and is anchored on the surface of the nano-particle as a more stable ligand, so that stable dispersion of the nano-particle in an aqueous solution can be realized, and meanwhile, N, N-dimethylformamide is adopted as a solvent in a nitrous tetrafluoroborate solution, so that stable dispersion of the nano-particle in the aqueous solution is realized. Not only is the dispersion of the nitrous tetrafluoroborate facilitated, but also the acceleration of ligand exchange is facilitated. The method is simple and convenient to operate and efficient, and has a broad-spectrum application range.

Description

Technical Field

[0001] The present invention belongs to a method for surface modification of nanoparticles, and relates to a method for converting oil-soluble nanoparticles into water-soluble nanoparticles. Background Art

[0002] Inorganic nanoparticles are widely used in the fields of optoelectronics, catalysis, biotechnology, etc. due to their unique properties related to size and shape. Currently, most synthetic routes for high-quality inorganic nanoparticles with adjustable size and shape mainly use long alkane molecules containing oleic acid (OA) or oleylamine (OAm) as ligands to stabilize the nanoparticles in non-polar oil-phase solvents and play a key role in the self-assembly of ordered nanoparticle arrays or superlattices. However, the presence of such capping molecules forms an insulating barrier around each nanoparticle and prevents polar molecular species from accessing the nanoparticle surface. When nanoparticles are applied in the field of biotechnology, it is usually required that the nanoparticles be completely dispersed in hydrophilic or aqueous media without performance degradation. Therefore, oil-soluble nanoparticles limit their applications in biomedical and other fields.

[0003] To solve the above problems, the synthesized oil-phase dispersed nanoparticles must be surface-treated or modified, usually by replacing the original ligands with specially designed substances through a ligand exchange process. CN105754380B discloses a method for converting oil-soluble nanoparticles into water-soluble nanoparticles, which includes the following steps: (1) dispersing the oil-soluble nanoparticles in a weakly polar solvent; (2) adding a tetrahydrofuran solution of polyethylene glycol phosphate to the dispersion of the oil-soluble nanoparticles; (3) adding an appropriate amount of medium-polarity solvent to the solution obtained in step (2); (4) adding an appropriate amount of water to the solution obtained in step (3); (5) stirring the mixed solution obtained in step (4) for 3 - 10 min, then separating the layers with a separating funnel, and taking the lower layer for rotary evaporation to remove the organic solvent to obtain water-soluble nanoparticles. However, the above method has cumbersome steps.

[0004] In addition to the above ligand exchange methods, many non-exchange methods have also been developed, such as coordinating with surface ligands through hydrophobic van der Waals interactions by using amphiphilic molecules. Although surface modification based on ligand exchange reactions has been actively explored in various nanoparticle systems, a general, efficient, and broad-spectrum strategy has far from been developed. This makes it difficult to further functionalize oil-phase dispersed nanoparticles.

[0005] Therefore, developing a simple, efficient, broad-spectrum, and stable modification method for converting oil-phase dispersed nanoparticles into water-phase dispersed nanoparticles is an urgent problem to be solved by those skilled in the art. Summary of the Invention

[0006] The object of the present invention is to provide a method for converting oil-soluble nanoparticles into water-soluble nanoparticles. The method is simple and efficient to operate, has a broad application scope, can quickly convert oil-phase dispersed nanoparticles into water-phase dispersed nanoparticles, and at the same time ensures the uniform dispersion of nanoparticles during the phase transfer process. The obtained water-soluble nanoparticles have high stability.

[0007] To achieve the object of this invention, the following technical solutions are adopted in the present invention:

[0008] The present invention provides a method for converting oil-soluble nanoparticles into water-soluble nanoparticles, the method comprising:

[0009] Mixing an oil-soluble nanoparticle dispersion and a nitrous tetrafluoroborate solution to carry out a ligand exchange reaction to obtain water-soluble nanoparticles;

[0010] The solvent in the nitrous tetrafluoroborate solution includes N,N-dimethylformamide.

[0011] The method of the present invention uses nitrous tetrafluoroborate (NOBF 4 ) to replace the long alkane ligands on the surface of oil-soluble nanoparticles and anchor them on the nanoparticle surface as more stable ligands, so as to achieve the stable dispersion of nanoparticles in an aqueous solution. At the same time, the nitrous tetrafluoroborate solution uses N,N-dimethylformamide (DMF) as the solvent, which not only facilitates the dispersion of NOBF 4 , but also helps to accelerate the ligand exchange and the stable dispersion of water-soluble nanoparticles.

[0012] Compared with the methods for transferring oil-phase dispersed nanoparticles to an aqueous medium in the prior art, the method of the present invention is simple, convenient and low-cost. Moreover, the nanoparticles obtained by the method can be stably dispersed in water for up to one year. In addition, the nanoparticles after ligand exchange can be further exchanged and modified with other stronger ligand molecules, increasing the application scenarios of the nanoparticles.

[0013] The water-soluble nanoparticles obtained by the present invention can be applied to the fields of diagnosis and treatment, catalysis or batteries in biomedicine.

[0014] As a preferred technical solution of the present invention, the surface of the oil-soluble nanoparticles is modified with a hydrophobic molecule.

[0015] The hydrophobic molecule described in the present invention includes a long alkane chain ligand.

[0016] Preferably, the hydrophobic molecule includes oleic acid and / or oleylamine.

[0017] As a preferred technical solution of the present invention, the solvent in the oil-soluble nanoparticle dispersion includes toluene.

[0018] Preferably, the concentration of the oil-soluble nanoparticle dispersion is 3-6 mg / mL, for example, it can be 3.2 mg / mL, 3.4 mg / mL, 3.5 mg / mL, 3.7 mg / mL, 3.9 mg / mL, 4 mg / mL, 4.2 mg / mL, 4.4 mg / mL, 4.5 mg / mL, 4.7 mg / mL, 4.9 mg / mL, 5 mg / mL, 5.2 mg / mL, 5.4 mg / mL, 5.5 mg / mL, 5.7 mg / mL or 5.9 mg / mL, etc., but not limited to the listed values, and other unlisted values within the numerical range are equally applicable.

[0019] As a preferred technical solution of the present invention, the concentration of the nitrous tetrafluoroborate solution is 18-22 mg / mL, for example, it can be 18.2 mg / mL, 18.5 mg / mL, 18.7 mg / mL, 19 mg / mL, 19.2 mg / mL, 19.5 mg / mL, 19.7 mg / mL, 20 mg / mL, 20.2 mg / mL, 20.5 mg / mL, 20.7 mg / mL, 21 mg / mL, 21.2 mg / mL, 21.5 mg / mL, 21.7 mg / mL or 21.9 mg / mL, etc., but not limited to the listed values, and other unlisted values within the numerical range are equally applicable.

[0020] Preferably, the mass ratio of the oil-soluble nanoparticles to nitrous tetrafluoroborate is 1:(1.5-2.5), for example, it can be 1:1.7, 1:1.9, 1:2, 1:2.1, 1:2.2, 1:2.3 or 1:2.4, etc., but not limited to the listed values, and other unlisted values within the numerical range are equally applicable.

[0021] Preferably, the mixing of the oil-soluble nanoparticle dispersion and the nitrous tetrafluoroborate solution is specifically: adding the nitrous tetrafluoroborate solution to the oil-soluble nanoparticle dispersion.

[0022] As a preferred technical solution of the present invention, the ligand exchange reaction includes a first oscillation reaction and a second oscillation reaction that are carried out in sequence.

[0023] Preferably, the temperature of the first oscillation reaction is 23-27 °C, for example, it can be 23.5 °C, 24 °C, 24.5 °C, 25 °C, 25.5 °C, 26 °C or 26.5 °C, etc., but not limited to the listed values, and other unlisted values within the numerical range are equally applicable.

[0024] Preferably, the rotation speed of the first oscillating reaction is 400 - 700 r / min. For example, it can be 420 r / min, 440 r / min, 450 r / min, 470 r / min, 500 r / min, 520 r / min, 540 r / min, 550 r / min, 570 r / min, 600 r / min, 620 r / min, 640 r / min, 650 r / min, 670 r / min, or 690 r / min, etc. However, it is not limited to the listed values, and other unlisted values within the numerical range are equally applicable.

[0025] Preferably, the time of the first oscillating reaction is 5 - 10 min. For example, it can be 5.5 min, 6 min, 6.5 min, 7 min, 7.5 min, 8 min, 8.5 min, 9 min, or 9.5 min, etc. However, it is not limited to the listed values, and other unlisted values within the numerical range are equally applicable.

[0026] Preferably, the temperature of the second oscillating reaction is 23 - 27 °C. For example, it can be 23.5 °C, 24 °C, 24.5 °C, 25 °C, 25.5 °C, 26 °C, or 26.5 °C, etc. However, it is not limited to the listed values, and other unlisted values within the numerical range are equally applicable.

[0027] Preferably, the rotation speed of the second oscillating reaction is 30 - 100 r / min. For example, it can be 40 r / min, 50 r / min, 60 r / min, 70 r / min, 80 r / min, 90 r / min, or 95 r / min, etc. However, it is not limited to the listed values, and other unlisted values within the numerical range are equally applicable.

[0028] Preferably, the time of the second oscillating reaction is 2 - 5 h. For example, it can be 2.5 h, 3 h, 3.5 h, 4 h, or 4.5 h, etc. However, it is not limited to the listed values, and other unlisted values within the numerical range are equally applicable.

[0029] As a preferred technical solution of the present invention, after the ligand exchange reaction, it further includes: centrifuging after mixing the reaction solution and n - hexane to obtain a precipitate, then dissolving the precipitate in N,N - dimethylformamide, and then washing with isopropanol. After centrifuging and drying, water - soluble nanoparticles are obtained.

[0030] Preferably, the addition amount of N,N - dimethylformamide is 1 - 4 mL. For example, it can be 1.5 mL, 2 mL, 2.5 mL, 3 mL, or 3.5 mL, etc. However, it is not limited to the listed values, and other unlisted values within the numerical range are equally applicable.

[0031] Preferably, the number of washing times ≥ 2 times, for example, it can be 3 times, 4 times, 5 times or 6 times, etc., but not limited to the listed values, and other unlisted values within the numerical range are equally applicable.

[0032] In the present invention, the dosage of isopropanol is 15 - 25 times the dosage of DMF added.

[0033] Preferably, the drying is carried out by blowing dry with nitrogen.

[0034] As a preferred technical solution of the present invention, the preparation method of oil-soluble nanoparticles includes:

[0035] (I) Mixing a metal salt, a fatty acid salt and a first solvent, and reacting to obtain a fatty acid metal complex precursor;

[0036] (II) Mixing a hydrophobic material, a second solvent and the fatty acid metal complex precursor obtained in step (I), and carrying out a thermal decomposition reaction to obtain oil-soluble nanoparticles.

[0037] The oil-soluble nanoparticles of the present invention are prepared by a high-temperature thermal decomposition reaction, and the obtained oil-soluble nanoparticles can be dispersed in n-hexane for standby.

[0038] As a preferred technical solution of the present invention, the metal in the metal salt in step (I) includes any one of iron element, manganese element, gold element or rare earth element.

[0039] Preferably, the fatty acid salt in step (I) includes sodium oleate.

[0040] Preferably, the molar ratio of the metal salt to the fatty acid salt in step (I) is 1:(5 - 8), for example, it can be 1:5.2, 1:5.5, 1:5.7, 1:6, 1:6.2, 1:6.5, 1:6.7, 1:7, 1:7.2, 1:7.5, 1:7.7 or 1:7.9, etc., but not limited to the listed values, and other unlisted values within the numerical range are equally applicable.

[0041] Preferably, the temperature of the reaction in step (I) is 60 - 90 °C, for example, it can be 65 °C, 70 °C, 75 °C, 80 °C, 85 °C or 87 °C, etc., but not limited to the listed values, and other unlisted values within the numerical range are equally applicable.

[0042] Preferably, the reaction time in step (I) is 4 - 7 h, for example, it can be 4.5 h, 5 h, 5.5 h, 6 h or 6.5 h, etc., but not limited to the listed values, and other unlisted values within the numerical range are equally applicable.

[0043] As a preferred technical solution of the present invention, the hydrophobic material in step (II) includes oleic acid and / or oleylamine.

[0044] Preferably, the molar ratio of the hydrophobic material to the fatty acid metal complex precursor in step (II) is 1: (0.5 - 5), for example, it can be 1:1, 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:4.5, or 1:4.9, etc., but not limited to the listed values, and other unlisted values within the numerical range are equally applicable.

[0045] Preferably, a vacuum pumping treatment is also included before the thermal decomposition reaction in step (II).

[0046] Preferably, the temperature of the vacuum pumping treatment is 70 - 100 °C, for example, it can be 75 °C, 80 °C, 85 °C, 90 °C, 95 °C, or 97 °C, etc., but not limited to the listed values, and other unlisted values within the numerical range are equally applicable.

[0047] Preferably, the time of the vacuum pumping treatment is 2 - 6 h, for example, it can be 2.5 h, 3 h, 3.5 h, 4 h, 4.5 h, 5 h, or 5.5 h, etc., but not limited to the listed values, and other unlisted values within the numerical range are equally applicable.

[0048] Preferably, the vacuum pumping treatment is carried out until the vacuum degree ≤ 10 -3 Pa.

[0049] Preferably, the heating rate of the thermal decomposition reaction in step (II) is 2 - 10 °C / min, for example, it can be 3 °C / min, 4 °C / min, 5 °C / min, 6 °C / min, 7 °C / min, 8 °C / min, or 9 °C / min, etc., but not limited to the listed values, and other unlisted values within the numerical range are equally applicable.

[0050] Preferably, the temperature of the thermal decomposition reaction in step (II) is 200 - 350 °C, for example, it can be 220 °C, 240 °C, 250 °C, 270 °C, 290 °C, 300 °C, 320 °C, or 340 °C, etc., but not limited to the listed values, and other unlisted values within the numerical range are equally applicable.

[0051] Preferably, the heat preservation time of the thermal decomposition reaction in step (II) is 30 - 60 min, for example, it can be 35 min, 40 min, 45 min, 50 min, 55 min, or 59 min, etc., but not limited to the listed values, and other unlisted values within the numerical range are equally applicable.

[0052] As a preferred technical solution of the present invention, the method includes the following steps:

[0053] (1) Prepare oil-soluble nanoparticles, and then add a nitrous tetrafluoroborate solution with a concentration of 18 - 22 mg / mL to the oil-soluble nanoparticle dispersion with a concentration of 3 - 6 mg / mL to conduct a ligand exchange reaction;

[0054] The surface of the oil-soluble nanoparticles is modified with hydrophobic molecules; the hydrophobic molecules include oleic acid and / or oleylamine;

[0055] The solvent in the oil-soluble nanoparticle dispersion includes toluene; the solvent in the nitrous tetrafluoroborate solution includes N,N-dimethylformamide; the mass ratio of the oil-soluble nanoparticles to nitrous tetrafluoroborate is 1:(1.5 - 2.5);

[0056] The ligand exchange reaction includes a first oscillation reaction and a second oscillation reaction carried out in sequence;

[0057] The temperature of the first oscillation reaction is 23 - 27 °C, the rotation speed is 400 - 700 r / min, and the time is 5 - 10 min;

[0058] The temperature of the second oscillation reaction is 23 - 27 °C, the rotation speed is 30 - 100 r / min, and the time is 2 - 5 h;

[0059] (2) Mix n-hexane and the reaction solution obtained from the ligand exchange reaction in step (1), then centrifuge to obtain a precipitate, then dissolve the precipitate in 1 - 4 mL of N,N-dimethylformamide, and then wash with isopropanol. After centrifugation and drying, water-soluble nanoparticles are obtained.

[0060] The numerical ranges described in the present invention include not only the above-listed point values, but also any point values between the above numerical ranges that are not listed. Due to space limitations and for the sake of brevity, the present invention does not exhaustively list the specific point values included in the ranges.

[0061] Compared with the prior art, the present invention has the following beneficial effects:

[0062] The method provided by the present invention uses nitrous tetrafluoroborate to replace the long alkane ligands on the surface of oil-soluble nanoparticles and anchor them on the nanoparticle surface as more stable ligands, so as to achieve the stable dispersion of nanoparticles in aqueous solution. At the same time, the nitrous tetrafluoroborate solution uses N,N-dimethylformamide as a solvent, which not only facilitates the dispersion of NOBF 4 , but also helps to accelerate the ligand exchange. The method is simple, efficient, has a broad application range, can quickly convert oil-phase dispersed nanoparticles into water-phase dispersed nanoparticles, and at the same time ensures the uniform dispersion of nanoparticles during the phase transfer process. Description of the Drawings

[0063] Figure 1TEM image of the oil-soluble nanoparticles obtained in Example 1;

[0064] Figure 2 TEM image of the water-soluble nanoparticles obtained in Example 1;

[0065] Figure 3 Physical image of the conversion of the oil-soluble nanoparticles to water-soluble nanoparticles in Example 1;

[0066] Figure 4 TEM image of the oil-soluble nanoparticles obtained in Example 2;

[0067] Figure 5 TEM image of the water-soluble nanoparticles obtained in Example 2;

[0068] Figure 6 Physical image of the conversion of the oil-soluble nanoparticles to water-soluble nanoparticles in Example 2;

[0069] Figure 7 TEM image of the oil-soluble nanoparticles obtained in Example 3;

[0070] Figure 8 TEM image of the water-soluble nanoparticles obtained in Example 3;

[0071] Figure 9 Physical image of the conversion of the oil-soluble nanoparticles to water-soluble nanoparticles in Example 3;

[0072] Figure 10 Graph of the Zeta potential test results of the water-soluble nanoparticles obtained in Example 1 dispersed in water;

[0073] Figure 11 Physical images of the water-soluble nanoparticles obtained in Example 1 dispersed in water on day 0 and day 14;

[0074] wherein, A - day 0, B - day 14;

[0075] Figure 12 Graph of the cytotoxicity test results of the water-soluble nanoparticles obtained in Example 1 in mouse breast cancer cells. Detailed implementation manners

[0076] The technical solution of the present invention will be further described below through specific implementation manners. Those skilled in the art should understand that the described embodiments are only for helping to understand the present invention and should not be regarded as specific limitations on the present invention.

[0077] Example 1

[0078] This example provides a method for converting oil-soluble nanoparticles into water-soluble nanoparticles, and the method includes the following steps:

[0079] (1) Dissolve sodium oleate (9.1 g, 60 mmol) and iron(III) chloride hexahydrate (2.7 g, 10 mmol) in a mixed solvent of 15 mL of water, 20 mL of absolute ethanol, and 35 mL of n-hexane. Then, reflux and stir the reaction at 70 °C for 4 h. After the reaction, cool it to room temperature, wash it, rotary evaporate it, and dry it at 70 °C for 12 h to obtain an iron oleate complex precursor;

[0080] (2) Dissolve oleic acid (0.57 g, 2 mmol), oleyl alcohol (1.61 g, 6 mmol), and the iron oleate complex precursor described in step (1) (1.8 g, 2 mmol) in diphenyl ether (10 g, 58 mmol). Then, conduct a vacuum treatment at 90 °C for 3 h with a vacuum degree ≤ 10 -3 Pa. After that, under nitrogen protection, heat it to 250 °C at a heating rate of 10 °C / min for thermal decomposition reaction and keep it warm for 30 min. After the reaction, cool it to room temperature and wash it with ethanol to obtain oil-soluble nanoparticles (ESIONPs-OA);

[0081] (3) Disperse 60 mg of the ESIONPs-OA described in step (2) in 15 mL of toluene, and disperse 120 mg of NOBF 4 in 6 mL of DMF. Then, add the NOBF 4 solution to the ESIONPs-OA dispersion for ligand exchange reaction;

[0082] The ligand exchange reaction includes a first shaking reaction and a second shaking reaction carried out in sequence;

[0083] The temperature of the first shaking reaction is 25 °C, the rotation speed is 550 r / min, and the time is 8 min; the temperature of the second shaking reaction is 25 °C, the rotation speed is 50 r / min, and the time is 4 h;

[0084] (4) Add 70 mL of n-hexane to the reaction solution after the ligand exchange reaction in step (3), centrifuge to collect the precipitate, then dissolve the precipitate in 3 mL of DMF, and then wash it twice with 40 mL of isopropanol. After centrifugation and drying with nitrogen, obtain water-soluble nanoparticles (ESIONPs-BF 4 ).

[0085] Figure 1 This is the transmission electron microscopy image of the oil-soluble nanoparticles (ESIONPs-OA) obtained in this example. As can be seen from the figure, the particle size of ESIONPs-OA is uniform, and the average particle size is 3 nm.

[0086] Figure 2 This is the water-soluble nanoparticles (ESIONPs-BF 4) Transmission electron microscopy image. As can be seen from the figure, ESIONPs-BF 4 has a uniform particle size, with an average particle size of 3 nm. This indicates that the ligand exchange method provided by the present invention does not change the particle size of the nanoparticles.

[0087] Figure 3 is a physical image of the phase transition process of the 3 nm nanoparticles in this example. As can be seen from the figure, the method realizes efficient oil-phase to water-phase dispersion.

[0088] Example 2

[0089] This example provides a method for converting oil-soluble nanoparticles into water-soluble nanoparticles. Except that steps (2) and (3) are adjusted to:

[0090] (2) Oleic acid (0.57 g, 2 mmol) and the iron oleate complex precursor (1.8 g, 2 mmol) described in step (1) are dispersed in octadecene (10 g, 58 mmol), and then vacuum treatment is carried out at a temperature of 80 °C for 3 h, with a vacuum degree ≤ 10 -3 Pa. Then, under argon protection, the temperature is raised to 320 °C at a heating rate of 10 °C / min for thermal decomposition reaction and kept warm for 30 min. After the reaction, it is cooled to room temperature and washed with ethanol to obtain oil-soluble nanoparticles (INOPs-OA);

[0091] (3) 60 mg of the INOPs-OA described in step (2) is dispersed in 15 mL of toluene, and 120 mg of NOBF 4 is dispersed in 6 mL of DMF. Then the NOBF 4 solution is added to the INOPs-OA dispersion for ligand exchange reaction;

[0092] The ligand exchange reaction includes a first oscillation reaction and a second oscillation reaction carried out in sequence;

[0093] The temperature of the first oscillation reaction is 25 °C, the rotation speed is 400 r / min, and the time is 10 min; the temperature of the second oscillation reaction is 25 °C, the rotation speed is 30 r / min, and the time is 4 h;

[0094] Other conditions are the same as those in Example 1.

[0095] Figure 4 is the transmission electron microscopy image of the oil-soluble nanoparticles (INOPs-OA) obtained in this example. As can be seen from the figure, INOPs-OA has a uniform particle size, with an average particle size of 12 nm.

[0096] Figure 5 are the water-soluble nanoparticles (INOPs-BF 4The transmission electron microscopy image of (), it can be seen from the figure that INOPs-BF 4 has a uniform particle size, and the average particle size is 12 nm.

[0097] Figure 6 This is the physical image of the phase transition process of the 12-nm nanoparticles in Example 1. It can be seen from the figure that the method realizes efficient oil-phase to water-phase dispersion.

[0098] Example 3

[0099] This example provides a method for converting oil-soluble nanoparticles into water-soluble nanoparticles. Except that steps (2) and (3) are adjusted to:

[0100] (2) Oleic acid (0.16 g, 0.57 mmol) and the iron oleate complex precursor described in step (1) (1.8 g, 2 mmol) are dispersed in octadecene (10 g, 58 mmol), and then vacuum treatment is carried out at a temperature of 80 °C for 3 h, and the vacuum degree ≤ 10 -3 Pa. Then, under the protection of argon, it is heated to 320 °C at a heating rate of 2 °C / min for thermal decomposition reaction and kept warm for 60 min. After the reaction, it is cooled to room temperature and washed with ethanol to obtain oil-soluble nanoparticles (INOPs-OA);

[0101] (3) 60 mg of the INOPs-OA described in step (2) is dispersed in 15 mL of toluene, and 120 mg of NOBF 4 is dispersed in 6 mL of DMF, and then the NOBF 4 solution is added to the INOPs-OA dispersion for ligand exchange reaction;

[0102] The ligand exchange reaction includes a first oscillation reaction and a second oscillation reaction carried out in sequence;

[0103] The temperature of the first oscillation reaction is 25 °C, the rotation speed is 500 r / min, and the time is 5 min; the temperature of the second oscillation reaction is 25 °C, the rotation speed is 100 r / min, and the time is 4 h;

[0104] All other conditions are the same as those in Example 1.

[0105] Figure 7 This is the transmission electron microscopy image of the oil-soluble nanoparticles (INOPs-OA) obtained in this example. It can be seen from the figure that INOPs-OA has a uniform particle size, and the average particle size is 20 nm.

[0106] Figure 8 This is the transmission electron microscopy image of the water-soluble nanoparticles (INOPs-BF 4 ) obtained in this example. It can be seen from the figure that INOPs-BF 4The particle size is uniform, and the average particle size is 20 nm.

[0107] Figure 9 This is a physical picture of the phase transition process of the 20-nm nanoparticles in Example 20. As can be seen from the figure, the method realizes efficient oil-phase to water-phase dispersion.

[0108] Example 4

[0109] This example provides a method for converting oil-soluble nanoparticles into water-soluble nanoparticles. Except that the dosage of NOBF in step (3) 4 is 60 mg, other conditions are the same as those in Example 1.

[0110] When the dosage of NOBF 4 is too small, due to the insufficient amount of the ligand provided by NOBF 4 the oleic acid ligand cannot be completely exchanged, resulting in the water-soluble nanoparticles not being able to be stably dispersed in water for a long time.

[0111] Example 5

[0112] This example provides a method for converting oil-soluble nanoparticles into water-soluble nanoparticles. Except that the dosage of NOBF in step (3) 4 is 150 mg, other conditions are the same as those in Example 1.

[0113] When the concentration of the NOBF 4 solution is too high, because the number of ligands of NOBF 4 is large enough, the oil-soluble nanoparticles can be completely converted into water-soluble nanoparticles and stably dispersed in water, but it will cause waste of raw materials.

[0114] Example 6

[0115] This example provides a method for converting oil-soluble nanoparticles into water-soluble nanoparticles. Except that the rotation speed of the first oscillation reaction in step (3) is 200 r / min, other conditions are the same as those in Example 1.

[0116] When the rotation speed of the first oscillation reaction is too slow, since it is necessary to shake vigorously at the beginning to carry out rapid ligand exchange, the oleic acid ligand cannot be completely exchanged, resulting in the water-soluble nanoparticles not being able to be stably dispersed in water.

[0117] Example 7

[0118] This example provides a method for converting oil-soluble nanoparticles into water-soluble nanoparticles. Except that the rotation speed of the first oscillation reaction in step (3) is 900 r / min, other conditions are the same as those in Example 1.

[0119] When the rotation speed of the first oscillation reaction is too fast, ligand exchange can occur rapidly, causing NOBF 4 The ligand can fully exchange the oleic acid ligand, enabling the transformation of oil-soluble nanoparticles into water-soluble nanoparticles and their stable dispersion in water. However, considering cost, the rotation speed of the first oscillation reaction is controlled at 400 - 700 r / min.

[0120] Example 8

[0121] This example provides a method for converting oil-soluble nanoparticles into water-soluble nanoparticles. Except that the first oscillation reaction is not carried out in step (3), other conditions are the same as those in Example 1.

[0122] When the first oscillation reaction is not carried out, since the ligand exchange reaction occurs throughout at low speed oscillation, the oleic acid ligand cannot be fully exchanged, resulting in the water-soluble nanoparticles not being stably dispersed in water.

[0123] Comparative Example 1

[0124] This comparative example provides a method for converting oil-soluble nanoparticles into water-soluble nanoparticles. Except that "6 mL DMF" in step (3) is replaced with "6 mL dichloromethane", other conditions are the same as those in Example 1.

[0125] If NOBF 4 is dispersed in dichloromethane, because the solubility of NOBF 4 molecules in dichloromethane is very low and it is in a slightly soluble state, it may cause the NOBF 4 molecules not to fully exchange the oleic acid ligand, resulting in the unstable state of the obtained nanoparticles and their variable dispersion state in water, and they cannot be stably dispersed in water for a long time.

[0126] Performance Test

[0127] (I) Potential Test of Water-Soluble Nanoparticles

[0128] Disperse the 3 nm ESIONPs-BF obtained in Example 1 4 in an aqueous solution and perform a potential test on it using Malvern 3600. The results are as Figure 10 shown. It can be seen that the nanoparticles modified with NOBF 4 by the method are at a positive potential of +49.9 mV, further proving the successful modification with NOBF 4 .

[0129] (II) Dispersion Stability of Water-Soluble Nanoparticles

[0130] Disperse the 3 nm ESIONPs-BF obtained in Example 14 Dispersed in the aqueous solution and left standing, the results of the change in the dispersibility of the solution on the 0th day and the 14th day of standing are as Figure 11 shown, and it can be seen that for ESIONPs-BF 4 there is no difference in the dispersibility of the solution before and after standing for two weeks. This shows that the method is an effective and stable method, and the obtained aqueous-phase dispersed nanoparticles have excellent stability and can be dispersed in water for a long time.

[0131] (III) Applications of water-soluble nanoparticles

[0132] The 3 nm ESIONPs-BF obtained in Example 1 4 was subjected to toxicity testing, and the cytotoxicity of ESIONPs-BF 4 nanoparticles on mouse breast cancer cells (4T1) was measured using CCK-8. The specific test method is as follows:

[0133] The 3 nm ESIONPs-BF obtained in Example 1 4 was dialyzed for 3 days using a dialysis bag with a cut-off rate of 14,000 and concentrated. Then, 100 μL of 4T1 cells were seeded into each well of a 96-well plate at a density of 5000 cells per well. The 96-well plate was placed in a CO 2 incubator and cultured at 37 °C for 24 h. Then, the ESIONPs-BF obtained in Example 1 4 was dissolved in the culture medium as a contrast agent and gradient-diluted to multiple concentrations (8 different concentrations of 0.06 - 1.00 mM were used in this test), and added to the wells of the 96-well plate to co-incubate with the cells for 24 h. Then, 100 μL of 10% CCK-8 solution was added to each well and incubated in the cell culture incubator for 3 h. The absorbance OD at 450 nm was measured using an enzyme-linked immunosorbent assay reader 450nm . Four parallel samples were made for each contrast agent concentration (referred to as the experimental group) and the control group. The relative survival rate of the cells was calculated according to the absorbance value. The relative survival rate of the cells was calculated using the following formula:

[0134] Relative survival rate of cells (%) = 100 × (OD of experimental group - OD of blank group) / (OD of control group - OD of blank group)

[0135] where the blank group is the complete culture medium without cells, and the control group is the cells cultured without the material of ESIONPs-BF obtained in Example 1 4 .

[0136] The test results of the cytotoxicity are as Figure 12As shown, it can be seen from the figure that the viability of 4T1 cells all showed a relatively high activity level. Even at an iron concentration of 1 mM, the cell viability of 4T1 cells was above 96%. The results indicate that the cytotoxicity of the aqueous phase-dispersed 3nm ESIONPs-BF4 nanoparticles obtained in Example 1 of the present invention can be ignored. It further demonstrates that the ligand exchange method for converting oil phase-dispersed nanoparticles into aqueous phase-dispersed nanoparticles of the present invention broadens the application scenarios of oil phase-dispersed nanoparticles.

[0137] The applicant declares that the present invention illustrates the detailed structural features of the present invention through the above embodiments, but the present invention is not limited to the above detailed structural features, that is, it does not mean that the present invention must rely on the above detailed structural features to be implemented. Those skilled in the art should understand that any improvement to the present invention, the equivalent replacement of the components selected by the present invention, the addition of auxiliary components, and the selection of specific methods, etc., all fall within the protection scope and the disclosure scope of the present invention.

[0138] The preferred embodiments of the present invention have been described in detail above. However, the present invention is not limited to the specific details in the above embodiments. Within the scope of the technical concept of the present invention, various simple modifications can be made to the technical solutions of the present invention, and these simple modifications all belong to the protection scope of the present invention.

[0139] In addition, it should be noted that, in the above specific embodiments, the various specific technical features described can be combined in any suitable manner without contradiction. To avoid unnecessary repetition, the present invention will not separately describe various possible combination methods.

[0140] Furthermore, any combination can be made between different embodiments of the present invention as long as it does not violate the idea of the present invention, and it should also be regarded as the content disclosed by the present invention.

Claims

1. A method for converting oil-soluble nanoparticles into water-soluble nanoparticles, characterized in that, the method comprises: mixing an oil-soluble nanoparticle dispersion and a nitrous tetrafluoroborate solution to carry out a ligand exchange reaction to obtain water-soluble nanoparticles; the solvent in the nitrous tetrafluoroborate solution comprises N,N-dimethylformamide.

2. The method according to claim 1, characterized in that, the surface of the oil-soluble nanoparticles is modified with a hydrophobic molecule; preferably, the hydrophobic molecule comprises oleic acid and / or oleylamine.

3. The method according to claim 1 or 2, characterized in that, the solvent in the oil-soluble nanoparticle dispersion comprises toluene; preferably, the concentration of the oil-soluble nanoparticle dispersion is 3-6 mg / mL.

4. The method according to any one of claims 1-3, characterized in that, the concentration of the nitrous tetrafluoroborate solution is 18-22 mg / mL; preferably, the mass ratio of the oil-soluble nanoparticles to the nitrous tetrafluoroborate is 1:(1.5-2.5); preferably, the mixing of the oil-soluble nanoparticle dispersion and the nitrous tetrafluoroborate solution is specifically: adding the nitrous tetrafluoroborate solution to the oil-soluble nanoparticle dispersion.

5. The method according to any one of claims 1-4, characterized in that, the ligand exchange reaction comprises a first shaking reaction and a second shaking reaction carried out in sequence; preferably, the temperature of the first shaking reaction is 23-27 °C; preferably, the rotation speed of the first shaking reaction is 400-700 r / min; preferably, the time of the first shaking reaction is 5-10 min; preferably, the temperature of the second shaking reaction is 23-27 °C; preferably, the rotation speed of the second shaking reaction is 30-100 r / min; preferably, the time of the second shaking reaction is 2-5 h.

6. The method according to any one of claims 1-5, characterized in that, after the ligand exchange reaction, it further comprises: mixing the reaction solution and n-hexane and then centrifuging to obtain a precipitate, then dissolving the precipitate in N,N-dimethylformamide, and then washing with isopropanol, and after centrifuging and drying, obtaining water-soluble nanoparticles; preferably, the addition amount of the N,N-dimethylformamide is 1-4 mL; preferably, the number of times of washing ≥ 2 times; preferably, the drying is carried out by blowing dry with nitrogen.

7. The method according to any one of claims 1-6, characterized in that, the preparation method of the oil-soluble nanoparticles comprises: (I) mixing a metal salt, a fatty acid salt and a first solvent, and carrying out a reaction to obtain a fatty acid metal complex precursor; (II) mixing a hydrophobic material, a second solvent and the fatty acid metal complex precursor obtained in step (I), and carrying out a thermal decomposition reaction to obtain oil-soluble nanoparticles.

8. The method according to claim 7, characterized in that, the metal in the metal salt in step (I) comprises any one of iron element, manganese element, gold element or rare earth element; preferably, the fatty acid salt in step (I) comprises sodium oleate; preferably, the molar ratio of the metal salt to the fatty acid salt in step (I) is 1:(5-8); Preferably, the temperature of the reaction in step (I) is 60 - 90 °C; Preferably, the reaction time in step (I) is 4 - 7 h.

9. The method according to claim 7 or 8, characterized in that the hydrophobic material in step (II) comprises oleic acid and / or oleylamine; Preferably, the molar ratio of the hydrophobic material to the fatty acid metal complex precursor in step (II) is 1:(0.5 - 5); Preferably, a vacuum pumping treatment is also included before the thermal decomposition reaction in step (II); Preferably, the temperature of the vacuum pumping treatment is 70 - 100 °C; Preferably, the time of the vacuum pumping treatment is 2 - 6 h; Preferably, the evacuation treatment is carried out until the vacuum degree ≤ 10 -3 Pa; Preferably, the heating rate of the thermal decomposition reaction in step (II) is 2 - 10 °C / min; Preferably, the temperature of the thermal decomposition reaction in step (II) is 200 - 350 °C; Preferably, the heat preservation time of the thermal decomposition reaction in step (II) is 30 - 60 min.

10. The method according to any one of claims 1 - 9, characterized in that the method comprises the following steps: (1) Prepare oil-soluble nanoparticles, and then add a nitrous tetrafluoroborate solution with a concentration of 18 - 22 mg / mL to the oil-soluble nanoparticle dispersion with a concentration of 3 - 6 mg / mL to carry out a ligand exchange reaction; The surface of the oil-soluble nanoparticles is modified with hydrophobic molecules; the hydrophobic molecules comprise oleic acid and / or oleylamine; The solvent in the oil-soluble nanoparticle dispersion comprises toluene; the solvent in the nitrous tetrafluoroborate solution comprises N,N-dimethylformamide; the mass ratio of the oil-soluble nanoparticles to nitrous tetrafluoroborate is 1:(1.5 - 2.5); The ligand exchange reaction comprises a first shaking reaction and a second shaking reaction carried out in sequence; The temperature of the first shaking reaction is 23 - 27 °C, the rotation speed is 400 - 700 r / min, and the time is 5 - 10 min; The temperature of the second shaking reaction is 23 - 27 °C, the rotation speed is 30 - 100 r / min, and the time is 2 - 5 h; (2) Mix n-hexane and the reaction solution obtained from the ligand exchange reaction in step (1), then centrifuge to obtain a precipitate, then dissolve the precipitate in 1 - 4 mL of N,N-dimethylformamide, and then wash with isopropanol. After centrifugation and drying, water-soluble nanoparticles are obtained.

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