Preparation of fluorinated hydrogel nanoparticles and their stable perfluorocarbon emulsion

Abstract

The invention discloses a preparation method of fluorine-containing hydrogel nanoparticles and a perfluorocarbon emulsion stabilized therewith. A preparation method of fluorine-containing hydrogel nanoparticles comprises the following steps: sodium vinylbenzenesulfonate, an initiator, tert-butyl acrylate, trifluoroethyl methacrylate, 2,2-dithiodiethanol dimethacrylate and a solvent are mixed to carry out a polymerization reaction to obtain fluorine-containing nanoparticles; a mixed solution of trifluoroacetic acid and formic acid is mixed with the fluorine-containing nanoparticles to remove tert-butyl ester to obtain the fluorine-containing hydrogel nanoparticles; the solvent comprises at least one of water and an alcohol solution. The fluorine-containing hydrogel nanoparticles prepared by the method can be effectively used as a solid surfactant to stabilize a liquid perfluorocarbon emulsion; the liquid perfluorocarbon Pickering emulsion stabilized by the fluorine-containing hydrogel nanoparticles has long-term stability.

Description

Technical Field

[0001] The invention belongs to the technical field of functional nano colloids, and specifically relates to the preparation of fluorine-containing hydrogel nanoparticles and their stable perfluorocarbon emulsion. Background Art

[0002] Liquid perfluorocarbon compounds (PFCs) are a class of compounds with very stable chemical structures. Their high stability gives them good biological safety. Since oxygen has a high solubility in liquid perfluorocarbons (100 mL of liquid perfluorocarbons can dissolve up to 45 mL of oxygen), liquid perfluorocarbons have been one of the star molecules in the field of artificial blood research since the 1970s. In addition, due to the low boiling point of perfluorocarbons, they can be vaporized under the action of ultrasound, and can be used as ultrasound imaging contrast agents to improve the accuracy of ultrasound imaging. In recent years, with the development of 19 F-NMR technology ( 19 The development of FMRI, liquid perfluorocarbons with high fluorine content as an effective 19 FMRI probe. How to prepare liquid perfluorocarbon compounds into drugs with nano- or micro-sized structures, and effectively use them for in vivo ultrasound and 19 FMRI diagnosis has important clinical economic value.

[0003] Due to the special dipole-dipole interaction between the CF covalent bonds in liquid perfluorocarbon compounds, liquid perfluorocarbon compounds have superhydrophobic and superoleophobic properties. The interfacial tension between liquid perfluorocarbon compounds and water is 38-56 dyn / cm. Therefore, how to prepare a liquid perfluorocarbon compound that meets the requirements of ultrasound imaging and 19 The stable liquid perfluorocarbon nano / micro emulsion required for FMRI imaging is an important key scientific and technological issue that needs to be solved. At present, materials of different properties are used to prepare and stabilize liquid perfluorocarbon nano / micro emulsions, including albumin-based biomaterials, small molecule surfactant materials, phospholipid liposome materials, and high molecular polymer materials. The nano / micro liquid perfluorocarbon emulsions emulsified and stabilized by the above materials have achieved good research results in terms of stability, targeting, and safety of use. Some of these samples have successfully moved from the laboratory to the clinic, providing efficient tools for the diagnosis of a variety of diseases and creating economic value.

[0004] From the perspective of the stability of liquid perfluorocarbon nano / micro emulsions, the above-mentioned emulsions stabilized by using molecular emulsifiers have always faced the problem of poor stability. In recent years, using nanoparticles as solid surfactants has received widespread attention in improving the stability of emulsions. Emulsions stabilized by solid nanoparticles are also called Pickering emulsions. The main reason why Pickering emulsions have excellent stability is that the surface of the nanoparticles is wetted by two liquids at the water-oil interface. Due to the special superhydrophobic and superoleophobic properties of liquid perfluorocarbon molecules, nanoparticles that can stabilize liquid perfluorocarbon nano / micro emulsions need to have the dual characteristics of being wetted by liquid perfluorocarbon and water at the same time. From the perspective of material research, there are certain challenges.

[0005] In summary, in order to further improve the stability of liquid perfluorocarbon nano / micro emulsions and expand their applications in ultrasound imaging, 19 For applications in FMRI and other related fields, it is of great practical significance to prepare nanoparticles whose surfaces can be wetted by both superhydrophobic liquid perfluorocarbon and water. Summary of the invention

[0006] In order to overcome the above-mentioned deficiencies of the prior art, the present invention provides a fluorine-containing hydrogel nanoparticle and a preparation method thereof and a stable perfluorocarbon emulsion thereof.

[0007] In order to achieve the above object, the technical solution adopted by the present invention is:

[0008] The first aspect of the present invention provides a method for preparing fluorine-containing hydrogel nanoparticles, comprising the following steps:

[0009] (1) mixing sodium vinylbenzene sulfonate, an initiator, tert-butyl acrylate, trifluoroethyl methacrylate, 2,2-dithiodiethanol dimethacrylate and a solvent to carry out a polymerization reaction to obtain fluorine-containing nanoparticles;

[0010] (2) mixing a mixed solution of trifluoroacetic acid and formic acid with the fluorine-containing nanoparticles to remove tert-butyl ester, thereby obtaining the fluorine-containing hydrogel nanoparticles;

[0011] The solvent includes at least one of water and alcohol solution.

[0012] Preferably, in step (1), the mass ratio of the sodium vinylbenzene sulfonate, the initiator and tert-butyl acrylate is 2:1:(18-162).

[0013] Preferably, in step (1), the mass ratio of tert-butyl acrylate to trifluoroethyl methacrylate is (0.1-10):1; the present invention achieves regulation of the fluorine content in the nanoparticles by controlling the mass ratio of tert-butyl acrylate to trifluoroethyl methacrylate.

[0014] Preferably, in step (1), the temperature of the polymerization reaction is 60-80°C; further preferably, in step (1), the temperature of the polymerization reaction is 65-75°C; the polymerization reaction in step (1) is carried out under a protective atmosphere, specifically, the protective gas can be argon.

[0015] Preferably, in step (1), the polymerization reaction time is 14 to 22 hours; further preferably, in step (1), the polymerization reaction time is 16 to 20 hours; even further preferably, in step (1), the polymerization reaction time is 17 to 19 hours.

[0016] Preferably, in step (1), the solvent is a mixed solution of water and alcohol; further preferably, the volume ratio of water to alcohol is (5-13):1.

[0017] Preferably, in step (1), the initiator comprises at least one of potassium persulfate and sodium persulfate.

[0018] Preferably, in step (2), the volume ratio of trifluoroacetic acid to formic acid is 8:2; the mass ratio of the mixed solution of trifluoroacetic acid and formic acid to the fluorine-containing nanoparticles is (50-60):1; and the mixing time of the mixed solution of trifluoroacetic acid and formic acid and the fluorine-containing nanoparticles is 36-48 hours.

[0019] The second aspect of the present invention provides a fluorine-containing hydrogel nanoparticle, which is prepared by the preparation method of the fluorine-containing hydrogel nanoparticle.

[0020] Preferably, the fluorine content of the fluorine-containing hydrogel nanoparticles is 7-40 wt %.

[0021] Preferably, the hydrated diameter of the fluorine-containing hydrogel nanoparticles is 100-800 nm; the hydrated diameter is measured by dynamic light scattering (DLS).

[0022] Preferably, the Zeta potential of the fluorine-containing hydrogel nanoparticles is -30 mV to -20 mV.

[0023] The third aspect of the present invention provides a perfluorocarbon emulsion, which comprises perfluorocarbon and the fluorine-containing hydrogel nanoparticles.

[0024] Preferably, the concentration of the fluorinated hydrogel nanoparticles in the perfluorocarbon emulsion is 0.1 to 1.5 mg / mL; further preferably, the concentration of the fluorinated hydrogel nanoparticles in the perfluorocarbon emulsion is 0.5 to 1 mg / mL.

[0025] In some embodiments of the present invention, the perfluorocarbon in the perfluorocarbon emulsion includes at least one of tetradecafluorohexane and perfluoropentane.

[0026] A fourth aspect of the present invention provides a method for preparing a perfluorocarbon emulsion, comprising the following steps:

[0027] The fluorine-containing hydrogel nanoparticles are prepared into an aqueous solution, perfluorocarbon is added, and then ultrasonic emulsification is performed; the ultrasonic emulsification time is 1 to 8 minutes, and the ultrasonic emulsification is performed under ice bath conditions.

[0028] Compared with the prior art, the present invention has the following beneficial effects:

[0029] The present invention discloses a method for preparing hydrogel nanoparticles with a high fluorine content. Experimental results show that: (1) the fluorine content in the hydrogel nanoparticles can be effectively controlled within a range of 7% to 40%; (2) even under high fluorine content conditions, the hydrogel nanoparticles still have very good dispersion properties in water (PDI: <0.1); (3) the fluorine-containing hydrogel nanoparticles prepared by the method can effectively serve as a solid surfactant to stabilize liquid perfluorocarbon (tetradecafluorohexane and perfluoropentane) Pickering emulsions; the fluorine-containing hydrogel nanoparticles used to stabilize liquid perfluorocarbon Pickering emulsions have long-term stability (1 to 90 days). BRIEF DESCRIPTION OF THE DRAWINGS

[0030] Figure 1 The technical roadmap for preparing fluorinated hydrogel nanoparticles of the embodiment;

[0031] Figure 2 A schematic diagram of the preparation of a perfluorocarbon Pickering emulsion according to an embodiment;

[0032] Figure 3 is a scanning electron microscope image of the fluorine-containing hydrogel nanoparticles of Example 1;

[0033] Figure 4 is a diagram of the hydration diameter of the fluorine-containing hydrogel nanoparticles of Example 1;

[0034] Figure 5 is the Zeta potential diagram of the fluorine-containing hydrogel nanoparticles of Example 1;

[0035] Figure 6 is a scanning electron microscope image of the fluorine-containing hydrogel nanoparticles of Example 2;

[0036] Figure 7 is a diagram of hydration diameters of fluorine-containing hydrogel nanoparticles of Example 2;

[0037] Figure 8 is the Zeta potential diagram of the fluorine-containing hydrogel nanoparticles of Example 2;

[0038] Fig. 9is a scanning electron microscope image of the fluorine-containing hydrogel nanoparticles of Example 3;

[0039] Fig.10 is a diagram of hydration diameters of fluorine-containing hydrogel nanoparticles of Example 3;

[0040] Fig.11 is the Zeta potential diagram of the fluorine-containing hydrogel nanoparticles of Example 3;

[0041] Fig.12 is a scanning electron microscope image of the fluorine-containing hydrogel nanoparticles of Example 4;

[0042] Fig.13 is a diagram of hydrated diameters of fluorine-containing hydrogel nanoparticles of Example 4;

[0043] Fig.14 is the Zeta potential diagram of the fluorine-containing hydrogel nanoparticles of Example 4;

[0044] Fig.15 Optical microscope photographs of Pickering emulsions of tetradecafluorohexane stabilized as a solid surfactant in Examples 1-4 at 1-90 days;

[0045] Fig.16 These are optical microscope photographs of Pickering emulsions of perfluoropentane as a solid surfactant stabilized in Examples 1-4 at 1 to 90 days. DETAILED DESCRIPTION

[0046] The specific embodiments of the present invention are further described below. It should be noted that the description of these embodiments is used to help understand the present invention, but does not constitute a limitation of the present invention. In addition, the technical features involved in each embodiment of the present invention described below can be combined with each other as long as they do not conflict with each other.

[0047] The experimental methods in the following examples are conventional methods unless otherwise specified, and the experimental materials used in the following examples are commercially available unless otherwise specified.

[0048] Example 1

[0049] This embodiment provides a method for preparing fluorine-containing hydrogel nanoparticles and liquid perfluorocarbon Pickering emulsion, which specifically comprises the following steps:

[0050] Fluorinated nanoparticles were synthesized by surfactant-free emulsion polymerization. 40 mg of water-soluble comonomer sodium vinylbenzenesulfonate (NaVBs) (CAS No.: 2695-37-6) and 20 mg of potassium persulfate (KPS) (CAS No.: 7727-21-1) were dissolved in a mixed solution containing 90 mL of pure water and 10 mL of methanol (CAS No.: 67-56-1), respectively. 9 g of monomer tert-butyl acrylate (tBt-MA), 1 g of monomer trifluoroethyl methacrylate (CF3-MMA) and 40 mg of crosslinking agent 2,2-dithiodiethanol dimethacrylate (DSDMA) (CAS No.: 36837-97-5) were added to the above solution. Argon was introduced for 20 minutes to remove oxygen from the solution and the container. The polymerization reaction was carried out under argon protection for 18 hours, and the reaction temperature was maintained at 70°C. The prepared fluorinated nanoparticles were washed by centrifugation with ethanol and pure water. The fluorinated hydrogel nanoparticles were prepared by hydrolyzing the tert-butyl ester in the fluorinated nanoparticles with a mixed solution of trifluoroacetic acid and formic acid, and then washed by centrifugation with ethanol and pure water. Figure 1 shown.

[0051] In a 20 ml vial, prepare 5 ml of an aqueous solution of 1 mg / ml fluorinated hydrogel nanoparticles. At room temperature, add 1 ml of liquid perfluorocarbon. The above solvent is ultrasonically emulsified using an ultrasonic disruptor (ultrasonic probe power: 40% (40% of the maximum power of the ultrasonic cell disruptor equipment (Ningbo Haishuke Ultrasonic Equipment Co., Ltd.)), emulsification time: 2-5 minutes, emulsification temperature: 0°C ice bath). The prepared perfluorocarbon Pickering emulsion is stored at 4°C. The preparation schematic diagram is shown in the figure below. Figure 2 shown.

[0052] Example 2

[0053] This embodiment provides a method for preparing fluorine-containing hydrogel nanoparticles and liquid perfluorocarbon Pickering emulsion. The difference from Example 1 is that the amount of tBt-MA used is 5 g, the amount of CF3-MMA used is 5 g, and the rest is the same as Example 1.

[0054] Example 3

[0055] This embodiment provides a method for preparing fluorine-containing hydrogel nanoparticles and liquid perfluorocarbon Pickering emulsion. The difference from Example 1 is that the amount of tBt-MA used is 2 g, the amount of CF3-MMA used is 8 g, and the rest is the same as Example 1.

[0056] Example 4

[0057] This embodiment provides a method for preparing fluorine-containing hydrogel nanoparticles and liquid perfluorocarbon Pickering emulsion. The difference from Example 1 is that the amount of tBt-MA used is 1 g, the amount of CF3-MMA used is 9 g, and the rest is the same as Example 1.

[0058] The statistical graph of the monomer ratio composition, fluorine content and corresponding hydrated particle size results of the synthesis of fluorine-containing hydrogel nanoparticles in Examples 1-4 is shown in Table 1 below.

[0059] Table 1

[0060]

[0061] The SEM and light scattering data of fluorinated hydrogel nanoparticles are shown in the attached figure. Figure 3-14 Scanning electron microscopy Figure 3 The nanoparticles of Example 1 are spherical in shape with a diameter of 190-260 nm, which is similar to the particle size measured by DLS. Figure 6 The nanoparticles of Example 2 are spherical in shape with a diameter of 100-150 nm, which is similar to the particle size measured by DLS. Fig. 9 The nanoparticles of Example 3 are spherical in shape with a diameter of 90-140 nm, which is similar to the particle size results measured by DLS. Fig.12 The nanoparticles of Example 4 were shown to be spherical in shape with a diameter of 110-160 nm, which was similar to the particle size result measured by DLS. Figure 5 , 8, 11, 14 show that the Zeta potential of the nanoparticles of Examples 1-4 is between -30 mV and -20 mV, and the surface of the nanoparticles is negatively charged. The above data show that the particle size of the nanoparticles of Examples 1-4 is uniform and stable, has good dispersibility in aqueous solution, and is not easy to agglomerate. Characterization of liquid perfluorocarbon Pickering emulsion

[0062] The structure of the Pickering emulsion was characterized by using a fluorescent optical microscope. Specifically, the emulsion was dropped onto a glass slide and then observed and photographed. The optical microscope photographs of the Pickering emulsions of tetradecafluorohexane stabilized as a solid surfactant in Examples 1-4 at 1-90 days were as follows: Fig.15 The optical microscope pictures of the Pickering emulsions of perfluoropentane stabilized by the above-mentioned Examples 1-4 as solid surfactants at 1-90 days are shown in FIG. Fig.16 shown. Fig.15 and Fig.16It shows that the diameters of the Pickering emulsion droplets of two liquid perfluorocarbons stabilized by Examples 1-4 are all 1 to 10 μm, and they are still stable after 90 days. It can be seen that the diameters of the two Pickering emulsion droplets stabilized by Examples 1 and 4 are smaller than the diameters of the two Pickering emulsion droplets stabilized by Examples 2 and 3. The above data show that the fluorine-containing hydrogel nanoparticles provided by the present invention can effectively serve as a solid surfactant to stabilize liquid perfluorocarbon emulsions and have long-term stability.

[0063] The embodiments of the present invention are described in detail above, but the present invention is not limited to the described embodiments. For those skilled in the art, various changes, modifications, substitutions and variations of these embodiments are made without departing from the principles and spirit of the present invention, and still fall within the protection scope of the present invention.

Claims

1. A perfluorocarbon emulsion, characterized in that The perfluorocarbon emulsion comprises perfluorocarbon and fluorine-containing hydrogel nanoparticles; The preparation method of the fluorine-containing hydrogel nanoparticles comprises the following steps: (1) mixing sodium vinylbenzene sulfonate, an initiator, tert-butyl acrylate, trifluoroethyl methacrylate, 2,2-dithiodiethanol dimethacrylate and a solvent to carry out a polymerization reaction to obtain fluorine-containing nanoparticles; (2) mixing a mixed solution of trifluoroacetic acid and formic acid with the fluorine-containing nanoparticles to remove tert-butyl ester, thereby obtaining the fluorine-containing hydrogel nanoparticles; The solvent includes at least one of water and alcohol solution.

2. The perfluorocarbon emulsion according to claim 1, characterized in that In step (1), the mass ratio of the sodium vinylbenzene sulfonate, the initiator and tert-butyl acrylate is 2:1:(18-162).

3. The perfluorocarbon emulsion according to claim 1, characterized in that In step (1), the mass ratio of tert-butyl acrylate to trifluoroethyl methacrylate is (0.1-10):

1.

4. The perfluorocarbon emulsion according to claim 1, characterized in that In step (1), the polymerization reaction temperature is 60 to 80° C., and the polymerization reaction time is 14 to 22 hours.

5. The perfluorocarbon emulsion according to claim 1, characterized in that The fluorine content of the fluorine-containing hydrogel nanoparticles is 7-40 wt %.

6. The perfluorocarbon emulsion according to claim 1, characterized in that The hydrated diameter of the fluorine-containing hydrogel nanoparticles is 100-800 nm.

7. The perfluorocarbon emulsion according to claim 1, characterized in that The concentration of the fluorine-containing hydrogel nanoparticles in the perfluorocarbon emulsion is 0.1-1.5 mg / mL.

8. A method for preparing the perfluorocarbon emulsion according to any one of claims 1 to 7, characterized in that: The following steps are involved: The fluorinated hydrogel nanoparticles are formulated into an aqueous solution, perfluorocarbon is added, and then ultrasonic emulsification is performed; The ultrasonic emulsification time is 1 to 8 minutes, and the ultrasonic emulsification is performed under ice bath conditions.

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