CN110064063B - Double-layer hydrophobic-hydrophilic modified hollow nano silicon ball, and preparation method and application thereof - Google Patents
Double-layer hydrophobic-hydrophilic modified hollow nano silicon ball, and preparation method and application thereof Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/22—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations
- A61K49/222—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations characterised by a special physical form, e.g. emulsions, liposomes
- A61K49/223—Microbubbles, hollow microspheres, free gas bubbles, gas microspheres
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Acoustics & Sound (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Radiology & Medical Imaging (AREA)
- Epidemiology (AREA)
- Physics & Mathematics (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Manufacturing Of Micro-Capsules (AREA)
- Silicon Compounds (AREA)
Abstract
The invention relates to a double-layer hollow nano silicon ball with a hydrophobic inner layer and a hydrophilic outer layer, a preparation method and application thereof, belonging to the field of ultrasonic imaging contrast materials. The hollow nano silicon spheres prepared by the invention have the advantages of uniform particle size distribution, good dispersibility, proper cavity size, relatively simple preparation and good biocompatibility, and greatly improves the ultrasonic signal intensity and prolongs the contrast duration.
Description
Technical Field
The invention belongs to the field of ultrasonic imaging contrast materials, and particularly relates to a double-layer hollow nano silicon sphere with a hydrophobic inner layer and a hydrophilic outer layer.
Background
Early contrast agents, including liquids containing free bubbles; colloidal bodies containing suspended particles; emulsified liquids, and the like. The disadvantages are large size, instability and poor effect. Free bubbles are the simplest form of ultrasonic contrast agent, and H is adopted clinically in China2O2As an ultrasound contrast agent, it generates free oxygen after entering blood, and is mostly used for imaging in cardiology. Since the free bubble size is too large and unstable, it cannot circulate through the lungs and is not suitable for cardiac imaging. The colloid containing suspended particles can be used for enhancing the back scattering of soft tissues, has better contrast effect and long survival time. However, considering the toxic effect, the preparation can be used in small dosage, which limits the application range. Lipid compounds as ultrasound contrast agents are suggested from the echogenic enhancement of fatty liver, which is less efficient. After the aqueous solution composed of many compounds is fed into human body, the sound velocity and density of circulatory system can be changed according to the concentration of contrast agent, so that the acoustic resistance can be caused between vascular tissue and non-vascular tissueAnti-differential, thereby enhancing backscattering of the vasculature, but the enhancement is too inefficient.
Since the early 90 s, the research work on ultrasound contrast agents has progressed significantly. Compared with the early ultrasonic contrast agent, the coated ultrasonic contrast agent with the diameter of several micrometers and capable of passing through pulmonary circulation has the advantages of optimal application effect, wider application range and better stability. Meanwhile, several companies and research institutes in the world have developed different ultrasound contrast agents, and ultrasound contrast agents for animal experiments and clinical studies have been put on the market. Various contrast agents enhance the echogenicity of tissue to varying degrees and can be used for harmonic measurement and imaging.
The generation of contrast agents is mainly classified according to the type of gas encapsulated in microbubbles. The first generation of contrast agent microbubbles contain air and the envelope is typically a polymer such as albumin or galactose. The physical properties of the first generation of ultrasound contrast agents, including thicker coating, poor elasticity, and the fact that the coated air is easily soluble in water, etc., determine that it has a short duration and is easily broken, thereby limiting the observation and diagnosis time in clinical applications. The second generation ultrasonic contrast agent is a thin and soft bubble with an outer membrane mainly wrapping high-density inert gas (not easy to dissolve in water or blood), the diameter of the bubble is about 2-5 mu m generally, the stability time is long, and the vibration and echo characteristics are good.
In recent years, silicon spheres are concerned about due to good biocompatibility, easy modification and the like, wherein the hollow nano silicon spheres expose the corners in the aspect of ultrasonic contrast agents due to the fact that the hollow nano silicon spheres are small in size and air can be loaded inside the hollow nano silicon spheres, but the hollow nano silicon spheres have a hole structure on the surfaces, so that the air coated in the hollow nano silicon spheres is very easy to dissolve in blood, ultrasonic signals are weakened, the duration is short, and the clinical observation and diagnosis time is limited to a certain extent, so that the development of a relatively stable ultrasonic contrast agent based on the hollow silicon spheres is needed.
Disclosure of Invention
The invention aims to provide a double-layer hydrophobic-hydrophilic modified hollow nano silicon sphere based on the prior art, the hollow nano silicon sphere has uniform particle size distribution, good monodispersity, superior hollow structure and good biocompatibility, provides feasibility for industrial production, provides a new way for the research of an ultrasonic contrast agent, and has good social and economic benefits.
The invention also aims to provide a preparation method of the double-layer hydrophobic-hydrophilic modified hollow nano silicon spheres.
The third purpose of the present invention is to provide the application of the double-layer hydrophobic-hydrophilic modified hollow nano silicon spheres mentioned above as an ultrasound contrast material, especially as an ultrasound contrast agent.
The technical scheme of the invention is as follows:
a double-layer hydrophobic-hydrophilic modified hollow nano silicon ball comprises an inner shell which is formed by hybrid hydrolytic polymerization of organosilane containing hydrophobic groups and tetraethoxysilane and is provided with hydrophobic groups, and a hydrophilic outer shell which is formed by hydrolytic polymerization of the inner shell and 3-aminopropyltriethoxysilane.
In a preferred scheme, the hollow nano silicon spheres provided by the invention have uniform particle size distribution, good dispersibility and proper cavity size, and the particle size is 300-450 nm, preferably 350-400 nm; the thickness of the shell layer is 20-40 nm, preferably 25-35 nm.
The organosilanes containing hydrophobic groups mentioned in the present invention are organosilanes containing hydrophobic groups of the prior art, for example: octyl triethoxysilane, octadecyl triethoxysilane or heptadecafluorodecyl triethoxysilane.
The heptadecafluorodecyltriethoxysilane referred to herein, with the name 1H,1H,2H, 2H-perfluorodecyltriethoxysilane, may be abbreviated PFDTS.
The double-layer hydrophobic-hydrophilic modified hollow nano silicon spheres provided by the invention have the advantages of uniform particle size distribution, good dispersibility, proper cavity size, relatively simple preparation and good biocompatibility, and can greatly improve the ultrasonic signal intensity and prolong the contrast duration.
A preparation method of double-layer hydrophobic-hydrophilic modified hollow nano silicon spheres comprises the following steps: after a core-shell structure with hydrophobic groups is formed on polystyrene microspheres (PS) through hybrid hydrolytic polymerization of organosilane containing the hydrophobic groups and Tetraethoxysilane (TEOS), extraction is carried out, core polystyrene is removed to obtain a hollow silicon sphere structure, and 3-aminopropyl triethoxysilane (APTES) is subjected to hydrolytic polymerization on the hollow silicon sphere structure to form hollow nano silicon spheres with hydrophobic inner layers and hydrophilic outer layers.
In a preferred embodiment, the invention provides a preparation method of double-layer hydrophobic-hydrophilic modified hollow nano silicon spheres, which comprises the following steps:
(1) preparing polystyrene microspheres: PVP-40000, AIBA and styrene react at 60-80 ℃ to obtain polystyrene microspheres;
(2) formation of inner hydrophobic groups: CTAB reacts with the polystyrene microsphere prepared in the step (1), ammonia water, tetraethoxysilane and organosilane containing hydrophobic groups at 50-70 ℃;
(3) forming a hollow silicon ball structure: extracting the product obtained in the step (2);
(4) formation of the hydrophilic layer: and (4) reacting the product obtained in the step (3) with 3-aminopropyltriethoxysilane at 90-110 ℃ to obtain the product.
In a more preferred embodiment, the present invention provides a method for preparing double-layer hydrophobic-hydrophilic modified hollow nano silicon spheres, which comprises the following steps:
(1) preparing polystyrene microspheres: PVP-40000, AIBA and styrene react at 60-80 ℃ while stirring, and polystyrene microspheres are obtained after washing;
(2) formation of inner hydrophobic groups: dissolving CTAB in isopropanol and deionized water, adding a mixed solution of the polystyrene microspheres prepared in the step (1), ammonia water, tetraethoxysilane and organosilane containing hydrophobic groups, reacting at 50-70 ℃ while stirring, centrifuging and washing;
(3) forming a hollow silicon ball structure: dispersing the product obtained in the step (2) in toluene or tetrahydrofuran, extracting at 100-120 ℃, stirring, and washing;
(4) formation of the hydrophilic layer: and (3) reacting the product obtained in the step (3) with 3-aminopropyltriethoxysilane at 90-110 ℃, stirring, centrifuging and washing to obtain the product.
In the preparation of the double-layer hydrophobic-hydrophilic modified hollow nano silicon spheres, the organosilane containing the hydrophobic group is the organosilane containing the hydrophobic group in the prior art, such as: octyl triethoxysilane, octadecyl triethoxysilane or heptadecafluorodecyl triethoxysilane.
The particle size of the hollow silica spheres is affected by the particle size of the core polystyrene spheres, the volume of silane and ammonia added, and the temperature and reaction time. Meanwhile, different low-polarity extracting agents have different degrees of extraction on the core PS. According to the invention, the reaction temperature and the volumes of the added silane and ammonia water are controlled, the nano-level polystyrene spheres are selectively prepared, and the extraction is carried out under the condition of toluene or tetrahydrofuran to synthesize the nano-level double-layer hollow silicon spheres, so that the volume of the inner cavity of the spheres is greatly increased, the air adsorption capacity is increased, and the excellent ultrasonic signal enhancement effect is achieved.
According to the preparation method of the double-layer hollow nano silicon spheres with the inner layer being hydrophobic and the outer layer being hydrophilic, in a preferred scheme, isopropanol and deionized water are used as solvents, ammonia water is used as a catalyst, CTAB is used as a pore-forming agent, an inner layer structure containing hydrophobic groups is prepared by adopting an organic-inorganic silane hybrid hydrolytic polymerization method, then core Polystyrene (PS) is removed by extraction under the condition of toluene or THF, and finally APTES is modified by taking toluene as a solvent under the protection of nitrogen.
In a preferred embodiment, in step (1), PVP-40000, AIBA and styrene are reacted at 70 ℃, and after washing, polystyrene microspheres are obtained.
In a more preferable scheme, in the step (1), the particle size of the polystyrene microsphere is 250-400 nm.
In a preferred embodiment, in the step (2), during the formation of the hydrophobic group of the inner layer, CTAB is dissolved in isopropanol and deionized water, and the mixed solution of the polystyrene microsphere prepared in the step (1), ammonia water, tetraethoxysilane and organosilane containing the hydrophobic group is added, and the reaction is carried out at 60 ℃ while stirring.
Further, in the step (2), the reaction time is 4 to 12 hours, for example, 6 hours.
The polystyrene microspheres can be washed with ethanol to prepare an ethanol solution of the polystyrene microspheres, for example, the concentration of the ethanol solution can be 0.1g/mL, that is, the mass of the polystyrene microspheres with cores in 1mL of the ethanol solution is 0.1 g.
Further, the mass-volume ratio of the polystyrene microspheres to the tetraethoxysilane is 0.8: 1-2.0: 1 g/mL; preferably 0.8: 1-1.4: 1 g/mL; particularly preferably 1.1:1 g/mL.
Further, adding ammonia water to adjust the pH value to 8-10; preferably 9. For example, the mass concentration of ammonia water is 25% to 28%.
Further, the volume ratio of tetraethoxysilane to organosilane containing hydrophobic groups is 2: 1-6: 1; preferably 4: 1.
In a preferred embodiment, the product obtained in step (3) is reacted with 3-aminopropyltriethoxysilane at 110 ℃.
Further, in the step (4), the concentration of the 3-aminopropyltriethoxysilane in the reaction solution is 0.5-1.5% (v/v); preferably 1%.
In a preferred embodiment, in step (4), the product obtained in step (3) is reacted with 3-aminopropyltriethoxysilane at 100 ℃.
Further, in the step (4), the reaction time is 8 to 20 hours, for example, 12 hours.
Further, the stirring speed in the steps (1) and (3) is 250-350 rpm, preferably 300 rpm; in the step (2), the stirring speed is 450-550 rpm, preferably 500 rpm.
In a preferred embodiment, the washing is performed in steps (1) to (4) while the ultrasonic treatment assists the blowing of the pasteur pipette, so that the precipitate obtained by centrifugation is well dispersed.
In a particularly preferred embodiment, the invention provides a preparation method of double-layer hydrophobic-hydrophilic modified hollow nano silicon spheres, which comprises the following steps:
(1) polystyrene (PS)) Preparing a ball: dissolving PVP-40000 in isopropanol and deionized water, mixing with ultrasonic wave, adding AIBA and styrene, and adding N2Degassing for 1h, performing oil bath at 70 ℃, heating and refluxing at 300rpm for 24h, freezing in a refrigerator at-20 ℃ overnight, taking out, thawing at room temperature, centrifuging at 8000rpm for 20min, and washing with ethanol to obtain the ethanol solution of PS microspheres.
(2) Preparing an inner layer structure containing hydrophobic groups by adopting an organic-inorganic silane hybridization hydrolytic polymerization method: dissolving CTAB in isopropanol and deionized water, ultrasonically accelerating dissolution, adding ethanol solution of prepared PS microspheres, ammonia water, TEOS and organosilane (V) containing hydrophobic groupTEOS/VOrganosilanes containing hydrophobic groups4/1), stirring at 300rpm, reacting at 60 ℃ for 6h, centrifuging after the reaction is finished, and washing the precipitate with absolute ethyl alcohol and toluene.
(3) Forming a hollow silicon ball structure: redispersing the product obtained in step (2) in toluene or tetrahydrofuran, stirring at 500rpm, heating in an oil bath at 110 ℃ under reflux for 24h, washing with toluene, and dispersing in toluene.
(4) Construction of outer hydrophilic layer: and (3) dispersing the product obtained in the step (3) in toluene, adding APTES, stirring at 300rpm under the protection of nitrogen, heating and refluxing in an oil bath at 100 ℃ for 12h, sequentially centrifugally washing with toluene, THF, ethanol and deionized water, and freeze-drying for 12h to obtain the double-layer hydrophobic-hydrophilic modified hollow nano silicon sphere powder.
Compared with hollow silicon spheres obtained by directly polymerizing TEOS on PS spheres and extracting with a low-polarity organic solvent, the double-layer modified hollow silicon spheres prepared by the invention have larger cavity structures and better morphological characteristics, and meanwhile, the cavity structures are easier to maintain by inner-layer hydrophobic groups, so that the intensity of ultrasonic scattering signals can be greatly enhanced, and the double-layer modified hollow silicon spheres are expected to become novel ultrasonic contrast agents. The double-layer hydrophobic-hydrophilic modified hollow nano silicon spheres have simpler reaction conditions and uniform particle size distribution, provide feasibility for industrial production and provide a new way for development of ultrasonic contrast agents.
At present, the research on the silicon dioxide microspheres at home and abroad is mainly in the aspects of drug or DNA transportation, drug release and the like, but in the ultrasonic imaging fieldThe application research of the domain is rarely reported, and patent CN 102068706A discloses a preparation method of a silicon dioxide ultrasonic imaging contrast material, which comprises the steps of hydrolyzing an unfunctionalized silicon source and a functionalized silicon source with amino in a hydroalcoholic system by using a hard template to obtain silicon spheres with amino on the surface, extracting to remove the hard template to obtain hollow SiO with amino on the surface and uniform particle size2A ball; then the surface modification is carried out by the coupling of the amino on the surface and the carboxyl of polyethylene glycol (PEG), so that the polyethylene glycol with good biocompatibility can be modified on the surface to obtain SiO for ultrasonic imaging2Ultrasound imaging contrast material. However, the SiO prepared in the above patent2The average particle size of the nano microspheres is 960nm, the thickness of the shell layer is properly 30-50 nm, the nano microspheres are difficult to be applied to detecting myocardial necrosis, cannot enter human blood circulation through pulmonary circulation, and are not suitable for cardiography. When myocardial cell necrosis is detected, the nano ultrasonic contrast agent material is required to be deeply inserted into tissues, so that the requirement on the nano ultrasonic contrast agent material is high, for example, the particle size cannot be larger than 700 nanometers. However, the hollow nano silicon spheres with the hydrophobic inner layer and the hydrophilic outer layer prepared by the method have opposite polarities, the particle size of 300-450 nm, uniform particle size distribution, good dispersibility and appropriate cavity size, can enhance ultrasonic signals and prolong signal duration, can enter human blood circulation through pulmonary circulation, and are applied to myocardial cell necrosis detection.
In contrast, patent CN 102068706a discloses SiO for ultrasonic imaging2The particle size of the self-prepared polystyrene microsphere is 250-400 nm. After a core-shell structure with hydrophobic groups is formed on the polystyrene microsphere through hybrid hydrolytic polymerization of organosilane containing hydrophobic groups and tetraethoxysilane, extraction is carried out, core polystyrene is removed to obtain a hollow silicon sphere structure, and 3-aminopropyltriethoxysilane is subjected to hydrolytic polymerization on the hollow silicon sphere structure to form hollow nano silicon spheres with hydrophobic inner layers and hydrophilic outer layers, wherein the hollow nano silicon spheres are used for ultrasonic imaging materials, have the particle size of 300-450 nm, good biocompatibility and wider application prospect, greatly improve the ultrasonic signal intensity, prolong the imaging duration and have good social benefitsThe economic benefit can be reduced.
The double-layer hydrophobic-hydrophilic modified hollow nano silicon spheres provided by the invention can be used for ultrasonic contrast materials, and particularly can be used as an ultrasonic contrast agent.
By adopting the technical scheme of the invention, the advantages are as follows:
the invention provides a preparation method of double-layer hollow nano silicon spheres with hydrophobic inner layers and hydrophilic outer layers, which does not need high-pressure and other reaction conditions, has uniform particle size distribution, good monodispersity, proper cavity size, greatly improves the ultrasonic signal intensity, prolongs the contrast duration, has relatively simple preparation and good biocompatibility, provides feasibility for industrial production, provides a new way for the research of ultrasonic contrast agents, and has good social and economic benefits.
Drawings
FIG. 1 is a transmission electron microscope image;
wherein, the figure (a) is the double-layer hollow nano silicon ball prepared in the example 1; FIG. (b) is a single-layered hollow nano-silica sphere without hydrophobic groups prepared in comparative example 1; FIG. (c) is a double-layered hollow nano-silica sphere prepared in example 2;
FIG. 2 shows SiO in PBS solutions at different concentrations2Ultrasonic pictures of solutions in vitro of solid spheres and the double-layer hollow nano-silica spheres prepared in example 1;
wherein, the graph (a) shows SiO with different concentrations2A solid sphere; FIG. (b) shows different concentrations of single-layer hollow nano-silica spheres without hydrophobic groups prepared in comparative example 1; FIG. (c) shows double-layered hollow nano-silica spheres prepared in example 1 at different concentrations;
FIG. 3 is a line graph showing the variation of the mean gray value (contrast imaging intensity) of the single-layered hollow silica spheres having no hydrophobic group prepared in comparative example 1 and the double-layered hollow silica spheres prepared in example 1 in PBS solution at a concentration of 0.6mg/mL with the time of sonication;
FIG. 4 is an FT-IR image;
wherein, the picture (a) is a FT-IR picture of the double-layer hollow nano silicon ball prepared in the example 1; and (b) is a FT-IR diagram of the double-layer hollow nano silicon spheres prepared in the example 2.
Detailed Description
The preparation process of the present invention is further illustrated by the following examples in conjunction with the drawings, but the present invention is not limited to these examples.
Example 1
A preparation method of a double-layer hollow nano silicon sphere with an inner layer containing a hydrophobic group heptadecafluorodecyl and an outer layer containing hydrophilic groups comprises the following steps:
(1) preparation of (polystyrene) PS spheres: 100mL of deionized water is weighed into a 250mL three-neck flask, PVP-400001.0 g is added, after ultrasonic mixing, AIBA0.41g and 11mL of styrene and N are added2Degassing for 1h, performing oil bath at 70 ℃, heating and refluxing at 300rpm for 24h, freezing in a refrigerator at-20 ℃ overnight, taking out the frozen product at room temperature, centrifuging at 8000rpm for 20min, and washing with ethanol to obtain an ethanol solution of PS microspheres (0.1g/mL, namely the mass of the polystyrene microspheres in the ethanol solution of 1mL is 0.1g), wherein the particle size of the polystyrene microspheres in the ethanol solution of the PS microspheres is 250-400 nm.
(2) Formation of the inner hydrophobic group heptadecafluorodecyl: weighing 21mL of isopropanol and 10mL of deionized water in a 100mL three-neck flask, precisely weighing 0.25g of CTAB in a reaction system, ultrasonically accelerating dissolution, adding 4mL of prepared ethanol solution of PS microspheres, stirring at 60 ℃ in an oil bath at 300rpm for 30min, adding 750 mu L of ammonia water (with the mass concentration of 25-28%) and 450 mu L of mixed solution (V) of TEOS and PFDTSTEOS/VPFDTS4/1), the reaction was continued for 6 hours, and after completion of the reaction, the precipitate was centrifuged and washed with absolute ethanol and toluene.
(3) Forming a hollow silicon ball structure: and (3) dispersing the product obtained in the step (2) in 45mL of toluene, heating and refluxing in an oil bath at 110 ℃, stirring at 500rpm for 24h, and washing with toluene to obtain the hollow silicon sphere structure.
(4) Formation of the hydrophilic layer: dispersing the product of step (3) in 40mL of toluene, adding 400. mu.L of APTES, heating in 100 ℃ oil bath under reflux, and N2Protecting, stirring at 300rpm for 12h, sequentially centrifuging and washing with toluene, THF, ethanol and deionized water, lyophilizing for 12h to obtain double-layer hollow nanometer silicon ball powder with hydrophobic group heptadecafluorodecyl at inner layer and hydrophilic outer layer,as shown in FIG. 1(a), the prepared hollow nano silicon spheres have uniform particle size of about 380nm, the shell thickness of 30nm, and good hollow hole structure and monodispersity.
The FT-IR chart is shown in FIG. 4(a), in which 3300cm-1Caused by N-H stretching vibration; 1240. 1206, 1149cm-1Is composed of C-F, -CF2、-CF3Caused by stretching vibration; 1070cm-1Is caused by the asymmetric stretching vibration of Si-O-Si. Thus, PFDTS was successfully doped into the silica shell and the amino group was successfully modified.
In a preferred embodiment, in the preparation method of the double-layer hollow nano silicon spheres with the inner layer containing the hydrophobic group heptadecafluorodecyl and the outer layer containing the hydrophilic group, each step is to perform washing operation, and ultrasonic treatment is performed while an auxiliary pasteur pipette is blown and beaten so that the precipitate obtained by centrifugation is fully and uniformly dispersed.
Double-layer hollow nano silicon spheres (prepared in example 1) with hydrophobic group heptadecafluorodecyl at inner layer and hydrophilic at outer layer in-vitro solution ultrasonic imaging experiment:
in order to generate a contrast effect with a double-layer hollow nano silicon sphere with a hydrophobic group heptadecafluorodecyl as an inner layer and a hydrophilic outer layer, a single-layer hollow nano silicon sphere (prepared in comparative example 1) without the hydrophobic group is used as a contrast, and a solid silicon sphere with the particle size of about 150nm is synthesized as a contrast, and the specific synthesis steps are as follows:
measuring 37mL of absolute ethyl alcohol and 5mL of deionized water in a 100mL three-neck flask, adding 1.6mL of ammonia water, adding 3mL of TEOS after uniformly stirring, stirring at 500rpm for 1h at room temperature, and centrifugally washing three times by using the absolute ethyl alcohol to obtain silicon spheres with the particle size of about 150 nm.
Preparing SiO with the concentration of 0.1, 0.3, 0.6 and 1.0mg/mL respectively2Solid spheres, single-layer hollow silica spheres containing no hydrophobic group in comparative example 1, and heptadecafluorodecyl hydrophobic group-containing hollow silica spheres (prepared in example 1) were each 1.5mL in a 2mL EP tube, followed by addition of 0.4mL of 0.4% (m/V) aqueous agarose solution for capping, and the intensity of ultrasonic contrast was investigated as a function of concentration.
The results are shown in FIG. 2: hollow nanosilica sphere phase prepared in example 1Compared with SiO in the control group2Solid spheres as well as the single layer hollow silica spheres of comparative example 1 and the ultrasound intensity at concentrations of 0.1, 0.3, 0.6 and 1.0mg/mL increased significantly four times as much as in comparative example 1. Therefore, the double-layer hydrophobic-hydrophilic hollow nano silicon spheres prepared in the embodiment 1 of the invention are fully proved to have excellent ultrasonic development performance and can be used as an ultrasonic contrast agent.
The ultrasonic imaging stability experiment of the double-layer hydrophobic-hydrophilic hollow nano-silicon sphere in-vitro solution prepared in the example 1 comprises the following steps:
preparing 1.5mL of double-layer hydrophobic-hydrophilic hollow nano silicon spheres with the concentration of 0.6mg/mL in a PBS solution in a 2mL EP tube, then adding 0.4mL of agarose aqueous solution with the concentration of 0.4% (m/V) for sealing, measuring the change of the mean gray value of ultrasonic contrast after ultrasonic treatment for 1, 15, 30 and 60min, and taking the single-layer hollow silicon spheres without hydrophobic groups prepared in the comparative example 1 as a control to study the relation between the intensity of the ultrasonic contrast and the ultrasonic treatment time.
The results are shown in FIG. 3: the double-layer hydrophobic-hydrophilic hollow nano silicon spheres prepared in example 1 still have higher contrast intensity signals (four times of that of comparative example 1) compared with comparative example 1 under the condition of ultrasonic treatment time of 60min, and the signal intensity is not attenuated, which indicates that the double-layer hydrophobic-hydrophilic hollow nano silicon spheres prepared in example 1 have good ultrasonic development stability and can be used as an ultrasonic contrast agent.
Example 2
A preparation method of a double-layer hollow nano silicon sphere with an inner layer containing hydrophobic group octadecyl and an outer layer containing hydrophilicity comprises the following steps:
(1) preparation of (polystyrene) PS spheres: 100mL of deionized water is weighed into a 250mL three-neck flask, PVP-400001.0 g is added, after ultrasonic mixing, AIBA0.41g and 11mL of styrene and N are added2Degassing for 1h, oil-bathing at 70 deg.C, heating at 300rpm, refluxing for 24h, freezing at-20 deg.C overnight, thawing at room temperature, centrifuging at 8000rpm for 20min, and washing with ethanol to obtain ethanol solution of PS microspheres (0.1g/mL, i.e. 1mL ethanol solution with core polystyrene spheres mass of 0.1g) containing polystyrene in ethanol solution of PS microspheresThe particle size of the microspheres is 250-400 nm.
(2) Formation of inner hydrophobic group octadecyl: weighing 27mL of isopropanol and 4mL of deionized water in a 100mL three-neck flask, precisely weighing 0.4g of CTAB in a reaction system, ultrasonically accelerating dissolution, adding 4mL of prepared ethanol solution of PS microspheres, stirring at 50 ℃ in an oil bath at 300rpm for 30min, adding 500 mu L of ammonia water (the mass concentration is 25-28%), and 450 mu L of mixed solution (V) of TEOS and octadecyltriethoxysilaneTEOS/VC184/1), the reaction was continued for 6 hours, and after completion of the reaction, the precipitate was centrifuged and washed with absolute ethanol and toluene.
(3) Forming a hollow silicon ball structure: and (3) dispersing the product obtained in the step (2) in 45mL of toluene, heating and refluxing in an oil bath at 110 ℃, stirring at 500rpm for 24h, and washing with toluene to obtain the hollow silicon sphere structure.
(4) Formation of the hydrophilic layer: dispersing the product of step (3) in 40mL of toluene, adding 600. mu.L of APTES, heating in 100 ℃ oil bath under reflux, and N2And (c) protecting, stirring at 300rpm for 12h, then sequentially carrying out centrifugal washing by using toluene, THF (tetrahydrofuran), ethanol and deionized water, and freeze-drying for 12h to obtain double-layer hollow nano silicon sphere powder with an octadecyl hydrophobic group as an inner layer and hydrophilic outer layers, wherein the prepared hollow nano silicon spheres have uniform particle size of about 300nm, the thickness of a shell is 25nm, and the hollow hole structure is good and monodisperse, as shown in figure 1 (c).
The FT-IR chart is shown in FIG. 4(b), in which 3300cm-1Caused by N-H stretching vibration; 2975cm-1Is composed of-CH3Caused by stretching vibration; 2920. 2849cm-1Is composed of-CH2Caused by stretching vibration; 1070cm-1Is caused by the asymmetric stretching vibration of Si-O-Si. From this, it is known that the C18 group was successfully doped into the silica shell and the amino group was successfully modified.
In a preferred embodiment, in the preparation method of the double-layer hollow nano silicon spheres with the hydrophobic group-containing octadecyl as the inner layer and the hydrophilic group as the outer layer, each step is to perform washing operation while ultrasonically treating the mixture with an auxiliary pasteur pipette and blowing the mixture so that the precipitate obtained by centrifugation is fully and uniformly dispersed.
Comparative example 1
A preparation method of a single-layer hollow nano silicon ball formed by extracting PS on PS through TEOS polymerization comprises the following specific steps:
(1) preparation of Polystyrene (PS) spheres: the same as in example 1.
(2) Preparing a core-shell structure: measuring 21mL of deionized water and 10mL of absolute ethyl alcohol into a 100mL three-neck flask, precisely weighing 0.25g of CTAB into a reaction system, ultrasonically accelerating dissolution, adding 4mL of the prepared PS ethanol solution, stirring at 60 ℃ in an oil bath at 300rpm for 30min, adding 750 mu L of ammonia water (with the mass concentration of 25-28%), dropwise adding 450 mu L of TEOS, continuing to react for 6h, centrifuging after the reaction is finished, and washing precipitates with absolute ethyl alcohol and toluene.
(3) Preparing hollow silicon spheres: dispersing the product in the step (2) in 45mL of toluene, heating and refluxing in 110 ℃ oil bath, stirring at 500rpm for 24h to obtain single-layer SiO2Hollow silicon spheres of shell structure.
The TEM results are shown in FIG. 1(b), which shows that the inner cavity structure is smaller than that of example 1, the particle size is about 360nm, the shell thickness is about 70nm, and some core extraction is incomplete.
In conclusion, the double-layer hydrophobic-hydrophilic hollow nano silicon spheres constructed by the invention have the advantages of simple preparation process and good appearance structure, and can be used for developing novel ultrasonic contrast agents.
The foregoing description is only a preferred embodiment of the present invention, and various modifications and changes will occur to those skilled in the art. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (8)
1. The double-layer hydrophobic-hydrophilic modified hollow nano silicon ball is characterized by being prepared by the following steps:
(1) preparing polystyrene microspheres: PVP-40000, AIBA and styrene react at 60-80 ℃ while stirring, and polystyrene microspheres are obtained after washing; wherein the particle size of the polystyrene microsphere is 250-400 nm;
(2) formation of inner hydrophobic groups: dissolving CTAB in isopropanol and deionized water, adding the mixed solution of the polystyrene microspheres prepared in the step (1), ammonia water, tetraethoxysilane and heptadecafluorodecyltriethoxysilane, reacting at 50-70 ℃ while stirring, centrifuging and washing; wherein the volume ratio of the tetraethoxysilane to the heptadecafluorodecyltriethoxysilane is 2: 1-6: 1; the mass-volume ratio of the polystyrene microspheres to the tetraethoxysilane is 0.8: 1-2.0: 1 g/mL;
(3) forming a hollow silicon ball structure: dispersing the product obtained in the step (2) in toluene, extracting at 100-120 ℃, stirring, and washing;
(4) formation of the hydrophilic layer: reacting the product obtained in the step (3) with 3-aminopropyltriethoxysilane at 90-110 ℃, stirring, centrifuging and washing to obtain the product; wherein the particle size of the hollow nano silicon ball is 350-400 nm, and the thickness of the shell layer is 25-35 nm.
2. The preparation method of the double-layer hydrophobic-hydrophilic modified hollow nano silicon sphere of claim 1 is characterized by comprising the following steps:
(1) preparing polystyrene microspheres: PVP-40000, AIBA and styrene react at 60-80 ℃ while stirring, and polystyrene microspheres are obtained after washing; wherein the particle size of the polystyrene microsphere is 250-400 nm;
(2) formation of inner hydrophobic groups: dissolving CTAB in isopropanol and deionized water, adding the mixed solution of the polystyrene microspheres prepared in the step (1), ammonia water, tetraethoxysilane and heptadecafluorodecyltriethoxysilane, reacting at 50-70 ℃ while stirring, centrifuging and washing; wherein the volume ratio of the tetraethoxysilane to the heptadecafluorodecyltriethoxysilane is 2: 1-6: 1; the mass-volume ratio of the polystyrene microspheres to the tetraethoxysilane is 0.8: 1-2.0: 1 g/mL;
(3) forming a hollow silicon ball structure: dispersing the product obtained in the step (2) in toluene, extracting at 100-120 ℃, stirring, and washing;
(4) formation of the hydrophilic layer: and (3) reacting the product obtained in the step (3) with 3-aminopropyltriethoxysilane at 90-110 ℃, stirring, centrifuging and washing to obtain the product.
3. The preparation method of the double-layer hydrophobic-hydrophilic modified hollow nano silicon sphere according to claim 2, wherein in the step (2), the volume ratio of tetraethoxysilane to heptadecafluorodecyltriethoxysilane is 4: 1; the mass-volume ratio of the polystyrene microspheres to the tetraethoxysilane is 0.8: 1-1.4: 1 g/mL.
4. The preparation method of the double-layer hydrophobic-hydrophilic modified hollow nano-silica sphere according to claim 2, wherein in the step (2), the mass-to-volume ratio of the polystyrene microsphere to the tetraethoxysilane is 1.1:1 g/mL.
5. The preparation method of the double-layer hydrophobic-hydrophilic modified hollow nano silicon ball according to claim 3, wherein the stirring speed in the steps (1) and (3) is 250-350 rpm; the stirring speed in the step (2) is 450-550 rpm.
6. The method for preparing the double-layer hydrophobically-hydrophilically modified hollow nano-silica spheres as claimed in claim 3, wherein the washing in steps (1) to (4) is performed while ultrasonic treatment is used to assist blowing with a pasteur pipette.
7. Use of the double-layer hydrophobic-hydrophilic modified hollow nano-silica spheres of claim 1 in the preparation of ultrasound contrast materials.
8. Use according to claim 7, wherein the hollow nanosilica spheres are used in the preparation of ultrasound contrast agents.
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