CN112587673A - Preparation of sodium alginate nano-microspheres containing gadolinium mesoporous silica and application of sodium alginate nano-microspheres in ultrasound-magnetic resonance image registration fusion navigation - Google Patents
Preparation of sodium alginate nano-microspheres containing gadolinium mesoporous silica and application of sodium alginate nano-microspheres in ultrasound-magnetic resonance image registration fusion navigation Download PDFInfo
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- CN112587673A CN112587673A CN202011441282.0A CN202011441282A CN112587673A CN 112587673 A CN112587673 A CN 112587673A CN 202011441282 A CN202011441282 A CN 202011441282A CN 112587673 A CN112587673 A CN 112587673A
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- gadolinium
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- sodium alginate
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- A61K49/1818—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles
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Abstract
The invention discloses a gadolinium-containing mesoporous silica sodium alginate nano microsphere, which is prepared by taking mesoporous silica nano particles with the particle size of 100-200nm as a carrier for loading a gadolinium-containing magnetic resonance contrast agent and an ultrasonic imaging material, loading the gadolinium-containing magnetic resonance contrast agent to the mesoporous silica nano particles by utilizing the siphon effect, and taking the hydrogen bond of the pore channel encapsulant on the surface of the mesoporous silica nano particlesModifying, mixing with sodium alginate aqueous solution and calcium chloride aqueous solution sequentially, and using Ca2+And the alpha-L-guluronic acid block of alginate in the gadolinium-containing mesoporous silica sodium alginate suspension is crosslinked and solidified to form the gadolinium-containing mesoporous silica sodium alginate nano microsphere with the diameter of 3.8-4.2mm and the hardness of 10-25 Hw. The sodium alginate nano microsphere containing gadolinium mesoporous silica is used as a marker for registration fusion navigation of an ultrasonic-magnetic resonance image.
Description
Technical Field
The invention relates to a nano biomaterial and preparation thereof, in particular to a sodium alginate nano microsphere containing gadolinium mesoporous silica and preparation and application thereof.
Background
The gold standard for pre-clinical diagnosis of prostate cancer is transrectal ultrasound (TRUS) guided biopsy of prostate by aspiration and pathological diagnosis. However, the false negative rate and complication rate of prostate cancer detected by ultrasound-guided prostate aspiration biopsy are high, and the ultrasound imaging resolution is low, so that missed diagnosis or misdiagnosis is easily caused. The targeted prostate biopsy is an emerging technology, more effective suspicious prostate lesions can be detected by using high-resolution multi-parameter magnetic resonance images, and more accurate puncture target information is provided. In recent years, MRI/TRUS image fusion targeted biopsy has become the mainstream mode of prostate needle biopsy.
In theory, the MRI/TRUS image fusion puncture technology is that an MRI image of the prostate of a patient, which is obtained in advance and pre-stored in a system, is in registration fusion with a real-time TRUS image in cognition or vision through related software or experts, and an operator can perform TRUS real-time guidance according to target information provided by MRI in the fusion image to complete target puncture biopsy. The prerequisite and key for realizing the image fusion of different modalities are image registration technologies, the quality of an image fusion result is directly determined by the image registration precision, and the marker selection for registration is an important prerequisite for success or failure of the image registration.
Currently, the marginal points, contour and anatomical structure of prostate are widely used clinically as marking points for registration, such as calcification in prostate, intraurethral orifice, marginal contour of prostate and relevant focus in prostate. Although such methods are simple and non-invasive, the prostate is an organ that is prone to deformation, not only before and after prostatectomy. In addition, for example, the position of the patient, the inner diameters of the rectal ultrasonic probe and the MRI rectal coil are not uniform, the bladder with different filling degrees and the pressure caused by the insertion of the biopsy needle in the interventional process all cause the prostate to generate displacement and deformation with different degrees, and at the moment, the error of the method for registering depending on the geometrical shape of the prostate, local points, lines, surfaces, contour characteristics and the like is very large, so that the registration accuracy is influenced. The software-assisted MRI/TRUS fusion platform can utilize an electromagnetic tracking positioning system, a position encoder in an intelligent mechanical arm and a software tracking system to perform image registration fusion by applying an elastic registration or rigid registration method, although registration errors possibly caused by wrong judgment of an operator on an anatomical structure and a lesion position can be reduced to the maximum extent, in the image registration fusion process, a marker is required to be registered at an initial point level, and the marker required by the initial point level registration also has the defects.
Nano medicine achieves the purpose of detecting and treating diseases by applying various nano probes, brings revolutionary progress to the medical fields of clinical medicine, molecular imaging, medical detection technology and the like, and is rapidly developed in the aspects of operation positioning and navigation in recent years. Mesoporous silica is a rigid nano material approved by FDA clinical trials, has advantages including large pore volume, high surface area, adjustable pore size, functionalization, biodegradability and good biocompatibility, and has been widely used as a drug delivery platform, but most of the nanoprobes are still in preclinical or basic research stage. Sodium alginate is a natural anionic polymer, has the characteristics of no toxicity, biodegradability and the like, can form ionic crosslinked gel with cations, and is frequently researched by taking sodium alginate as a medicament carrier, but research on applying the gelling property of the sodium alginate to the prostate MRI/US image registration fusion puncture navigation technology by in vivo shaping and positioning is not reported.
Disclosure of Invention
Aiming at the prior art, the sodium alginate nano-microsphere containing the gadolinium mesoporous silica and the preparation method thereof provided by the invention have the advantages that the prepared gadolinium mesoporous silica alginate nano-microsphere has an MRI/US bimodal imaging effect, can be plastically solidified, is safe, non-toxic and biodegradable.
In order to solve the technical problems, the gadolinium-containing mesoporous silica sodium alginate nano microsphere provided by the invention comprises the components of mesoporous silica nano particles with the particle size of 100-200nm, a gadolinium-containing magnetic resonance contrast agent, a pore channel encapsulating agent, sodium alginate and calcium chloride; loading the gadolinium-containing magnetic resonance contrast agent to the mesoporous silica nanoparticles by using a siphon effect, modifying the surface of the mesoporous silica nanoparticles by using a hydrogen bond effect of the pore channel encapsulant, sequentially mixing the mesoporous silica nanoparticles with a sodium alginate aqueous solution and a calcium chloride aqueous solution, and using Ca to prepare the gadolinium-containing magnetic resonance contrast agent2+And the alpha-L-guluronic acid block of alginate in the gadolinium-containing mesoporous silica sodium alginate suspension is subjected to high affinity, and the gadolinium-containing mesoporous silica sodium alginate nano-microspheres with the diameter of 3.8-4.2mm and the hardness of 10-25Hw are formed through crosslinking and curing.
Furthermore, in the gadolinium-containing mesoporous silica sodium alginate nanosphere, the pore channel encapsulant is methyl oleate or oleic acid.
The preparation method of the sodium alginate nano-microsphere containing gadolinium mesoporous silica comprises the following steps:
step 1): dispersing mesoporous silica nanoparticles with the particle size of 100-200nm in a gadolinium-containing magnetic resonance contrast agent aqueous solution with the mass percentage of 0.1-6.4%, wherein the mass-volume ratio of the mesoporous silica nanoparticles to the gadolinium-containing magnetic resonance contrast agent aqueous solution is 1g/100mL, stirring and reacting for 24h at room temperature, and collecting a product after centrifugal drying, namely the mesoporous silica nanoparticles loaded with the gadolinium-containing magnetic resonance contrast agent;
step 2): dispersing the product obtained in the step 1) into a proper amount of organic solvent, adding methyl oleate or oleic acid, wherein the mass ratio of the methyl oleate or oleic acid to the mesoporous silica nanoparticles is 3:1, stirring and reacting for 24 hours at room temperature, evaporating the organic solvent, washing for 3 times by using absolute ethyl alcohol or an ethanol water solution, separating and drying to obtain the gadolinium-containing mesoporous silica nanoparticles;
step 3): dissolving sodium alginate in deionized water, and mechanically stirring to obtain a sodium alginate aqueous solution with the mass percent of 2-3%, preferably 3%.
Step 4): adding the gadolinium-containing mesoporous silica nanoparticles obtained in the step 2) into the sodium alginate aqueous solution prepared in the step 3), wherein the mass-to-volume ratio of the gadolinium-containing mesoporous silica nanoparticles to the gadolinium-containing mesoporous silica sodium alginate aqueous solution is 50 mg/mL-200 mg/mL, preferably 100 mg/mL; stirring the mixture at room temperature until the mixture is uniform to obtain a sodium alginate suspension containing gadolinium mesoporous silica;
step 5): crosslinking and curing the sodium alginate suspension containing the gadolinium mesoporous silica obtained in the step 4) with a calcium chloride aqueous solution with the molar concentration of 0.5-4 mol/L according to the volume ratio of 1:1, wherein the crosslinking reaction time is 3min, and the sodium alginate nano-microsphere containing the gadolinium mesoporous silica with the diameter of 3.8-4.2mm and the hardness of 10-25Hw is obtained.
Further, the preparation method of the sodium alginate nano-microsphere containing gadolinium mesoporous silica comprises the following steps:
in the step 1), the gadolinium-containing magnetic resonance contrast agent comprises gadobenate dimeglumine, gadopentetate dimeglumine, gadobutrol and gadoteric acid meglumine, and also comprises other contrast agents capable of imaging in magnetic resonance; the mass percentage of the gadolinium-containing magnetic resonance contrast agent aqueous solution is preferably 1.6%.
In the step 2), the organic solvent is tetrahydrofuran or absolute ethyl alcohol; the method for evaporating the organic solvent adopts a rotary evaporator or is placed in a fume hood to evaporate the organic solvent; the volume fraction of the ethanol water solution is 65-70%.
In the step 5), a double-channel micro-injection pump is adopted to perform a cross-linking and curing process of the sodium alginate suspension containing the gadolinium mesoporous silica and a calcium chloride aqueous solution with the molar concentration of 0.5-4 mol/L, wherein the double-channel micro-injection pump comprises two injectors which are respectively marked as a channel A injector and a channel B injector, and the method comprises the following steps:
filling the sodium alginate suspension containing the gadolinium mesoporous silica prepared in the step 4) into the channel A injector; filling a calcium chloride aqueous solution with the molar concentration of 0.5-4 mol/L into the injector of the channel B; the two injectors are respectively arranged on a channel A and a channel B of the double-channel micro-injection pump, needle heads of the two injectors are located at the same position, the double-channel micro-injection pump is started, the speed of the double-channel micro-injection pump is 0.01-0.05m/s, when the liquid amount pushed out by the injector A and the injector B is 0.2mL, the pushing is stopped, the liquid stays for 3 minutes, and finally the sodium alginate nano-microspheres containing gadolinium mesoporous silica with the diameter of 3.8-4.2mm are formed at the positions of liquid outlets of the needle heads of the two injectors.
The sodium alginate microspheres (the diameter is about 4mm) containing the gadolinium mesoporous silica prepared by the preparation method take mesoporous silica nano with the particle size of 100-200nm as a carrier and an ultrasonic imaging material, a gadolinium-containing magnetic resonance contrast agent is loaded by utilizing the siphon action, and the surfaces of the mesoporous silica are modified by the hydrogen bond action of methyl oleate to seal the pore passages, so that the cargo leakage is prevented; using Ca2+And the high affinity between the alpha-L-guluronic acid block of alginate in the gadolinium-containing mesoporous silica sodium alginate suspension, and crosslinking and curing to form the gadolinium-containing mesoporous silica sodium alginate nano-microsphere. The gadolinium-containing mesoporous silica sodium alginate nanospheres are safe and non-toxic, can be metabolized, have MRI/US bimodal imaging capability and can be plastically cured, so that the gadolinium-containing mesoporous silica sodium alginate nanospheres can be applied to ultrasound-magnetic resonance image registration fusion navigation, namely the gadolinium-containing mesoporous silica sodium alginate nanospheres are used for registration fusion navigation of a Magnetic Resonance Image (MRI) and an ultrasound image (US) as markers, and can be particularly applied to prostate MRI/US image registration fusion puncture navigation technology as the markers.
Compared with the prior art, the invention has the beneficial effects that:
(1) the raw materials of the sodium alginate nano microsphere containing the gadolinium mesoporous silica are safe, nontoxic, metabolizable and absorbable.
(2) The sodium alginate nanosphere containing gadolinium mesoporous silica is used for registration fusion navigation of MRI/US images of prostate, is simple, accurate and rapid, and can be implanted only by injecting a calcium chloride aqueous solution and a sodium alginate suspension containing gadolinium mesoporous silica through a double-needle injection mode during actual operation.
(3) The sodium alginate nano microsphere containing the gadolinium mesoporous silica has MRI/US bimodal imaging capability, can be used as a marker in the registration fusion navigation process of a prostate MRI/US image, can overcome the damage of an implanted marker in the prostate and the instability of a prostate anatomical structure as the marker and the uncertainty due to insufficient experience of an operator, improves the MRI/US image fusion success rate, and further improves the puncture accuracy rate.
Drawings
FIG. 1(a) is a transmission electron micrograph of gadolinium-containing mesoporous silica nanoparticles prepared in example 1;
FIG. 1(b) is a particle size distribution diagram of the mesoporous silica nanoparticles containing gadolinium prepared in example 1;
FIG. 2 is a schematic diagram showing the appearance and size of the sodium alginate nanospheres containing gadolinium mesoporous silica prepared in example 1;
fig. 3(a) to 3(d) are graphs showing the relationship between the mass concentration of different gadolinium-containing mesoporous silica nanoparticles prepared in example 3, the concentration of sodium alginate aqueous solution and the hardness of the prepared gadolinium-containing mesoporous silica sodium alginate nanospheres, wherein:
FIG. 3(a) is a relationship curve of the hardness of sodium alginate microspheres containing gadolinium mesoporous silica, which is prepared with a mass-to-volume ratio of gadolinium-containing mesoporous silica nanoparticles to sodium alginate aqueous solution of 50mg/ml, and 1%, 2% and 3% sodium alginate aqueous solution mass percentages, respectively;
FIG. 3(b) is a graph showing the relationship between the hardness of gadolinium-containing mesoporous silica sodium alginate microspheres prepared with gadolinium-containing mesoporous silica nanoparticles and sodium alginate aqueous solution at a mass-to-volume ratio of 100mg/ml, with 1%, 2% and 3% sodium alginate aqueous solution mass percent, respectively;
FIG. 3(c) is a graph showing the relationship between the hardness of gadolinium-containing mesoporous silica sodium alginate microspheres prepared with a mass-to-volume ratio of gadolinium-containing mesoporous silica nanoparticles to sodium alginate aqueous solution of 150mg/ml, and 1%, 2% and 3% sodium alginate aqueous solution mass percentages, respectively;
FIG. 3(d) is a graph showing the relationship between the hardness of gadolinium-containing mesoporous silica sodium alginate microspheres prepared with gadolinium-containing mesoporous silica nanoparticles and sodium alginate aqueous solution at a mass-to-volume ratio of 200mg/ml, with 1%, 2% and 3% sodium alginate aqueous solution mass percent, respectively;
FIG. 4 is a magnetic resonance T1WI image of gadolinium-containing mesoporous silica sodium alginate nanospheres implanted in the prostate gel model described in example 5;
fig. 5 is an US image of gadolinium-containing mesoporous silica sodium alginate nanospheres implanted into the prostate gel model described in example 5.
Detailed Description
The invention will be further described with reference to the following figures and specific examples, which are not intended to limit the invention in any way.
All of the starting materials of the present invention, without particular limitation as to their source, may be purchased commercially or prepared according to conventional methods well known to those skilled in the art. The mesoporous silica nanoparticles in the following examples can be prepared according to a sol-gel method, with a particle size of 100-200 nm.
Example 1: the preparation method of the sodium alginate nano microsphere containing gadolinium mesoporous silica comprises the following specific steps:
1) weighing 1g of mesoporous silica nanoparticles (the particle size is 107nm), adding 100mL of gadobenate dimeglumine aqueous solution with the mass percent of 0.1%, and stirring at room temperature for 24 h;
2) the product was isolated, dispersed in 50mL absolute ethanol solution, 3g methyl oleate was added, and stirred in a fume hood at room temperature for 24 h. Then, in order to remove the excess reactant, the product was washed 3 times by absolute ethanol, then centrifuged at 3000rpm for 5min and dried under vacuum at 40 ℃ for 24 hours to obtain gadolinium-containing mesoporous silica nanoparticles having a spherical shape, a Transmission Electron Microscope (TEM) as shown in FIG. 1(a), a particle size distribution diagram as shown in FIG. 1(b), and an average particle size of 160 nm.
3) Dissolving 3g of sodium alginate in deionized water, and mechanically stirring to obtain a sodium alginate aqueous solution with the mass percent of 3%;
4) weighing 100mg of mesoporous silica nanoparticles containing gadolinium, adding 1mL of sodium alginate aqueous solution with the mass percentage of 3%, and mechanically stirring and uniformly mixing to obtain a sodium alginate suspension containing gadolinium mesoporous silica with the mass concentration of 100 mg/mL;
5) filling a channel A injector of the double-channel micro-injection pump with the sodium alginate suspension containing the gadolinium mesoporous silica prepared in the step 4), and filling a channel B injector with a calcium chloride aqueous solution with the molar concentration of 1 mol/L; the two injectors are respectively arranged on a channel A and a channel B of a double-channel micro-injection pump, needle heads of the two injectors are mutually contacted, and are injected with 0.2mL of sodium alginate at a constant speed of 0.03m/s, the sodium alginate suspension containing the gadolinium mesoporous silica contacts with a calcium chloride aqueous solution during injection, so that crosslinking solidification occurs, and after 3min of crosslinking solidification reaction, the sodium alginate nano-microsphere containing the gadolinium mesoporous silica with the diameter of about 4mm is formed, as shown in figure 2.
The hardness of the sodium alginate nanosphere containing gadolinium mesoporous silica obtained in the embodiment is 18.4Hw measured by a shore durometer (O-type), and the molding effect is good.
Example 2: the preparation method of the sodium alginate nano microsphere containing gadolinium mesoporous silica comprises the following specific steps:
1) weighing 1g of mesoporous silica nanoparticles, adding 100mL of gadobenate dimeglumine aqueous solution with the mass percent of 6.4%, and stirring at room temperature for 24 h;
2) the product was isolated, dispersed in 50mL tetrahydrofuran, 3g methyl oleate was added, and stirred in a fume hood at room temperature for 24 h. Then, in order to remove the excessive reactants, the product is washed 3 times by ethanol water solution with 65% volume fraction, then is centrifuged at 3000rpm for 5min at low speed, and is dried in vacuum at 40 ℃ for 24 hours, so as to obtain the gadolinium-containing mesoporous silica nanoparticles.
3) Dissolving 2g of sodium alginate in deionized water, and mechanically stirring to obtain a sodium alginate aqueous solution with the mass percent of 2%;
4) weighing 100mg of mesoporous silica nanoparticles containing gadolinium, adding 1mL of sodium alginate aqueous solution with the mass percentage of 2%, and mechanically stirring and uniformly mixing to obtain a sodium alginate suspension containing gadolinium mesoporous silica with the mass concentration of 100 mg/mL;
5) filling a channel A injector of the double-channel micro-injection pump with the sodium alginate suspension containing the gadolinium mesoporous silica prepared in the step 3), and filling a channel B injector with 0.5mol/L calcium chloride aqueous solution; the needle heads of the two syringes are contacted with each other, 0.2mL of sodium alginate solution is injected at a constant speed of 0.03m/s, the sodium alginate suspension containing the gadolinium mesoporous silica is contacted with a calcium chloride aqueous solution to be crosslinked and solidified in the injection process, and the sodium alginate nanospheres containing the gadolinium mesoporous silica with the diameter of about 4mm are formed after 3 min.
The hardness of the sodium alginate nanosphere containing gadolinium mesoporous silica obtained in the embodiment is 12.8Hw measured by a shore durometer (O type), and the molding effect is good.
Example 3: the sodium alginate nano-microsphere containing gadolinium mesoporous silica prepared by the method has a plastic effect.
A series of samples for measuring the Shore hardness of the product are prepared by utilizing components with different contents according to the following steps:
1) weighing 1g of mesoporous silica nanoparticles, adding 100mL of gadobenate dimeglumine aqueous solution with the mass percent of 1%, and stirring at room temperature for 24 h;
2) the product was isolated, dispersed in 50mL tetrahydrofuran, 3g methyl oleate was added, and stirred in a fume hood at room temperature for 24 h. Then, to remove excess reactants, the product was washed 3 times with an aqueous ethanol solution (ethanol volume fraction of 65%), then centrifuged at 3000rpm for 5min at a low speed, and vacuum-dried at 40 ℃ for 24 hours to obtain gadolinium-containing mesoporous silica nanoparticles.
3) Preparing 3 containers, dissolving 1g, 2g and 3g of sodium alginate in a proper amount of deionized water in each container, and mechanically stirring to obtain 1%, 2% and 3% sodium alginate aqueous solutions in percentage by mass;
4) weighing the prepared gadolinium-containing mesoporous silica nanoparticles, and respectively blending the gadolinium-containing mesoporous silica nanoparticles with sodium alginate aqueous solutions with the mass percentages of 1%, 2% and 3%, so as to prepare gadolinium-containing mesoporous silica sodium alginate suspension with the gadolinium-containing mesoporous silica nanoparticles mass concentrations of 50mg/ml, 100mg/ml, 150mg/ml and 200 mg/ml;
5) and (2) injecting 0.2mL of gadolinium-containing mesoporous silica sodium alginate suspension prepared in the step 4) and calcium chloride aqueous solution with the concentration of 0.0625, 0.125, 0.25, 0.5, 1, 2 and 4mol/L at a constant speed of 0.03m/s respectively according to the method of the step 5) in the example 1, and forming the gadolinium-containing mesoporous silica sodium alginate nano-microspheres after crosslinking and curing for 3 min.
FIG. 3(a) shows a relationship curve of the hardness of sodium alginate microspheres containing gadolinium mesoporous silica, which are prepared with a mass-to-volume ratio of gadolinium-containing mesoporous silica nanoparticles to sodium alginate aqueous solution of 50mg/ml, and a mass percentage of sodium alginate aqueous solution of 1%, 2% and 3%, respectively; FIG. 3(b) shows a relationship curve of the hardness of sodium alginate microspheres containing gadolinium mesoporous silica, which are prepared with a mass-to-volume ratio of gadolinium-containing mesoporous silica nanoparticles to sodium alginate aqueous solution of 100mg/ml, and a mass percentage of sodium alginate aqueous solution of 1%, 2% and 3%, respectively; FIG. 3(c) shows a relationship curve of the hardness of gadolinium-containing mesoporous silica sodium alginate microspheres prepared with a mass-to-volume ratio of gadolinium-containing mesoporous silica nanoparticles to sodium alginate aqueous solution of 150mg/ml, with the mass percentages of sodium alginate aqueous solution being 1%, 2% and 3%, respectively; FIG. 3(d) shows a relationship curve of the hardness of the sodium alginate microspheres containing gadolinium mesoporous silica, which is prepared with 200mg/ml of gadolinium-containing mesoporous silica nanoparticles and 1%, 2% and 3% of sodium alginate aqueous solution by mass. The obtained sodium alginate microspheres containing gadolinium mesoporous silica are measured by a Shore durometer (O type), the measurement results are shown in Table 1, and as can be seen from Table 1, the hardness of the sodium alginate microspheres containing gadolinium mesoporous silica obtained under the process conditions defined in the preparation method is within the range of 10.8-24.6 Hw, namely the obtained sodium alginate microspheres containing gadolinium mesoporous silica have a good shaping effect.
TABLE 1
Example 4: the sodium alginate nano-microsphere containing gadolinium mesoporous silica prepared by the invention is used as a marker and is applied to prostate MRI/US image registration fusion navigation.
(1) Preparing gadolinium-containing mesoporous silica sodium alginate nano microspheres:
weighing 1g of mesoporous silica nanoparticles (the particle size is 160nm), adding 100mL of 1% gadobenate dimeglumine aqueous solution in mass percent, stirring at room temperature for 24h, separating the product, dispersing into 50mL of absolute ethanol solution, adding 3g of methyl oleate, and stirring at room temperature for 24h in a fume hood. Then, in order to remove the excess reactant, the product was washed 3 times by absolute ethanol, then centrifuged at 3000rpm for 5min at a low speed, and vacuum-dried at 40 ℃ for 24 hours to obtain gadolinium-containing mesoporous silica nanoparticles. Dissolving 3g of sodium alginate in 97g of deionized water, and mechanically stirring to obtain a sodium alginate aqueous solution with the mass percent of 3%; weighing 100mg of mesoporous silica nanoparticles containing gadolinium, adding 1mL of sodium alginate aqueous solution with the mass percentage of 3%, and mechanically stirring and uniformly mixing to obtain a sodium alginate suspension containing gadolinium mesoporous silica with the mass concentration of 100 mg/mL; filling a channel A injector of the double-channel micro-injection pump with the sodium alginate suspension containing the gadolinium mesoporous silica prepared in the step 3), and filling a channel B injector with 1mol/L calcium chloride aqueous solution; and (3) mutually contacting and injecting the needle heads of the two injectors into the prostate gel model, injecting 0.2mL of the solution at a constant speed of 0.03m/s, and in the injection process, contacting the gadolinium-containing mesoporous silica sodium alginate suspension with calcium chloride to perform crosslinking and solidification for 3min to form the gadolinium-containing mesoporous silica sodium alginate microspheres.
(2) The gadolinium-containing mesoporous silica sodium alginate nano-microsphere prepared by the method is applied.
Implanting the solidified sodium alginate microspheres containing gadolinium mesoporous silica prepared by the method into a prostate gel model by using a particle implantation needle, and then performing nuclear magnetic resonance scanning to obtain a nuclear magnetic resonance T1WI image, wherein the sodium alginate microspheres containing gadolinium mesoporous silica are high-signal in a T1WI image, as shown by the positions indicated by arrows in figure 4. Ultrasonic scanning is carried out on the same position of the prostate gel model implanted with the prepared gadolinium-containing mesoporous silica sodium alginate nano-microsphere, and ultrasonic echo of the gadolinium-containing mesoporous silica sodium alginate nano-microsphere is obvious as shown by the position indicated by an arrow in figure 5. The sodium alginate microspheres containing gadolinium mesoporous silica obtained by the preparation method are used as markers, and the ultrasonic layer of the sodium alginate microspheres is positioned on the layer displayed on magnetic resonance, so that registration of two image modes is realized.
The principle of registration fusion navigation of the sodium alginate nano-microspheres containing gadolinium mesoporous silica is as follows: before the ultrasonic guided puncture, the sodium alginate nano-microspheres containing gadolinium mesoporous silica are implanted beside the prostate simulant of the prostate model by a double-channel micro-injection pump with a double-needle injection method or a particle implantation method, acquiring image data of the prostate model by nuclear magnetic resonance scanning, copying nuclear magnetic resonance image data to an image fusion workstation, then the prostate model is subjected to prostate puncture guided by ultrasound, the sodium alginate nano-microspheres containing gadolinium mesoporous silica can be developed under nuclear magnetic resonance and ultrasonic imaging, the accurate registration of two image modes can be realized, then, the nuclear magnetic resonance image of the prostate model is automatically called by manual or related software to perform two image fusion, the focus image on the nuclear magnetic resonance can be superimposed and displayed on the ultrasonic image by adopting methods such as semitransparent display or focus highlighting, and then the focus is subjected to targeted puncture.
The sodium alginate nano-microsphere containing gadolinium mesoporous silica has the characteristics in the application aspect that:
the gadolinium-containing mesoporous silica sodium alginate nano microspheres are safe, non-toxic, metabolizable and absorbable, and good in molding effect; the sodium alginate nano-microspheres containing gadolinium mesoporous silica present high signals on nuclear magnetic resonance T1WI, and can generate clear signal contrast with surrounding tissues; the sodium alginate nano-microspheres containing gadolinium mesoporous silica also generate echoes clearly contrasting with surrounding tissues under ultrasonic scanning; the sodium alginate nano-microspheres containing gadolinium mesoporous silica can be solidified at an implanted part by a double-needle injection method, and can also be implanted in a particle implantation mode after being solidified in vitro.
In conclusion, the gadolinium-containing mesoporous silica sodium alginate nanospheres are convenient to obtain materials, are prepared from mesoporous silica nanoparticles, gadolinium-containing magnetic resonance contrast agents, pore canal encapsulating agents, sodium alginate and calcium chloride, have the advantages of magnetic resonance and ultrasonic bimodal imaging, in-vivo and in-vitro moulding and curing, safety, no toxicity, metabolizable absorption and the like, and can ensure the stability and reliability of the final imaging result. The preparation process is simple, the cost is low, when the method is actually applied, a double-needle injection method or a particle implantation method is used, the operation is simple and quick, only the gadolinium-containing mesoporous silica sodium alginate nanometer microsphere images in two imaging modes are registered, the damage of the prostatic implantable marker and the instability of the prostatic anatomical structure as the registration marker and the uncertainty caused by insufficient experience of an operator can be overcome, the MRI/US image registration fusion success rate is improved, and the puncture accuracy is further improved. On the other hand, the synthesis process is simple, the raw material cost is low, the mass production is easy, and great economic benefit and social benefit are brought.
While the present invention has been described with reference to the accompanying drawings, the present invention is not limited to the above-described embodiments, which are illustrative only and not restrictive, and various modifications which do not depart from the spirit of the present invention and which are intended to be covered by the claims of the present invention may be made by those skilled in the art.
Claims (10)
1. The sodium alginate nano-microsphere containing gadolinium mesoporous silica is characterized by comprisingThe components comprise mesoporous silica nanoparticles with the particle size of 100-200nm, gadolinium-containing magnetic resonance contrast agents, pore canal encapsulating agents, sodium alginate and calcium chloride; loading the gadolinium-containing magnetic resonance contrast agent to the mesoporous silica nanoparticles by using a siphon effect, modifying the surface of the mesoporous silica nanoparticles by using a hydrogen bond effect of the pore channel encapsulant, sequentially mixing the mesoporous silica nanoparticles with a sodium alginate aqueous solution and a calcium chloride aqueous solution, and using Ca to prepare the gadolinium-containing magnetic resonance contrast agent2+And the alpha-L-guluronic acid block of alginate in the gadolinium-containing mesoporous silica sodium alginate suspension is subjected to high affinity, and the gadolinium-containing mesoporous silica sodium alginate nano-microspheres with the diameter of 3.8-4.2mm and the hardness of 10-25Hw are formed through crosslinking and curing.
2. The sodium alginate nanosphere containing gadolinium mesoporous silica as claimed in claim 1, wherein said pore channel encapsulant is methyl oleate or oleic acid.
3. The preparation method of the sodium alginate nanosphere containing gadolinium mesoporous silica as claimed in claim 1, which comprises the following steps:
step 1): dispersing mesoporous silica nanoparticles with the particle size of 100-200nm in a gadolinium-containing magnetic resonance contrast agent aqueous solution with the mass percentage of 0.1-6.4%, wherein the mass-volume ratio of the mesoporous silica nanoparticles to the gadolinium-containing magnetic resonance contrast agent aqueous solution is 1g/100mL, stirring and reacting for 24h at room temperature, and collecting a product after centrifugal drying, namely the mesoporous silica nanoparticles loaded with the gadolinium-containing magnetic resonance contrast agent;
step 2): dispersing the product obtained in the step 1) into a proper amount of organic solvent, adding methyl oleate or oleic acid, wherein the mass ratio of the methyl oleate or oleic acid to the mesoporous silica nanoparticles is 3:1, stirring and reacting for 24 hours at room temperature, evaporating the organic solvent, washing for 3 times by using absolute ethyl alcohol or an ethanol water solution, separating and drying to obtain the gadolinium-containing mesoporous silica nanoparticles;
step 3): dissolving sodium alginate in deionized water, and mechanically stirring to obtain a sodium alginate aqueous solution with the mass percent of 2-3%;
step 4): adding the gadolinium-containing mesoporous silica nanoparticles obtained in the step 2) into the sodium alginate aqueous solution prepared in the step 3), wherein the mass-to-volume ratio of the gadolinium-containing mesoporous silica nanoparticles to the gadolinium-containing mesoporous silica sodium alginate aqueous solution is 50 mg/mL-200 mg/mL, and stirring at room temperature until the mixture is uniform to obtain gadolinium-containing mesoporous silica sodium alginate suspension;
step 5): crosslinking and curing the sodium alginate suspension containing the gadolinium mesoporous silica obtained in the step 4) with a calcium chloride aqueous solution with the molar concentration of 0.5-4 mol/L according to the volume ratio of 1:1, wherein the crosslinking reaction time is 3min, and the sodium alginate nano-microsphere containing the gadolinium mesoporous silica with the diameter of 3.8-4.2mm and the hardness of 10-25Hw is obtained.
4. The preparation method of the sodium alginate microspheres containing gadolinium mesoporous silica according to claim 3, wherein in the step 1), the gadolinium-containing magnetic resonance contrast agent comprises gadobenate dimeglumine, gadopentetate dimeglumine, gadobutrol, gadoteric acid meglumine, and also comprises other contrast agents capable of imaging in magnetic resonance; the mass percentage of the gadolinium-containing magnetic resonance contrast agent aqueous solution is 1.6%.
5. The preparation method of sodium alginate microspheres containing gadolinium mesoporous silica as in claim 3, wherein in the step 2), the organic solvent is tetrahydrofuran or absolute ethyl alcohol; the method for evaporating the organic solvent adopts a rotary evaporator or is placed in a fume hood to evaporate the organic solvent; the volume fraction of the ethanol water solution is 65-70%.
6. The preparation method of sodium alginate microspheres containing gadolinium mesoporous silica according to claim 3, wherein in step 3), the mass percent of the sodium alginate aqueous solution is 3%.
7. The preparation method of sodium alginate microspheres containing gadolinium mesoporous silica according to claim 3, wherein in the step 4), the mass-to-volume ratio of the gadolinium mesoporous silica nanoparticles to the gadolinium mesoporous silica sodium alginate aqueous solution is 100 mg/mL.
8. The preparation method of sodium alginate microspheres containing gadolinium mesoporous silica as claimed in claim 3, wherein in step 5), the crosslinking and curing process of sodium alginate suspension containing gadolinium mesoporous silica and calcium chloride aqueous solution with the molar concentration of 0.5 mol/L-4 mol/L is performed by using a two-channel micro-injection pump, wherein the two-channel micro-injection pump comprises two injectors which are respectively marked as a channel A injector and a channel B injector, and comprises the following steps:
filling the sodium alginate suspension containing the gadolinium mesoporous silica prepared in the step 4) into the channel A injector;
filling a calcium chloride aqueous solution with the molar concentration of 0.5-4 mol/L into the injector of the channel B;
the two injectors are respectively arranged on a channel A and a channel B of the double-channel micro-injection pump, needle heads of the two injectors are located at the same position, the double-channel micro-injection pump is started, the speed of the double-channel micro-injection pump is 0.01-0.05m/s, when the liquid amount pushed out by the channel A injector and the channel B injector is 0.2mL, the pushing is stopped, the liquid stays for 3 minutes, and finally the sodium alginate nano-microspheres containing the gadolinium mesoporous silica with the diameter of 3.8-4.2mm are formed at the positions of liquid outlets of the needle heads of the two injectors.
9. The preparation method of the sodium alginate microspheres containing gadolinium mesoporous silica as claimed in claim 8, wherein the speed of the dual-channel micro-injection pump is 0.03 m/s.
10. The application of the sodium alginate microspheres containing gadolinium mesoporous silica according to claim 1, prepared by the preparation method of claim 3, in registration fusion navigation of ultrasonic-magnetic resonance images, is characterized in that the sodium alginate microspheres containing gadolinium mesoporous silica are used as markers for registration fusion navigation of ultrasonic-magnetic resonance images.
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