CN111467509B - Phase-change nano diagnosis and treatment agent composite material, preparation method and application thereof - Google Patents
Phase-change nano diagnosis and treatment agent composite material, preparation method and application thereof Download PDFInfo
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Abstract
The invention relates to the technical field of medical biological nano materials, and discloses a phase-change nano diagnosis and treatment agent composite material which is characterized in that mesoporous carbon nano particles MCNs with mesopores on the surface and ordered pore channel structures inside are used as carriers, mesoporous carbon nano particles OMCNs obtained through oxidation modification are used as carriers, temperature-sensitive phase-change materials are loaded in the pore channel structures of the particles to obtain the composite material OMCNs-PFP, and the composite material OMCNs-PFP has small mesopore shape difference, uniform particle appearance and size, good water solubility and biocompatibility, and has the properties of optothermal effect and optoacoustic/ultrasonic imaging. The invention also discloses a preparation method and application of the composite material. The invention can realize the nano-scale structure of the composite material, and the composite material has good stability, uniformity and biocompatibility, high biological safety, easy mass production and easy industrialization.
Description
Technical Field
The invention relates to the technical field of medical biological nano materials, in particular to a mesoporous carbon-based phase-change nano diagnosis and treatment agent composite material, a preparation method and application thereof in tumor photothermal therapy and multi-mode imaging diagnosis.
Background
Under the long-term influence of carcinogenic factors, some tissues of the body can be diseased, the pathological changes are mostly caused by mutation at the gene level, the diseased and abnormal tissues of the body are called tumors, and malignant tumors are called cancers. Today, cancer is still a serious threat to human life and health worldwide, and the treatment of cancer is also a serious topic and problem to be overcome in medicine. Nanotechnology has been developed rapidly in recent years and can be applied in the field of multidisciplinary cross and comprehensive research. In the age of nanotechnology, the most representative is the appearance of nano materials, which now show wide application prospects in multiple subject fields such as materials, photoelectrons, energy, biomedicine and the like, and gradually become the research focus of scientists all over the world.
Due to its unique properties, nanomaterials are gaining increasing attention from the scientific community and countries around the world. In the field of cancer treatment, the characteristics of the nano material also provide a new research direction for cancer treatment and diagnosis. Due to the structure of a tumor microenvironment and the particularity of the size of the nano material, the nano material has high permeability and detention at a tumor part, is highly enriched at the tumor part and rarely exists in a normal tissue, and reduces the toxic and side effect of the nano material on an organism. The nanoparticles loaded with the cancer treatment drug are gathered at the tumor part, so that the drug utilization rate is improved, the drug diffusion to normal tissues is reduced, and the cancer treatment effect is improved.
The multifunctional molecular imaging technology combining multiple imaging modes with the contrast agent is mature day by day, not only can provide rich and comprehensive information of tumor tissue parts and facilitate better tumor diagnosis, but also can treat tumor focuses while imaging, and greatly improves the effect of accurate diagnosis and treatment of tumors. Among the techniques of medical noninvasive imaging, photoacoustic imaging, ultrasound imaging, and magnetic resonance imaging are most representative.
Photothermal therapy is a novel therapeutic method for achieving the purpose of treatment by increasing the local or overall temperature of the body. With the rapid development of nanotechnology, many nanomaterials have emerged in recent years that can efficiently convert light energy into heat. The organic solar cell comprises an inorganic metal material, an inorganic non-metal material and an organic photo-thermal material, and the photo-thermal materials can play a good role in treating tumors in the tumor treatment process. Although carbon nanorods and graphene in the carbon material have been widely used in medical research such as biosensing, bioimaging, photothermal therapy and the like, the poor dispersibility and stability limit further application of the carbon nanorods and graphene in organisms. However, many metal materials can not be effectively eliminated after being retained in vivo for a long time, so that the biological safety problem exists, and the clinical application of the metal materials is seriously hindered. Therefore, the combination of photothermal therapy and imaging techniques effectively benefits the treatment of tumors.
In the prior art, Chinese patent 201410712157.7 discloses a hollow mesoporous Prussian blue nano photothermal diagnostic agent with an ultrasonic contrast function and a preparation method thereofThe method comprises prussian blue nanoparticles with mesoporous surfaces and hollow interiors and a temperature-sensitive phase-change material loaded in the prussian blue nanoparticles, wherein the temperature-sensitive phase-change material comprises fluorocarbon and/or menthol. However, the technology of the patent has the disadvantages that: 1. the preparation process of the hollow mesoporous Prussian blue nanoparticles is time-consuming, and the particle size of the prepared nanoparticles is 100-500 nm, so that the hollow mesoporous Prussian blue nanoparticles cannot be effectively utilized in organisms; 2. the patent introduces that the Prussian blue is a dye, so that the prepared nano particles have poor stability to light and certain limitation on storage conditions; 3. in the sixth example of the patent, a high power density (5W/cm) is used2) The photothermal conversion characteristics are measured, and the excellent photothermal conversion characteristics of the prepared prussian blue nanoparticles cannot be proved; 4. in vitro cell photothermal therapy experiment and in vivo ultrasonic imaging experiment, the patent respectively uses 5W/cm2And 2W/cm2The power density is higher, which indicates that the biosafety of the material is not high enough.
The mesoporous carbon is a novel non-silicon-based mesoporous material with the particle size of 2nm<Pore diameter<50nm, and has huge specific surface area (up to 2500 m)2Per gram) and pore volume (up to 2.25cm3And/g) are currently used in catalyst carriers, hydrogen storage materials, electrode materials and other aspects. However, the existing preparation process of mesoporous carbon is complicated, the controllability of conditions is poor, the prepared nano material has large difference of aperture size and mesoporous shape, the uniformity of appearance is poor, and industrialization is difficult; meanwhile, the surface performance of the material is poor, so that the stability of the material prepared by the material is poor.
The template method is an important method for controlling the morphology and size of crystals, and is divided into a hard template and a soft template according to the characteristics of the template and the difference of the domain-limiting capacity, wherein the soft template mainly comprises various ordered polymers formed by amphiphilic molecules, such as liquid crystals, micelles, microemulsions, vesicles, LB membranes, self-assembled membranes and the like, and macromolecular self-organization structures, biological macromolecules and the like. The soft template has the main characteristics that: (1) as the soft templates are mostly ordered aggregates formed by amphiphilic molecules, the soft templates have the greatest characteristic of having absolute advantages in the aspect of simulating biomineralization; (2) the shape of the soft template has diversity; (3) soft forms are generally easy to construct and do not require complex equipment. The application of the soft template method is gradually increased due to the advantages of simple method, convenient operation, low cost and the like, but the application of the soft template method is limited because the size and the shape of a product cannot be strictly controlled.
In view of the above disadvantages, there is a need to develop a new nano-composite material with good stability, good morphology uniformity and good biological safety and a preparation process thereof, and a new nano-composite material is obtained by synchronously improving the material and the process, so that the nano-composite material can be used as a novel material for both photo-thermal treatment and contrast agent, and the purpose of integrating photo-thermal treatment and imaging diagnosis and treatment is satisfied.
Disclosure of Invention
The invention provides a new nano diagnosis and treatment agent composite material based on mesoporous carbon and soft template method and a preparation process aiming at the defects of the prior art, and the preparation method has the characteristics of simplicity, convenience, good condition controllability and easy industrialization by synchronously improving the material components and the process; and the prepared composite material has the characteristics of good stability, high uniformity of appearance and size and high biological safety, and can meet the integrated requirements of clinical diagnosis and treatment, namely photo-thermal treatment and photo-thermal imaging/ultrasonic imaging, so that the composite material can be applied to the diagnosis and treatment process of tumor diagnosis and treatment integration, and the diagnosis and treatment effect can be greatly improved.
In order to achieve the purpose, the invention adopts the following technical scheme:
a phase-change nano diagnosis and treatment agent composite material is characterized in that mesoporous carbon nano particles MCNs with mesopores on the surface and ordered pore canal structures inside are used as carriers, mesoporous carbon nano particles OMCNs obtained through oxidation modification are used as carriers, temperature-sensitive phase-change materials are loaded in the pore canal structures of the particles to obtain the composite material OMCNs-PFP, and the composite material has the advantages of small mesopore shape difference, uniform particle appearance and size, good water solubility and biocompatibility, and optothermal effect and optoacoustic/ultrasonic imaging attributes.
In the finished dry matter of the composite material OMCNs-PFP, the mass fraction of the mesoporous carbon nano-particles OMCNs is 95-97.0%, and the mass fraction of the temperature-sensitive phase-change material PFP is 3.0-5%; the temperature-sensitive phase-change material PFP is perfluoro-n-pentane.
The preparation method of the phase-change nano diagnosis and treatment agent composite material is characterized by comprising the following steps of:
(1) preparing mesoporous carbon nano-particle MCNs: dissolving 0.96g F127 in 15mL of deionized water by adopting a soft template method; accurately weighing 0.6g of phenol, 2.1mL of formaldehyde and 15mL of 0.1 mol.L-1NaOH is evenly mixed at the temperature of 70 ℃ for 340 r.min-1Stirring at constant speed for 0.5 hour at the rotating speed to synthesize the low molecular weight phenolic resin; then pouring the dissolved F127 into phenolic resin, changing the temperature to 66 ℃, continuously stirring for 2 hours, adding 50mL of deionized water, and continuously stirring for 16-18 hours until the precipitate is dissolved; after dissolving the precipitate, taking 17.7mL of dissolved liquid, uniformly diluting with 56mL of deionized water, and transferring into a high-pressure reaction kettle; taking out after carrying out hydrothermal reaction for 24 hours at the temperature of 130 ℃, cleaning the obtained product by using deionized water for centrifugal separation, drying and grinding the obtained product, putting the obtained product into a tubular furnace, calcining the obtained product for 3 hours at the temperature of 700 ℃ under the protection of nitrogen, and fully grinding the burnt black particles to obtain mesoporous carbon nano-particles MCNs with mesopores on the surface and ordered pore structure in the interior;
(2) preparing oxidation modified mesoporous carbon nano-particles OMCNs: adding the obtained mesoporous carbon nano-particle powder into a double-mouth bottle, adding 4mL of mixed solution of concentrated sulfuric acid and concentrated nitric acid into the bottle, wherein the volume ratio of sulfuric acid to nitric acid is 3:1, carrying out ultrasonic and heating stirring for 2 hours respectively, continuously washing with ultrapure water, centrifuging to obtain surface oxidation modified mesoporous carbon nano-particles, and dispersing in an aqueous solution;
(3) preparing composite material OMCNs-PFP: and (3) vacuumizing and stirring the obtained oxidized mesoporous carbon nano particle aqueous solution by 3mg/L, adding the temperature-sensitive type phase change material PFP according to the volume ratio of 1:20, and washing with ultrapure water to obtain the phase change nano diagnostic agent composite material OMCNs-PFP.
The step (1) comprises the following specific steps:
(11) dissolving 0.96g F127 in 15mL of deionized water; accurately weighing 0.6g of phenol, 2.1mL of formaldehyde and 15 mL0.1mol.L-1NaOH is evenly mixed at the temperature of 70 ℃ for 340 r.min-1Stirring at constant speed for 0.5 hour at the rotating speed to synthesize the low molecular weight phenolic resin; then pouring the dissolved F127 into phenolic resin, changing the temperature to 66 ℃, continuously stirring for 2 hours, adding 50mL of deionized water, and continuously stirring for 16-18 hours;
(12) after standing, precipitating and dissolving, taking 17.7mL of dissolved liquid, uniformly diluting with 56mL of deionized water, and transferring into a high-pressure reaction kettle; carrying out hydrothermal reaction at the temperature of 130 ℃ for 24 hours, taking out, and cooling to room temperature;
(13) and (3) cleaning the product by using deionized water for centrifugal separation, drying, grinding, putting the product into a tubular furnace, calcining the product for 3 hours at the temperature of 700 ℃ under the protection of nitrogen, and uniformly grinding the product by using a grinding bowl to obtain the mesoporous carbon nanoparticles.
The formaldehyde used in the step (11) is 37% formaldehyde aqueous solution; adding F127 into deionized water 4-6 hours in advance and placing at 4 ℃ for accelerated dissolution; after stirring for 16-18 hours, when the solution is precipitated, immediately stopping stirring and standing until the precipitate is dissolved and disappears.
The step (2) comprises the following specific steps:
(21) uniformly grinding the calcined product to obtain powdery mesoporous carbon nanoparticles, and adding the powdery mesoporous carbon nanoparticles into a 25mL double-mouth bottle;
(22) adding 4mL of mixed solution of concentrated sulfuric acid and concentrated nitric acid into a bottle, wherein the volume ratio of sulfuric acid to nitric acid is 3:1, ultrasonically treating and heating and stirring for 2 hours respectively, continuously washing with ultrapure water, centrifuging to obtain mesoporous carbon nanoparticles with surface oxidation modification, and dispersing in an aqueous solution.
The heating and stirring temperature in the step (22) is 60 ℃, and the rotating speed is 750 r/min; centrifuging an acid product obtained by ultrasonic and heating stirring in the step (22), and centrifugally washing a centrifugal precipitate by using ultrapure water, wherein the centrifugal rotating speed is 13000 r/min;
in the step (2), washing the centrifugal precipitate with ultrapure water until the pH of the centrifugal supernatant is neutral; in the step (3), the processes of centrifugation, washing and freeze drying are as follows: centrifuging for 10-15 min at 13000r/min by using a freezing high-speed centrifuge; and then washed several times with deionized water.
The application of the phase-change nano diagnosis and treatment agent composite material is characterized in that the phase-change nano diagnosis and treatment agent composite material is used as a material for preparing a photoacoustic imaging and ultrasonic imaging contrast agent.
The application of the phase-change nano diagnosis and treatment agent composite material is characterized in that the phase-change nano diagnosis and treatment agent composite material is used as a material for preparing a photothermal reagent for near-infrared photothermal treatment.
The invention has the advantages that:
(1) aiming at the defects that other common mesoporous carbon nanoparticles are synthesized by a hard template method, the process is complex, the process controllability is poor, the mesoporous carbon nanoparticles with ordered pore structures inside cannot be prepared and the like, the composite material and the preparation method thereof provided by the invention have the key points that the components and the preparation process are improved simultaneously, an improved soft template method is adopted, a precursor is synthesized based on mesoporous carbon, and a product is obtained by calcining, so that the mesoporous carbon nanoparticles MCNs with mesoporous surfaces and ordered pore structures inside are obtained; the synthesis process has the advantages of few steps and convenient operation, and the size and the shape of the product can be strictly controlled. The preparation process of the composite material is efficient, stable and high in repeatability. The invention can realize the nano-scale structure, and has the advantages of good stability, uniformity, biocompatibility, high biological safety, easy mass production and easy industrialization.
(2) The phase change nano diagnosis and treatment agent composite material based on mesoporous carbon provided by the invention is characterized in that mesoporous carbon nano particles MCNs with mesopores on the surface and ordered pore structure inside are expanded and applied to the field of biological medicine, and are modified by using a conventional strong acid oxidation mode, so that the water solubility of the nano particle MCNs composite material is increased, and the biological safety of the nano particle MCNs composite material is improved. Meanwhile, the material has degradable performance, overcomes the danger that a plurality of inorganic materials stay in the body for a long time at present, and can be used as an inorganic nano platform material for manufacturing and removing in time.
(3) The phase change nano diagnosis and treatment agent composite material based on the mesoporous carbon provided by the invention is characterized in that the surface of the nano particle material is modified, and the interior of the nano particle material has an ordered pore structure, so that the nano particle material has excellent biocompatibility, can more uniformly load a temperature-sensitive phase change material, and has better consistency when the phase change occurs. The nano material prepared by the invention has high photo-thermal conversion efficiency in a near infrared region, can be used for preparing a photo-thermal therapeutic agent to be applied to photo-thermal treatment, has the photo-acoustic/ultrasonic multi-mode imaging property, can be used for preparing a multi-mode imaging diagnosis and treatment agent to be applied to the diagnosis and treatment integrated treatment process of cancers, and has a very wide application prospect in biomedicine.
(4) The phase-change nano diagnosis and treatment agent composite material based on the mesoporous carbon nano can be widely applied to the manufacture of diagnosis agents or treatment agents in tumor photothermal therapy and multi-mode imaging. The composite material has application values of photothermal therapy, photoacoustic imaging, ultrasonic imaging and the like, has small particle size and good consistency of size and appearance, and has a wide application prospect in the fields of tumor diagnosis, treatment and the like.
The present invention will be described in further detail with reference to the accompanying drawings and specific embodiments.
Drawings
Fig. 1 is an electron microscope image of the phase-change nano diagnosis and treatment agent composite material prepared by the embodiment of the invention.
Fig. 2 is a pore size analysis diagram of the phase-change nano-composite medical agent prepared according to the embodiment of the present invention.
Fig. 3 is a dynamic light scattering diagram of the phase-change nano diagnostic and therapeutic agent composite material OMCNs prepared by the embodiment of the present invention in water.
Fig. 4 is an ultraviolet absorption diagram of the phase-change nano diagnosis and treatment agent composite material prepared by the embodiment of the invention.
FIG. 5 is a photo-thermal graph of the phase-change nano-composite medical agent prepared according to the embodiment of the present invention, wherein the light irradiation condition is 1W/cm2(a) And 2W/cm2(b) 808nm near infrared illumination.
Fig. 6 is a graph showing the effect of the nanomaterial on resisting HeLa cell proliferation in the absence of near-infrared light on the phase-change nano diagnostic agent composite material prepared by the embodiment of the present invention.
Fig. 7 is a graph showing the effect of the nanomaterial on resisting HeLa cell proliferation in the absence of near-infrared light on the phase-change nano diagnostic agent composite material prepared by the embodiment of the present invention. Wherein the illumination condition is 1W/cm2And (3) performing near-infrared illumination at 808nm for 5 min.
Fig. 8 shows a photoacoustic imaging graph (a) and a signal intensity quantitative graph (b) of the phase-change nano diagnostic agent composite material as a photoacoustic contrast agent enhanced HeLa tumor prepared by the embodiment of the present invention.
Fig. 9 is a tumor growth curve diagram in an inhibition experiment of a photothermal reagent prepared from the phase-change nano diagnosis and treatment agent composite material for resisting a HeLa cell tumor-bearing Balb/C mouse tumor.
FIG. 10 is a weight change curve of Balb/C mice in the inhibition experiment of the photothermal reagent prepared from the phase-change nano diagnosis and treatment agent composite material for resisting the tumor of the Balb/C mice with HeLa cells.
Detailed Description
Referring to fig. 1 to 10, the technical solution of the present invention is explained in detail by the following embodiments and drawings.
Example 1:
the phase-change nano diagnosis and treatment agent composite material provided by the embodiment of the invention is a composite material OMCNs-PFP obtained by loading a temperature-sensitive phase-change material in a particle pore passage structure by taking mesoporous carbon nano particles MCNs with mesopores on the surface and an ordered pore passage structure in the interior as a carrier and taking mesoporous carbon nano particles OMCNs obtained by oxidation modification, and the composite material OMCNs-PFP has the advantages of small mesopore shape difference, uniform particle appearance and size, good water solubility and biocompatibility, and has the properties of photo-thermal effect and photo-acoustic/ultrasonic imaging.
In the finished dry matter of the composite material OMCNs-PFP, the mass fraction of the mesoporous carbon nano-particles OMCNs is 95-97.0%, and the mass fraction of the temperature-sensitive phase-change material PFP is 3.0-5%; the temperature-sensitive phase-change material PFP is perfluoro-n-pentane. Compared with other existing porous materials, the composite material can load more temperature-sensitive phase-change materials, the loading capacity of the composite material is 2-3 times that of the prior art, and the water solubility, stability, biocompatibility and biological safety of the material are greatly improved. In this embodiment, the mass fraction of the mesoporous carbon nanoparticles OMCNs is 95%, and the mass fraction of the temperature-sensitive phase change material PFP is 5%.
The preparation method of the phase-change nano diagnosis and treatment agent composite material comprises the following steps:
(1) preparing mesoporous carbon nano-particle MCNs: dissolving 0.96g F127 in 15mL of deionized water by adopting a soft template method; accurately weighing 0.6g of phenol, 2.1mL of formaldehyde and 15mL of 0.1 mol.L-1NaOH is evenly mixed at the temperature of 70 ℃ for 340 r.min-1Stirring at constant speed for 0.5 hour at the rotating speed to synthesize the low molecular weight phenolic resin; then pouring the dissolved F127 into phenolic resin, changing the temperature to 66 ℃, continuously stirring for 2 hours, adding 50mL of deionized water, and continuously stirring for 16-18 hours until the precipitate is dissolved; after dissolving the precipitate, taking 17.7mL of dissolved liquid, uniformly diluting with 56mL of deionized water, and transferring into a high-pressure reaction kettle; taking out after carrying out hydrothermal reaction for 24 hours at the temperature of 130 ℃, cleaning the obtained product by using deionized water for centrifugal separation, drying and grinding the obtained product, putting the obtained product into a tubular furnace, calcining the obtained product for 3 hours at the temperature of 700 ℃ under the protection of nitrogen, and fully grinding the burnt black particles to obtain mesoporous carbon nano-particles MCNs with mesopores on the surface and ordered pore structure in the interior;
(2) preparing oxidation modified mesoporous carbon nano-particles OMCNs: adding the obtained mesoporous carbon nano-particle powder into a double-mouth bottle, adding 4mL of mixed solution of concentrated sulfuric acid and concentrated nitric acid into the bottle, wherein the volume ratio of sulfuric acid to nitric acid is 3:1, carrying out ultrasonic and heating stirring for 2 hours respectively, continuously washing with ultrapure water, centrifuging to obtain surface oxidation modified mesoporous carbon nano-particles, and dispersing in an aqueous solution;
(3) preparing composite material OMCNs-PFP: and (3) vacuumizing and stirring the obtained oxidized mesoporous carbon nano particle aqueous solution by 3mg/L, adding the temperature-sensitive type phase change material PFP according to the volume ratio of 1:20, and washing with ultrapure water to obtain the phase change nano diagnostic agent composite material OMCNs-PFP.
The step (1) comprises the following specific steps:
(11) dissolving 0.96g F127 in 15mL of deionized water; accurately weighing 0.6g of phenol, 2.1mL of formaldehyde and 15 mL0.1mol.L-1NaOH is evenly mixed at 70 DEG CAt 340 r.min at temperature-1Stirring at constant speed for 0.5 hour at the rotating speed to synthesize the low molecular weight phenolic resin; then pouring the dissolved F127 into phenolic resin, changing the temperature to 66 ℃, continuously stirring for 2 hours, adding 50mL of deionized water, and continuously stirring for 16-18 hours;
wherein the formaldehyde used is 37% formaldehyde aqueous solution; adding F127 into deionized water 4-6 hours in advance and placing at 4 ℃ for accelerated dissolution; after stirring for 16-18 hours, when the solution is precipitated, immediately stopping stirring and standing until the precipitate is dissolved and disappears;
(12) after standing, precipitating and dissolving, taking 17.7mL of dissolved liquid, uniformly diluting with 56mL of deionized water, and transferring into a high-pressure reaction kettle; carrying out hydrothermal reaction at the temperature of 130 ℃ for 24 hours, taking out, and cooling to room temperature;
(13) and (3) cleaning the product by using deionized water for centrifugal separation, drying, grinding, putting the product into a tubular furnace, calcining the product for 3 hours at the temperature of 700 ℃ under the protection of nitrogen, and uniformly grinding the product by using a grinding bowl to obtain the mesoporous carbon nanoparticles.
The step (2) comprises the following specific steps:
(21) uniformly grinding the calcined product to obtain powdery mesoporous carbon nanoparticles, and adding the powdery mesoporous carbon nanoparticles into a 25mL double-mouth bottle;
(22) adding 4mL of mixed solution of concentrated sulfuric acid and concentrated nitric acid into a bottle, wherein the volume ratio of sulfuric acid to nitric acid is 3:1, ultrasonically treating and heating and stirring for 2 hours respectively, continuously washing with ultrapure water, centrifuging to obtain mesoporous carbon nanoparticles with surface oxidation modification, and dispersing in an aqueous solution. Washing the centrifugal precipitate with ultrapure water until the pH of the centrifugal supernatant is neutral; in the step (3), the processes of centrifugation, washing and freeze drying are as follows: centrifuging for 10-15 min at 13000r/min by using a freezing high-speed centrifuge; then washing the mixture for many times by deionized water; wherein the heating and stirring temperature is 60 ℃, and the rotating speed is 750 r/min; centrifuging the acid product obtained by ultrasonic and heating stirring in the step (22), and centrifugally washing the centrifugal precipitate with ultrapure water at the centrifugal speed of 13000r/min.
The phase-change nano diagnosis and treatment agent composite material is applied to preparing photoacoustic imaging and ultrasonic imaging contrast agents.
The application of the phase-change nano diagnosis and treatment agent composite material is used as a material for preparing a near-infrared photothermal treatment photothermal reagent.
The phase-change nano diagnosis and treatment agent composite material is synthesized by adopting an improved 'soft template' method and mesoporous carbon and is modified by strong acid oxidation, so that the characteristics of good stability, high biological safety, high proportion of loaded phase-change materials and the like can be achieved.
FIG. 1 is a TEM photograph of the mesoporous carbon nanomaterial prepared in this example 1, and it can be seen from observation that the particles are uniformly dispersed, which proves that the method of the present invention can obtain a nanomaterial with good morphology and good monodispersity; and the average particle size of the oxidized nano particles is about 100nm, which has important significance for circulation in organisms.
FIG. 2 is a pore size analysis diagram of the mesoporous carbon nanomaterial prepared in this example 1. Nitrogen adsorption-desorption mode they were tested. According to the nitrogen adsorption-desorption isothermal curve, the mesoporous carbon nanomaterial shows a typical IV-type isothermal line, the aperture of the synthesized mesoporous carbon nanomaterial is calculated to be about 1.9nm by using a Barrett-Joyner-Halenda (BJH) method according to the nitrogen adsorption-desorption isothermal curve, and the mesoporous carbon nanomaterial basically meets the specification (2-50nm) of the mesoporous size; the specific surface area of the mesoporous nano-particles is calculated to be 513.17m2/g.
Fig. 3 is a dynamic light scattering diagram of the mesoporous carbon nanomaterial prepared in this example 1 in water. And (3) putting 1mL of the nano material in a cuvette, and measuring the average particle size of the nano material by using a dynamic light scattering instrument to be 200nm and the distribution coefficient PDI to be 0.3.
FIG. 4 is the ultraviolet absorption chart of the nanomaterial prepared in this example 1. Preparing the nano material with the nano particle concentration of 200 mug/mL, putting 1mL into a cuvette, and measuring the absorption value of the nano material in the range of 400-1100 nm by using an ultraviolet spectrophotometer, wherein the nano material has strong absorption in a near infrared region.
Example 2:
the phase change nano diagnostic agent composite material based on mesoporous carbon, the preparation method and the application thereof provided in this embodiment are basically the same as those in embodiment 1, and the differences are as follows:
in the finished dry matter of the composite material OMCNs-PFP, the mass fraction of the mesoporous carbon nano-particles OMCNs is 95.5%, and the mass fraction of the temperature-sensitive phase-change material PFP is 4.5%.
The preparation method of the phase change nanometer diagnostic reagent composite material based on mesoporous carbon provided by the embodiment comprises the following steps:
(1) dissolving 0.98g F127 in 15mL of deionized water by adopting a soft template method; accurately weighing 0.65g of phenol, 2.1mL of formaldehyde and 15mL of 0.1 mol.L-1NaOH is evenly mixed at the temperature of 70 ℃ for 340 r.min-1Stirring at constant speed for 30min at a rotating speed to synthesize low molecular weight phenolic resin; then pouring the dissolved F127 into phenolic resin, changing the temperature to 66 ℃, continuously stirring for 2h, adding 50mL of deionized water, and continuously stirring for 16-18 h until the precipitate is dissolved; after dissolving the precipitate, taking 17.7mL of dissolved liquid, uniformly diluting with 56mL of deionized water, and transferring into a high-pressure reaction kettle; carrying out hydrothermal reaction at 130 ℃ for 24h, taking out, carrying out centrifugal separation, cleaning with deionized water, drying, grinding, putting into a tubular furnace, calcining at 700 ℃ under the protection of nitrogen for 3h, and fully grinding the burnt black particles to obtain mesoporous carbon nanoparticles;
(2) adding the obtained mesoporous carbon nano-particle powder into a double-mouth bottle, adding 4mL of mixed solution of concentrated sulfuric acid and concentrated nitric acid into the bottle, wherein the volume ratio of sulfuric acid to nitric acid is 3:1, carrying out ultrasonic and heating stirring for 2 hours respectively, washing with ultrapure water continuously, centrifuging to obtain surface oxidation modified mesoporous carbon nano-particles, and dispersing in aqueous solution.
(3) And (3) cleaning the obtained product by using deionized water for centrifugal separation, drying, grinding, putting the product into a tubular furnace, calcining for 3 hours at the temperature of 700 ℃ under the protection of nitrogen, and uniformly grinding the product by using a grinding bowl to obtain the composite mesoporous carbon nano-particles, namely the phase-change nano diagnostic agent composite material.
The step (1) comprises the following specific steps:
(11) dissolving 0.98g F127 in 15mL of deionized water; accurately weighing 0.65g of phenol, 2.1mL of formaldehyde and 15 mL0.1mol.L-1NaOH is evenly mixed at the temperature of 70 ℃ for 340 r.min-1Stirring at constant speed for 30min at a rotating speed to synthesize low molecular weight phenolic resin; then pouring the dissolved F127 into phenolic resin, changing the temperature to 66 ℃, continuously stirring for 2 hours, adding 50mL of deionized water, and continuously stirring for 16-18 hours;
(12) after standing, precipitating and dissolving, taking 17.7mL of dissolved liquid, uniformly diluting with 56mL of deionized water, and transferring into a high-pressure reaction kettle; carrying out hydrothermal reaction at the temperature of 130 ℃ for 24 hours, taking out, and cooling to room temperature;
(13) and (3) cleaning the obtained product by using deionized water for centrifugal separation, drying and grinding the product, then putting the product into a tubular furnace, calcining the product for 3 hours at the temperature of 700 ℃ under the protection of nitrogen, and uniformly grinding the product by using a grinding pot to obtain the mesoporous carbon nano particle composite material.
The formaldehyde used in the step (1) is 37% formaldehyde aqueous solution.
In the step (1), F127 is added into deionized water 4-6 hours in advance and placed at 4 ℃ for accelerated dissolution.
After stirring for 16-18 h in the step (1), precipitating the solution, and then stopping stirring and standing until the precipitate is dissolved and disappears;
the mesoporous carbon nanoparticles in the step (1) are MCNs.
The step (2) comprises the following specific steps:
(21) uniformly grinding the calcined product to obtain powdery mesoporous carbon nanoparticles, and adding the powdery mesoporous carbon nanoparticles into a 25mL double-mouth bottle;
(22) adding 4mL of mixed solution of concentrated sulfuric acid and concentrated nitric acid into a bottle, wherein the volume ratio of sulfuric acid to nitric acid is 3:1, ultrasonically stirring and heating for 2h respectively, washing with ultrapure water continuously, centrifuging to obtain mesoporous carbon nanoparticles with surface oxidation modification, and dispersing in aqueous solution.
The oxidized and modified mesoporous carbon nano particles in the step (2) are OMCNs;
the heating and stirring temperature in the step (2) is 60 ℃, and the rotating speed is 750r/min.
Centrifuging the acid product obtained by ultrasonic and heating stirring in the step (2), and centrifugally washing the centrifugal precipitate with ultrapure water at the centrifugal speed of 13000r/min.
And (3) in the step (2), washing the centrifugal precipitate with ultrapure water until the pH value of the centrifugal supernatant is neutral.
More specifically, the preparation method of the mesoporous carbon nanomaterial comprises the following steps:
(1) dissolving 0.98g F127 in 15mL of deionized water; accurately weighing 0.65g of phenol, 2.1mL of formaldehyde and 15 mL0.1mol.L-1Uniformly mixing NaOH at 70 ℃ and stirring at a constant speed of 340r/min for 30min to synthesize the low-molecular-weight phenolic resin;
(2) then pouring the dissolved F127 into phenolic resin, changing the temperature to 66 ℃, continuously stirring for 2h, adding 50mL of deionized water, continuously stirring for 16-18 h, observing whether a precipitate is generated, and stopping the reaction after the precipitate is generated; standing for a period of time, precipitating and dissolving, uniformly diluting 17.7mL of dissolved liquid with 56mL of deionized water, and transferring into a high-pressure reaction kettle; carrying out hydrothermal reaction at 130 ℃ for 24h, taking out, naturally cooling to room temperature, taking out the product, carrying out centrifugal separation, cleaning with deionized water, drying, grinding, putting into a tubular furnace, heating to 700 ℃ at a heating rate of 5 ℃/min under the protection of nitrogen, calcining for 3h, and fully grinding the fired black particles to obtain powdery mesoporous carbon nanoparticles;
(3) the resulting mesoporous carbon powder was added to a 20mL single neck flask, followed by addition of concentrated sulfuric acid (H)2SO4) And concentrated nitric acid (HNO)3) 4mL of mixed acid and the volume ratio of the sulfuric acid to the nitric acid is 3:1, and the step needs to be carried out slowly. And (3) after the mixture is subjected to ultrasonic treatment in an ultrasonic machine for 2 hours, stirring the mixture for 2 hours at the temperature of 60 ℃, wherein the rotating speed is 750r/min, centrifuging the obtained acid solution to remove excessive mixed acid solution, washing the precipitate by using ultrapure water, and repeatedly centrifuging the precipitate for many times at the centrifugal rotating speed of 13000r/min until the pH of the centrifuged supernatant is neutral to obtain the oxidized mesoporous carbon nanoparticles with good water solubility and dispersibility, namely the phase-change nano diagnostic agent composite material.
Example 3
The phase-change nano diagnosis and treatment agent composite material based on mesoporous carbon, the preparation method and the application provided by the embodiment are basically the same as those of the embodiments 1 and 2, and the difference is as follows:
in the finished dry matter of the composite material OMCNs-PFP, the mass fraction of the mesoporous carbon nano-particles OMCNs is 96%, and the mass fraction of the temperature-sensitive phase-change material PFP is 4%.
The method specifically uses the prepared phase-change nano diagnosis and treatment agent composite material as a material for preparing a near-infrared photothermal treatment photothermal reagent, and then is applied to a photothermal experiment, and comprises the following steps:
(1) respectively preparing the phase-change nano diagnosis and treatment agent composite materials with nano particle concentrations of 50 mug/mL, 100 mug/mL, 150 mug/mL and 200 mug/mL by using ultrapure water;
(2) taking 1mL of each of the samples in a cuvette, and using a 808nm laser at 1W/cm2And 2W/cm2Performing illumination at the power density of (a);
(3) the temperature rise of the materials with different concentrations along with the irradiation time is detected and monitored by a miniature thermocouple.
FIG. 5 is a photothermal graph of the nanomaterial prepared in example 2. The observation proves that the temperature of the sample gradually rises along with the increase of the concentration of the sample, and the prepared phase-change nano diagnosis and treatment agent composite material has good photo-thermal effect and high photo-stability.
Example 4:
the phase-change nano diagnosis and treatment agent composite material based on mesoporous carbon, the preparation method and the application provided by the embodiment are basically the same as those of the embodiments 1 to 3, and the difference is that:
in the finished dry matter of the composite material OMCNs-PFP, the mass fraction of the mesoporous carbon nano-particles OMCNs is 96.5%, and the mass fraction of the temperature-sensitive phase-change material PFP is 3.5%.
The application of the phase-change nano diagnosis and treatment agent composite material is used as a material for preparing a photoacoustic imaging and ultrasonic imaging contrast agent or a photothermal agent for near-infrared photothermal treatment, and the in-vitro toxicity verification and evaluation method comprises the following steps:
(1) preparing 30-40mg of water solution of the variable nano diagnosis and treatment agent composite material in a 20mL double-mouth bottle;
(2) vacuumizing and stirring the solution for 2min at the rotating speed of 750 r/min; then the vacuum was stopped and 100. mu.L of PFP solution was injected;
(3) ultrasonically treating the whole system in ice water for 2min, centrifugally washing the obtained product with ultrapure water for multiple times to remove redundant PFP, wherein the centrifugal speed is 13000r/min, and finally dispersing the obtained nano composite material in the ultrapure water and hermetically storing at 4 ℃;
(4) HeLa cell suspension was added to 96-well plates in 5% CO2After overnight culture in a constant-temperature incubator with 37 ℃ and the concentration of 95% humidity, the concentration of the nano particles is prepared to be 0 mu g/mL; adding 50 mu g/mL,100 mu g/mL,150 mu g/mL and 200 mu g/mL of the nano material into a 96-well plate, and incubating for 24 hours in an incubator;
(5) after that, the culture solution is absorbed, 100 mul of culture medium containing 10 mul of CCK-8 reagent is added into each hole to be cultured for 3h in an incubator, the absorbance value under each concentration is read by a microplate reader, and the relationship between the cell survival rate and the nano material concentration is plotted by calculating the absorbance value.
The nano composite material in the step (4) is OMCNs-PFP.
Fig. 6 is a graph showing the effect of the nanomaterial on the proliferation of HeLa cells in the absence of near-infrared light on the mesoporous carbon-based phase-change nano diagnostic and therapeutic agent composite material prepared in example 3. As can be seen from the figure, after the HeLa cell and the nanoparticles are incubated for 24h, the cell proliferation rate is only slightly influenced, and even at a concentration of 200 mug/mL, the proliferation rate is still more than 90%, which shows that the nano material has no significant influence on the proliferation capacity of the cells, and proves that the nano material has very low cytotoxicity and is very important for biological safety.
Example 5:
the phase-change nano diagnosis and treatment agent composite material based on mesoporous carbon, the preparation method and the application provided by the embodiment are basically the same as those of the embodiments 1 to 4, and the difference is that:
in the finished dry matter of the composite material OMCNs-PFP, the mass fraction of the mesoporous carbon nano-particles OMCNs is 97.0%, and the mass fraction of the temperature-sensitive phase-change material PFP is 3.0%.
The application of the prepared phase-change nano diagnosis and treatment agent composite material is used as a method for preparing a material of a near-infrared photothermal treatment photothermal reagent, and the method is specifically used as a method for testing the in-vitro photothermal treatment effect of the phase-change agent loaded nano diagnosis and treatment agent composite material, and comprises the following steps:
(1) HeLa cell suspension was added to 96-well plates in 5% CO2Culturing overnight in a 37 ℃ constant temperature incubator with the concentration and the humidity of 95%;
(2) preparation example 3 the prepared nanoparticles were at a concentration of 0. mu.g/mL; adding 50 mu g/mL,100 mu g/mL,150 mu g/mL and 200 mu g/mL of the nano material into a 96-well plate, and incubating for 4 hours;
(3) using 808nm laser at 2W/cm2Irradiating the pore plate for 5min by using power density;
(4) after that, the culture solution is absorbed, 100 mul of culture medium containing 10 mul of CCK-8 reagent is added into each hole to be cultured for 3h in an incubator, the absorbance value under each concentration is read by a microplate reader, and the relationship between the cell survival rate and the nano material concentration is plotted by calculating the absorbance value.
FIG. 7 is a graph showing the effect of the nanomaterial prepared in example 4 on the proliferation of HeLa cells in the absence of near-infrared light. As can be seen from the figure, after laser irradiation, the cell survival rate is reduced along with the increase of the concentration of the nano material, and the cell survival rate is rapidly reduced at higher concentration, which indicates that the nano composite material has the potential to be used as a photo-thermal therapeutic agent.
Example 6
The phase-change nano diagnosis and treatment agent composite material based on mesoporous carbon, the preparation method and the application provided by the embodiment are basically the same as those of the embodiments 1 to 5, and the difference is that:
in the finished dry matter of the composite material OMCNs-PFP, the mass fraction of the mesoporous carbon nano-particles OMCNs is 95.1%, and the mass fraction of the temperature-sensitive phase-change material PFP is 4.9%.
The phase-change nano diagnosis and treatment agent composite material is specifically used as a nano diagnosis and treatment agent composite material loaded with a phase-change agent, is used as a material for preparing photoacoustic imaging and ultrasonic imaging contrast agents, is applied to a method for in-vivo photoacoustic imaging, and comprises the following steps:
(1) inoculating a female Balb/C mouse with a HeLa tumor, and injecting 100 mu L of mesoporous carbon-based phase change nano diagnosis and treatment agent composite material into the tumor when the tumor diameter is 6-8 mm;
(2) according to the different injection time, 808nm laser is used at 1W/cm2Irradiating the tumor part for 5min under power, and performing photoacoustic imaging and ultrasonic imaging observation by using an ultrasonic imaging system.
Fig. 8 is a graph (a) of photoacoustic imaging of HeLa tumor enhanced by the nano material prepared in example 5 as a photoacoustic contrast agent and a graph (b) of signal intensity quantification. Therefore, the prepared composite material can provide a clearer and more accurate diagnosis window for the interior of the in-situ HeLa tumor.
Example 7
The phase-change nano diagnosis and treatment agent composite material based on mesoporous carbon, the preparation method and the application provided by the embodiment are basically the same as those of the embodiments 1 to 6, and the difference is that:
in the finished dry matter of the composite material OMCNs-PFP, the mass fraction of the mesoporous carbon nano-particles OMCNs is 95.8%, and the mass fraction of the temperature-sensitive phase-change material PFP is 4.2%.
The phase-change nano diagnosis and treatment agent composite material provided by the invention is specifically used as a nano diagnosis and treatment agent composite material loaded with a phase-change agent, is prepared into a nano diagnosis and treatment agent, and is applied to a method for in-vivo tumor photothermal treatment, and the method comprises the following steps:
(1) inoculating female Balb/C mice with HeLa tumor until the tumor diameter is 6-8 mm;
(2) dividing the tumor-bearing nude mice into 6 groups, respectively, controlling, PBS + NIR, OMCNs, OMCNs-PFP, OMCNs + NIR, OMCNs-PFP + NIR, injecting 100 μ L PBS, OMCNs or OMCNs-PFP for 2h to each group of nude mice, irradiating the nude mice of the group with laser, and irradiating the nude mice with 808nm laser at 1W/cm2Irradiating the tumor part under power for 10min, with time interval of 3min, injecting material and irradiating with laser every three days, and recording the tumor volume and weight of nude mice every other day for 14 days.
FIG. 9 tumor growth curve diagram in the inhibition experiment of the nanomaterial prepared in example 6 against the tumor-bearing Balb/C mouse tumor of HeLa cells. The tumor growth was rapid in the group not irradiated with laser, and in addition, the tumor volume remained increasing for the PBS + NIR group, indicating that the nanoparticles did not inhibit tumor growth inside the tumor. After the tumor mouse is injected with the nano material and is irradiated by laser, the change of the tumor volume is found to be in a descending trend in the observation of the tumor volume in 14 days, and the growth of the tumor is obviously inhibited, which indicates that the nano composite material can be used as a photo-thermal therapeutic agent for the photo-thermal treatment of the tumor.
FIG. 10 is the weight change curve of Balb/C mice in the inhibition experiment of the nanomaterial prepared in example 6 against the tumor-bearing Balb/C mice tumor. As can be seen from the figure, the body weight of each group of mice does not change significantly during the treatment period (14 days), which indicates that the nano-material has no significant toxicity to the mice and has higher biological safety.
The method provided by the invention focuses on simultaneously improving materials and processes to obtain the required technical effect. After the mesoporous carbon nano material is synthesized, the surface of the nano particles is modified in a strong acid oxidation mode, and the diagnosis and treatment integrated nano composite material with high water solubility and good biocompatibility is obtained by a physical adsorption method. The nano composite material provided by the invention has the advantages of uniform size, high stability and simple and controllable synthesis method. Making it have the properties of optothermal effect and photoacoustic/ultrasound imaging. It is used as a contrast agent for preparing photoacoustic imaging and ultrasonic imaging and a photothermal agent for near-infrared photothermal therapy. Can be applied to the diagnosis and treatment integrated treatment process of cancer, and has very wide application prospect in biomedicine.
The invention also focuses on the synthesis of precursors by a modified "soft template" method and the calcination to obtain the product. The synthetic process has few steps and convenient operation. The preparation process of the composite material is efficient, stable and high in repeatability. Compared with other common mesoporous carbon nanoparticles, the mesoporous carbon nanoparticles are synthesized by a hard template method, the process is complex, the process controllability is poor, the nanoscale structure can be realized, the stability, the uniformity, the biocompatibility and the biological safety are good, the loading rate of the phase-change material is high, the mass production can be realized, and the industrialization is easy.
The present invention is not limited to the above-mentioned embodiments, and other similar methods of producing nanocomposites by the same or similar methods are also possible, and the specific values, different organic molecules for further improving water solubility and functionalization, and the like are specifically selected from the ranges of the components described in the examples of the present invention, and are within the scope of the present invention.
The above description is only exemplary of the present invention and should not be taken as limiting the invention, and any modifications, equivalents, improvements and the like that are made within the spirit and principle of the present invention should be included in the scope of the present invention.
Claims (9)
1. A phase change nanometer diagnosis and treatment agent composite material is characterized in that mesoporous carbon nanometer particles MCNs with mesopores on the surface and ordered pore canal structures inside are used as carriers, mesoporous carbon nanometer particles OMCNs obtained through oxidation modification are used as carriers, temperature-sensitive phase change materials are loaded in the pore canal structures of the particles to obtain the composite material OMCNs-PFP, and the mesoporous shape of the composite material OMCNs-PFP has small difference, uniform particle appearance and size, good water solubility and biocompatibility, and has the properties of photothermal effect and photoacoustic/ultrasonic imaging; in the finished dry matter of the composite material OMCNs-PFP, the mass fraction of the mesoporous carbon nano-particles OMCNs is 95-97.0%, and the mass fraction of the temperature-sensitive phase-change material PFP is 3.0-5%; the temperature-sensitive phase-change material PFP is perfluoro-n-pentane.
2. A method for preparing the phase-change nano diagnostic and therapeutic agent composite material according to claim 1, which comprises the following steps:
(1) preparing mesoporous carbon nano-particle MCNs: dissolving 0.96g F127 in 15mL of deionized water by adopting a soft template method; accurately weighing 0.6g of phenol, 2.1mL of formaldehyde and 15mL of 0.1 mol.L-1 NaOH is evenly mixed at the temperature of 70 ℃ for 340 r.min-1Stirring at constant speed for 0.5 hour at the rotating speed to synthesize the low molecular weight phenolic resin; the dissolved F127 is then poured overAdding the mixture into phenolic resin, changing the temperature to 66 ℃, continuously stirring for 2 hours, adding 50mL of deionized water, and continuously stirring for 16-18 hours until the precipitate is dissolved; after dissolving the precipitate, taking 17.7mL of dissolved liquid, uniformly diluting with 56mL of deionized water, and transferring into a high-pressure reaction kettle; taking out after carrying out hydrothermal reaction for 24 hours at the temperature of 130 ℃, cleaning the obtained product by using deionized water for centrifugal separation, drying and grinding the obtained product, putting the obtained product into a tubular furnace, calcining the obtained product for 3 hours at the temperature of 700 ℃ under the protection of nitrogen, and fully grinding the burnt black particles to obtain mesoporous carbon nano-particles MCNs with mesopores on the surface and ordered pore structure in the interior;
(2) preparing oxidation modified mesoporous carbon nano-particles OMCNs: adding the obtained mesoporous carbon nano-particle powder into a double-mouth bottle, adding 4mL of mixed solution of concentrated sulfuric acid and concentrated nitric acid into the bottle, wherein the volume ratio of sulfuric acid to nitric acid is 3:1, carrying out ultrasonic and heating stirring for 2 hours respectively, continuously washing with ultrapure water, centrifuging to obtain surface oxidation modified mesoporous carbon nano-particles, and dispersing in an aqueous solution;
(3) preparing composite material OMCNs-PFP: and (3) vacuumizing and stirring the obtained oxidized mesoporous carbon nano particle aqueous solution by 3mg/L, adding the temperature-sensitive type phase change material PFP according to the volume ratio of 1:20, and washing with ultrapure water to obtain the phase change nano diagnostic agent composite material OMCNs-PFP.
3. The method for preparing a phase-change nano diagnostic and therapeutic agent composite material according to claim 2, wherein the step (1) comprises the following steps:
(11) dissolving 0.96g F127 in 15mL of deionized water; accurately weighing 0.6g of phenol, 2.1mL of formaldehyde and 15mL of 0.1 mol.L-1 NaOH is evenly mixed at the temperature of 70 ℃ for 340 r.min-1Stirring at constant speed for 0.5 hour at the rotating speed to synthesize the low molecular weight phenolic resin; then pouring the dissolved F127 into phenolic resin, changing the temperature to 66 ℃, continuously stirring for 2 hours, adding 50mL of deionized water, and continuously stirring for 16-18 hours;
(12) after standing, precipitating and dissolving, taking 17.7mL of dissolved liquid, uniformly diluting with 56mL of deionized water, and transferring into a high-pressure reaction kettle; carrying out hydrothermal reaction at the temperature of 130 ℃ for 24 hours, taking out, and cooling to room temperature;
(13) and (3) cleaning the product by using deionized water for centrifugal separation, drying, grinding, putting the product into a tubular furnace, calcining the product for 3 hours at the temperature of 700 ℃ under the protection of nitrogen, and uniformly grinding the product by using a grinding bowl to obtain the mesoporous carbon nanoparticles.
4. The method for preparing a phase-change nano diagnostic and therapeutic agent composite material according to claim 3, wherein the formaldehyde used in the step (11) is a 37% formaldehyde aqueous solution; adding F127 into deionized water 4-6 hours in advance and placing at 4 ℃ for accelerated dissolution; after stirring for 16-18 hours, when the solution is precipitated, immediately stopping stirring and standing until the precipitate is dissolved and disappears.
5. The method for preparing a phase-change nano diagnostic and therapeutic agent composite material according to claim 2, wherein the step (2) comprises the following steps:
(21) uniformly grinding the calcined product to obtain powdery mesoporous carbon nanoparticles, and adding the powdery mesoporous carbon nanoparticles into a 25mL double-mouth bottle;
(22) adding 4mL of mixed solution of concentrated sulfuric acid and concentrated nitric acid into a bottle, wherein the volume ratio of sulfuric acid to nitric acid is 3:1, ultrasonically treating and heating and stirring for 2 hours respectively, continuously washing with ultrapure water, centrifuging to obtain mesoporous carbon nanoparticles with surface oxidation modification, and dispersing in an aqueous solution.
6. The method for preparing a phase-change nano diagnostic and therapeutic agent composite material according to claim 5, wherein the heating and stirring temperature in the step (22) is 60 ℃ and the rotation speed is 750 r/min; centrifuging the acid product obtained by ultrasonic and heating stirring in the step (22), and centrifugally washing the centrifugal precipitate with ultrapure water at the centrifugal speed of 13000r/min.
7. The method for preparing a phase-change nano diagnostic and therapeutic agent composite material according to claim 2, wherein in the step (2), the centrifugal precipitate is washed with ultrapure water until the pH of the centrifugal supernatant is neutral; in the step (3), the processes of centrifugation, washing and freeze drying are as follows: centrifuging for 10-15 min at 13000r/min by using a freezing high-speed centrifuge; and then washed several times with deionized water.
8. The use of the phase-change nanophase agent composite material according to claim 1 as a material for preparing a contrast agent for photoacoustic imaging and ultrasonic imaging.
9. The use of the phase-change nanoparticie composite material according to claim 1 as a material for preparing a photothermal agent for near-infrared photothermal therapy.
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