CN111569066B - Near-infrared light controlled oxygen supply on-demand nano diagnosis and treatment agent and preparation method and application thereof - Google Patents

Near-infrared light controlled oxygen supply on-demand nano diagnosis and treatment agent and preparation method and application thereof Download PDF

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CN111569066B
CN111569066B CN201910481395.4A CN201910481395A CN111569066B CN 111569066 B CN111569066 B CN 111569066B CN 201910481395 A CN201910481395 A CN 201910481395A CN 111569066 B CN111569066 B CN 111569066B
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CN111569066A (en
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刘湘梅
田康
吴昊明
周严莉
赵强
黄维
刘淑娟
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Nanjing University of Posts and Telecommunications
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Nanjing University of Posts and Telecommunications
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
    • A61K41/0057—Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
    • A61K41/0052—Thermotherapy; Hyperthermia; Magnetic induction; Induction heating therapy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/001—Preparation for luminescence or biological staining
    • A61K49/0013—Luminescence
    • A61K49/0017—Fluorescence in vivo
    • A61K49/0019—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules
    • A61K49/0021—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules the fluorescent group being a small organic molecule
    • A61K49/0041—Xanthene dyes, used in vivo, e.g. administered to a mice, e.g. rhodamines, rose Bengal
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/001—Preparation for luminescence or biological staining
    • A61K49/0063—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres
    • A61K49/0069—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres the agent being in a particular physical galenical form
    • A61K49/0089—Particulate, powder, adsorbate, bead, sphere
    • A61K49/0091—Microparticle, microcapsule, microbubble, microsphere, microbead, i.e. having a size or diameter higher or equal to 1 micrometer
    • A61K49/0093—Nanoparticle, nanocapsule, nanobubble, nanosphere, nanobead, i.e. having a size or diameter smaller than 1 micrometer, e.g. polymeric nanoparticle
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/5115—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/513—Organic macromolecular compounds; Dendrimers
    • A61K9/5138—Organic macromolecular compounds; Dendrimers obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Abstract

The invention discloses a near infrared light control oxygen supply on-demand nano diagnosis and treatment agent, and a preparation method and application thereof. The nano diagnosis and treatment reagent adopts near infrared photosensitizer IR780 and rhodamine B to load simultaneously to obtain a silicon dioxide nano composite material, then polyvinyl pyrrolidone is used for modifying and loading hydrogen peroxide to obtain the nano diagnosis and treatment reagent which has good biocompatibility, small and uniform particle size and good stability and can supply oxygen according to needs, and the performance of the nano diagnosis and treatment reagent is tested. The nano diagnosis and treatment agent is beneficial to the self-oxygenation photodynamic therapy of cancer cells and tumors, has the technical advantages of simple preparation process, low cost, wide application range and the like, and has important application prospect in the fields of biological medicine, chemical industry, functional materials and the like.

Description

Near-infrared light controlled oxygen supply on-demand nano diagnosis and treatment agent as well as preparation method and application thereof
Technical Field
The invention belongs to the technical field of preparation technology of nano materials and special materials, and particularly relates to a near-infrared light controlled oxygen supply on-demand nano diagnosis and treatment agent as well as a preparation method and application thereof.
Background
Cancer was an unfamiliar vocabulary for Chinese people half a century ago. However, for as short as fifty years, cancer has become one of the most closely related diseases, and both morbidity and mortality are in the first three kingdoms. According to the prediction of cancer statistics in China in 2015, which is completed by the national cancer center, namely Hosiebol, the number of new cancer cases in 429.2 and cancer death cases in China in 2015 exceeds 281.4 ten thousand.
Hypoxia is a hallmark type characteristic of solid tumors, but this is contrary to the conditions of efficient PDT, so the hypoxic environment of tumors is a major factor in limiting solid tumors. In addition, oxygen is consumed during photodynamic therapy to further exacerbate the hypoxia condition of tumor tissues, and the hypoxia condition of the tumor persists. Blood vessels in tumor micro-regions may be damaged during the photodynamic therapy process, and the damage of the blood vessels causes oxygen transportation obstacle to further aggravate the hypoxia. To date, researchers have explored ways to improve oxygen concentration that affects photodynamic therapy, such as increasing blood vessel density, dilating blood vessels, and increasing oxygen transport. However, the experimental results prove that the endogenous hydrogen peroxide content at the tumor tissue is not enough to provide the oxygen required by the treatment, and the exogenous oxygen is difficult to transport to the tumor tissue.
Patent CN109395081A discloses a nano-photodynamic reagent capable of near-infrared light excitation and self-oxygen supply, which adopts near-infrared photosensitizer IR780 with photodynamic effect and photothermal effect as photothermal and photodynamic treatment reagent, adopts small-sized sea urchin-shaped manganese dioxide nano-material as nano-platform, and adopts bovine serum albumin for coating; the composite nano material improves the oxygen concentration through the reaction of the manganese dioxide nano particles and the endogenous hydrogen peroxide of the tumor. Although the patent can relieve the hypoxic environment of the tumor tissue, the patent cannot provide oxygen for the tumor tissue at fixed points and time.
Disclosure of Invention
The invention aims to solve the problems and provides a near-infrared light controlled oxygen supply on demand nano diagnosis and treatment agent, which can improve the biocompatibility of a near-infrared photosensitizer, can supply oxygen to the nano diagnosis and treatment agent on demand to improve the problem of tissue hypoxia, and can realize deep photodynamic therapy through effective delivery of the near-infrared photosensitizer.
In order to achieve the purpose, the invention adopts the technical scheme that:
a near-infrared controlled oxygen supply nano diagnosis and treatment agent is a nano material which is prepared by loading a near-infrared dye and a fluorescent dye in a silicon dioxide nano material through in-situ blending, and sequentially loading polyvinylpyrrolidone and hydrogen peroxide on the surface of the silicon dioxide nano material.
Preferably, the near-infrared dye is a near-infrared photosensitizer IR 780;
preferably, the fluorescent dye is rhodamine b (rb).
Preferably, the particle size of the silicon dioxide nano material is 60-80 nm.
Preferably, the polyvinylpyrrolidone has a relative number average molecular weight of 28K to 40K.
Preferably, the concentration of the hydrogen peroxide is 5.9-10.58 mol/L. With addition of sufficient amount of H2O2Can provide enough oxygen for the nano diagnosis and treatment agent to supplement endogenous H at tumor tissues2O2The content is insufficient; if H is2O2Too high concentration of (A), H supported on the outer layer of PVP2O2Will reach saturation, resulting in H2O2Waste of (2); if H is2O2Too low a concentration of (b) may result in insufficient oxygen supply at the tumor tissue and failure of the therapeutic effect.
The inventor loads near infrared photosensitizer IR780 and rhodamine B in silica nanoparticles through in-situ doping, and the prepared nanoparticles have the capability of molecular release and structural collapse, which is beneficial to deep tumor penetration of the photosensitizer; and then the PVP and the hydrogen peroxide are sequentially loaded on the surfaces of the nanoparticles to obtain the nano diagnosis and treatment agent. The nano diagnosis and treatment agent not only improves the biocompatibility of the photosensitizer IR780, but also can supply oxygen as required to improve the problem of oxygen lack in tissues, and can realize deep photodynamic therapy through the effective delivery of the photosensitizer. Therefore, the nano diagnosis and treatment agent is beneficial to self-oxygen supply photodynamic therapy and photothermal therapy.
The invention also provides a preparation method of the near infrared light controlled oxygen supply on-demand nano diagnosis and treatment agent, which comprises the following steps:
s1: dissolving 20-30 mg of near-infrared photosensitizer IR780 and 8-12 mg of rhodamine B in absolute ethyl alcohol at room temperature, and stirring for 25-45 min;
s2: slowly dripping 70-100 uL of tetraethoxysilane into the solution prepared in the step S1 at room temperature, and stirring for 20-30 min;
s3: rapidly adding 3-5 mL of ammonia water into the solution prepared in the step S2 at room temperature, reacting for 20-24 h at a stirring speed of 600r/min, centrifugally washing the product for 3 times by using ultrapure water, and drying; obtaining a nano particle solid product;
s4: dissolving 4mg of the nanoparticle solid product prepared in the step S3 in 2mL of ultrapure water at room temperature, dissolving 16-20 mg of polyvinylpyrrolidone in 2mL of ultrapure water, dropwise adding the nanoparticle solution into the ultrapure water solution of polyvinylpyrrolidone, and stirring for 8-12 h;
s5: and dispersing the product obtained in the step S4 in a hydrogen peroxide solution at room temperature, and stirring for 3-6 h to obtain a final product.
Preferably, in step S1 of the preparation method, the mass ratio of the near-infrared photosensitizer IR780 to the rhodamine B is 5: 2. if the rhodamine B is too low, the rhodamine B is not enough to collapse the silica nanoparticles after being released from the interior of the silica nanoparticles, and the silica nanoparticles cannot be completely decomposed; when the quality of rhodamine B is too high, the amount of doped near-infrared photosensitizer IR780 becomes low, and efficient photodynamic therapy cannot be achieved.
Preferably, in step S4, the mass ratio of the nanoparticle solid product to PVP is 1: 4 to 6. When the content of PVP is too small, the compatibility of the near-infrared photosensitizer IR780 is poor; when the content of PVP is too high, the prepared nano diagnosis and treatment agent composite nano particle has strong cohesiveness.
The invention provides a near-infrared light control oxygen supply on-demand nano diagnosis and treatment agent which is used for photodynamic, photothermal materials and fluorescent materials in self-oxygen supply photodynamic therapy and photothermal therapy guided by fluorescence imaging of cancer cells and tumors.
Compared with the prior art, the invention has the beneficial effects that:
1. the nano diagnosis and treatment agent can improve the photodynamic therapy effect, more importantly, the nano diagnosis and treatment agent controls the fixed-point timed release of oxygen through a photo-thermal conversion material, can be effectively used for diagnosis and treatment of cancer cells and tumors, and has better in-vivo biomedical application prospect;
2. the nano diagnosis and treatment agent is used as a good thermal control oxygen supply intelligent material according to needs, can effectively improve the hypoxic condition of tumors and enhance photodynamic therapy; meanwhile, the problems of biocompatibility and delivery efficiency of the near-infrared photosensitizer IR780 are improved, and meanwhile, the composite nano material improves the problem of penetration depth of light in photodynamic therapy;
3. the composite nano particle has small hydrated particle size, good biocompatibility and high specific surface area, and has good application prospect in the aspect of visual guided photodynamic therapy;
4. the functionalized composite nano material has the advantages of rich raw materials, easy preparation and wide application range, and can be used for industrial production.
Drawings
Fig. 1 is a transmission electron microscope photograph of the nano-sized medical agent prepared in example 1;
FIG. 2 is a transmission electron microscope photograph of the nano diagnostic and therapeutic agent prepared in comparative example 1;
FIG. 3 is a transmission electron microscope photograph of the nano therapeutic agent prepared in comparative example 2;
fig. 4 is a hydrated particle size diagram of composite nanoparticles of the nano-diagnostic and therapeutic agent prepared in example 1;
fig. 5 is a uv-vis absorption spectrum of the composite nanoparticle of the nano therapeutic agent prepared in example 1;
FIG. 6 is a graph showing the photothermal power of the composite nanoparticles of the nano diagnostic agent prepared in example 1
Fig. 7 is a fluorescence spectrum of the nano diagnostic and therapeutic agent prepared in example 1 in laser-triggered oxygen release;
FIG. 8 is a fluorescence spectrum of the nano diagnostic reagent prepared in example 1 heated in a water bath to trigger oxygen release;
FIG. 9 is a singlet oxygen generation diagram under different conditions for the nano-sized therapeutic agent prepared in example 1;
fig. 10 is a diagram showing the generation of singlet oxygen with different concentrations of hydrogen peroxide in application example 8.
Detailed Description
The technical solutions of the present invention will be described clearly and completely with reference to the accompanying drawings, and it is to be understood that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Example 1
The near-infrared light control oxygen supply on-demand nano diagnosis and treatment agent provided by the embodiment is prepared by the following steps:
s1: dissolving 25mg of near-infrared photosensitizer IR780 and 10mg of rhodamine B in 75mL of absolute ethyl alcohol at room temperature, and stirring for 30 min;
s2: slowly and dropwise adding 80uL of tetraethoxysilane into the solution prepared in the step S1 at room temperature, and stirring for 30 min;
s3: rapidly adding 4mL of ammonia water into the step S2 at room temperature, reacting for 24 hours at a stirring speed of 600r/min, centrifugally washing the product for 3 times by using ultrapure water, and drying;
s4: dissolving 4mg of the product prepared in step S3 in 2mL of ultrapure water at room temperature, dissolving 20mg of polyvinylpyrrolidone with a relative number average molecular weight of 40K in 2mL of ultrapure water, dropwise adding the solution of nanoparticles to the ultrapure water solution of polyvinylpyrrolidone, and stirring for 10 hours;
s5: dispersing the product of S4 in 4mL hydrogen peroxide solution with the concentration of 10mol/L at room temperature, and stirring for 4h to obtain the final product nano diagnosis and treatment agent;
example 2
Example 2 differs from example 1 in that S5: the concentration of hydrogen peroxide is 2.9 mol/L; the other steps are the same as the example 1, and the nano diagnosis and treatment agent is prepared.
Example 3
Example 3 differs from example 1 in that S5: the concentration of hydrogen peroxide is 5.9 mol/L; the other steps are consistent with the example 1, and the nano diagnosis and treatment agent is prepared.
Example 4
Example 4 differs from example 1 in that S5: the concentration of hydrogen peroxide is 10.58 mol/L; the other steps are consistent with the example 1, and the nano diagnosis and treatment agent is prepared.
Example 5
Example 5 differs from example 1 in that S5: the concentration of hydrogen peroxide is 11.17 mol/L; the other steps are consistent with the example 1, and the nano diagnosis and treatment agent is prepared.
Comparative example 1
Comparative example 1 differs from example 1 in that S4: the added polyvinylpyrrolidone was 40 mg; the other steps are consistent with the example 1, and the nano diagnosis and treatment agent is prepared.
Comparative example 2
Comparative example 2 differs from example 1 in that S1: dissolving 24mg of near-infrared photosensitizer IR780 and 16mg of rhodamine B in absolute ethyl alcohol at room temperature, and stirring for 30 min; the other steps are the same as the example 1, and the nano diagnosis and treatment agent is prepared.
To better understand the properties of the target substance obtained in this example, characterization was performed by the following tests:
application example 1
Morphology and particle size distribution tests of the nano diagnosis and treatment agents prepared in examples 1-5 and comparative examples 1-2
The specific testing steps are as follows: and dripping 15 mu L of sample solution of the nano diagnosis and treatment agent with the concentration of 0.1mg/mL on a copper mesh, and carrying out a shape test after the sample is dried.
Fig. 1 is a transmission electron microscope photograph of composite nanoparticles of the nano diagnostic agent in example 1, fig. 1 is a transmission electron microscope photograph of dialyzing in water for 8 days, it can be seen from the photograph that the particle size of the composite nanoparticles is 70-100nm, and it can be seen from the transmission electron microscope photograph result of fig. 1 that the composite nano agent provided by the present invention has good monodispersity, uniform particle size distribution, and no bonding between the nanoparticles; the morphology and particle size distribution of examples 2-5 are similar to that of example 1 and the figures will not be repeated here.
Fig. 2 is a transmission electron microscope image of the nano diagnostic and therapeutic agent prepared in comparative example 1, and it can be seen from the electron microscope image of the composite nanoparticles that when the mass ratio of the nanoparticle solid product and polyvinylpyrrolidone in step S4 is 1: at 10, the adhesion between the nanoparticles was severe.
FIG. 3 is a transmission electron microscope photograph of the nano diagnostic and therapeutic agent prepared in comparative example 3, which is a transmission electron microscope photograph after dialysis in water for 1 day, 5 days, and 8 days, in order from left to right; as can be seen from the electron micrograph of the composite nanoparticles, the morphology of the nanoparticles hardly changed after dialysis for 1 day, the surface structure began to break after 5 days, and the basic structure had collapsed after 8 days.
Application example 2
The hydrated particle size of the nano therapeutics of examples 1 to 5 and comparative examples 1 to 2 was measured
The specific test is as follows: 2mL of a sample having a concentration of 0.2mg/mL was taken in a quartz cuvette and tested for hydrated particle size. Fig. 4 is a graph of hydrated particle size of the composite nanoparticles of the nano medical agent in example 1, and it can be seen from the graph that the hydrated particle size distribution in example 1 is 70-100nm, and from analysis of the hydrated particle size test results, the prepared composite nanoparticles have good monodispersity and uniform particle size distribution.
The hydrated particle size distributions of examples 2-5 and comparative examples 1-2 are similar to those of example 1, and the figures will not be repeated here.
Application example 3
UV-VIS Spectroscopy test was performed on the nano-sized therapeutics of examples 1 to 5 and comparative examples 1 to 2
The specific test steps are as follows: 2mL of sample aqueous solution, an absolute ethyl alcohol solution of a near-infrared photosensitizer IR780 material and an aqueous solution of a fluorescent dye rhodamine B are respectively put in a cuvette to measure the ultraviolet visible absorption spectra of the three materials.
Fig. 5 is an ultraviolet-visible absorption spectrum of the composite nanoparticle of the nano diagnostic agent in example 1, and it can be seen from fig. 5 that the absorption peak of the composite nanoparticle is consistent with the absorption peaks of the near-infrared photosensitizer IR780 and the rhodamine B, which indicates that the nanoparticle successfully adsorbs the photosensitizer IR780 and the fluorescent dye rhodamine B.
The UV-VIS absorption spectra of examples 2 to 5 and comparative examples 1 to 2 are similar to those of example 1, and the figures will not be repeated here.
Application example 4
Photothermal test was performed on the nano therapeutics of examples 1 to 5 and comparative examples 1 to 2
The specific test steps are as follows: the composite nanoparticle material was formulated into two concentrations of solution (0 and 150ug/mL) using a 785nm laser at 1W/cm2The power of the light source is irradiated for 6min, and the change curves of the temperature of the two materials with different concentrations along with the time are obtained.
Fig. 6 is a graph showing a photothermal power test of the composite nanoparticles of example 1. The temperature change curves of the obtained two materials with different concentrations along with time are shown in fig. 6, and it can be known from fig. 6 that the composite nanoparticles prepared by the invention have obvious photothermal effect.
The photothermal test patterns of examples 2 to 5 and comparative examples 1 to 2 are similar to the curve of example 1 at a concentration of 150ug/mL, and the patterns will not be repeated here.
Application example 5
The nano diagnosis and treatment agents of examples 1 to 5 and comparative examples 1 to 2 were tested for oxygen release performance under laser irradiation
The specific experimental steps are as follows: preparing aqueous solution (150ug/mL) of composite nanoparticles, introducing nitrogen into the solution for 30min to remove oxygen in the solution, and adding 100uL (5 × 10) ethanol solution of oxygen-removed oxygen probe (RDPP)-6M) and sealed with liquid paraffin, using a laser with a wavelength of 785nm and a power of 1W/cm2The oxygen probe RDPP was tested for fluorescence intensity at 60s and 6 exposures.
FIG. 7 is a spectrum of the emission light of the nano-sized medical agent in example 1 in the laser triggered oxygen release; analysis of the test results plot revealed that the RDPP fluorescence decreased gradually with increasing light exposure time, indicating that the oxygen production increased gradually.
The photothermal test patterns under laser irradiation of examples 2 to 5 and comparative examples 1 to 2 are similar to those of example 1, and the patterns will not be repeated here.
Application example 6
Water bath heating triggered oxygen release performance test is carried out on the nano diagnosis and treatment agents of examples 1-5 and comparative examples 1-2
The specific experimental steps are as follows: firstly, preparing an aqueous solution (150ug/mL) of the composite nanoparticles, then introducing nitrogen into the solution for 30min to remove oxygen in the solution, adding 100uL (5X 10-6M) of ethanol solution of an oxygen-removed oxygen probe (RDPP), and sealing by using liquid paraffin. The RDPP was heated in a water bath at 50 ℃ and the fluorescence intensity of the RDPP was followed 5min apart.
FIG. 8 is a fluorescence spectrum of the nano diagnostic reagent in example 1 heated in a water bath to trigger oxygen release; analysis of the test results plot may reveal a gradual decrease in the fluorescence of the RDPP with increasing heating time, indicating a gradual increase in the oxygen produced. By comparison with fig. 5, it can be seen that the rate of oxygen generation is significantly lower in the case of water bath heating than in the case of laser irradiation, which is due to the fact that laser irradiation is internal heating at a faster rate, while water bath heating is external heating.
The photothermal test patterns triggered by water bath heating of examples 2 to 5 and comparative examples 1 to 2 are similar to those of example 1, and the patterns will not be repeated here.
Application example 7
The singlet oxygen test of the nano-sized therapeutics of example 1 and comparative examples 1 to 2
The specific experimental steps are as follows: preparing an oxygen-removed water solution (150ug/mL) of a nano material which is not loaded with hydrogen peroxide, then preparing a water solution (150ug/mL) of a composite nano particle loaded with hydrogen peroxide, heating in a water bath for 30min, irradiating for 6 times by using a laser with the wavelength of 785nm and the power of 50mW/cm2 for 60s each time, and using DPBF as a singlet oxygen indicator.
Fig. 9 is a singlet oxygen generation diagram of the nano diagnostic agent prepared in example 1 under different conditions, and it can be seen that the absorption strength of DPBF in the solution without hydrogen peroxide loading is hardly decreased, while the increase of the illumination time of the solution loaded with hydrogen peroxide gradually increases the yield of singlet oxygen, and after 350s, oxygen can be continuously released, which indicates that in the treatment of cancer cells and tumors, the hydrogen peroxide is loaded on the outer layer of the composite nanoparticles, so that the nano diagnostic agent can control the fixed-point timed release of oxygen.
The singlet oxygen test of comparative example 1 is similar to the curve for the aqueous solution of hydrogen peroxide-loaded composite nanoparticles of example 1, and the diagram will not be repeated here. The singlet oxygen test of the composite nanoparticles in comparative example 2 was similar to the curve of the aqueous solution of the composite nanoparticles without hydrogen peroxide loading in example 1, and the figure will not be repeated here.
Application example 8
The singlet oxygen test of the nano-diagnostic agents of examples 1 to 5
The procedure of the experiment was the same as in application example 7.
Fig. 10 is a singlet oxygen test chart of the nano diagnostic agents and the nano diagnostic agents not loaded with hydrogen peroxide in examples 1 to 5 after the light irradiation time is 360s, and it can be found that the DPBF absorption strength in the solution not loaded with hydrogen peroxide hardly decreases, while the yield of singlet oxygen gradually increases with the increase of the concentration of hydrogen peroxide in the solution loaded with hydrogen peroxide, and when the concentration of hydrogen peroxide is 2.9mol/L, the content of oxygen released by the nano diagnostic agents is relatively low, resulting in an insignificant therapeutic effect; when the concentration of the hydrogen peroxide is 5.9-10.58 mol/L, the yield of the singlet oxygen is gradually improved and is in a high content, so that the hydrogen peroxide can be effectively used for diagnosis and treatment of cancer cells and tumors; when the concentration of the hydrogen peroxide is continuously increased to 11.17mol/L, the yield of the singlet oxygen reaches a saturation value.
The foregoing shows and describes the general principles, principal features and advantages of the invention. However, the above description is only an example of the present invention, the technical features of the present invention are not limited thereto, and any other embodiments that can be obtained by those skilled in the art without departing from the technical solution of the present invention should be covered by the claims of the present invention.

Claims (8)

1. A near-infrared light controlled oxygen supply-on-demand nano diagnosis and treatment agent is characterized in that a near-infrared photosensitizer IR780 and rhodamine B are loaded in a silicon dioxide nano material through in-situ blending, and then polyvinylpyrrolidone and hydrogen peroxide are sequentially loaded on the nano material on the surface of the silicon dioxide nano material.
2. The near-infrared controlled oxygen supply on-demand nanometer diagnosis and treatment agent as claimed in claim 1, wherein the particle size of the silica nanometer material is 60-80 nm.
3. The near-infrared light controlled oxygen supply on-demand nano diagnostic and therapeutic agent as claimed in claim 1, wherein the molar concentration of the hydrogen peroxide is 5.9mol/L to 10.58 mol/L.
4. The near-infrared controlled oxygen-supply-on-demand nano diagnostic and therapeutic agent as claimed in claim 1, wherein the polyvinylpyrrolidone has a relative number average molecular weight of 28K to 40K.
5. The preparation method of the near-infrared light controlled oxygen supply on demand nano diagnosis and treatment agent as claimed in any one of claims 1 to 4, characterized by comprising the following steps:
s1: dissolving 20-30 mg of near-infrared photosensitizer IR780 and 8-12 mg of rhodamine B in absolute ethyl alcohol at room temperature, and stirring for 25-45 min;
s2: slowly dripping 70-100 uL of tetraethoxysilane into the solution prepared in the step S1 at room temperature, and stirring for 20-30 min;
s3: rapidly adding 3-5 mL of ammonia water into the solution prepared in the step S2 at room temperature, reacting for 20-24 h at a stirring speed of 600r/min, centrifugally washing the product for 3 times by using ultrapure water, and drying to obtain a nano particle solid product;
s4: dissolving 4mg of the solid product of the nanoparticles prepared in the step S3 in 2mL of ultrapure water at room temperature, dissolving 16-24 mg of polyvinylpyrrolidone in 2mL of ultrapure water, dropwise adding the nanoparticle solution into the ultrapure water solution of polyvinylpyrrolidone, and stirring for 8-12 h;
s5: and dispersing the product obtained in the step S4 into hydrogen peroxide solution at room temperature, and stirring for 3-6 h to obtain the final product.
6. The preparation method of the near-infrared light controlled oxygen supply nanometer diagnosis and treatment agent as claimed in claim 5, wherein the mass ratio of the near-infrared photosensitizer IR780 to rhodamine B in step S1 is 5: 2.
7. the method for preparing a near-infrared controlled oxygen supply on demand nano diagnostic and treatment agent as claimed in claim 5, wherein the mass ratio of the nano particle solid product to the polyvinylpyrrolidone in step S4 is 1: 4-6.
8. Use of the near-infrared light-controlled oxygen-supply-on-demand nano diagnostic and therapeutic agent as defined in any one of claims 1-4 in preparation of photodynamic materials, photothermal materials or fluorescent materials.
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