CN112370534A - Tumor microenvironment response degradation type diagnosis and treatment integrated nanoprobe and preparation method thereof - Google Patents
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Abstract
The invention relates to the technical field of preparation of nano biomedical materials, in particular to a tumor microenvironment response degradation type diagnosis and treatment integrated nanoprobe and a preparation method thereof. The nano probe takes novel mesoporous silicon dioxide nano particles as a template, and the nano particles take tetraethoxysilane and bis- [3- (triethoxysilyl) propyl ] silicate]Synthesizing tetrasulfide, surfactant, albumin, sodium hydroxide, ammonium nitrate and absolute ethyl alcohol as raw materials, and loading MnO on potassium permanganate2Then, bovine serum albumin is coated through electrostatic adsorption, and a fluorescent small molecule CQ4T is coupled on the bovine serum albumin, so that the nano probe with multi-modal imaging and treatment is constructed.
Description
Technical Field
The invention relates to the technical field of preparation of nano biomedical materials, in particular to a tumor microenvironment response degradation type diagnosis and treatment integrated nanoprobe and a preparation method thereof.
Background
Tumors are one of the important diseases threatening human health, and the early diagnosis and treatment of tumors are the key to improve the quality of life and cure rate of patients. With the rise of nanotechnology, the characteristics of nanomaterials are utilized to integrate the functions of drug targeted transportation, living body tracing, drug treatment, prognosis monitoring and the like into a whole, so that a new era is expected to be provided for developing a novel cancer diagnosis and treatment integrated nanoprobe.
Currently, with the development of nanotechnology, various nanoprobes have been developed to realize clinical transformation. Although the nano materials are widely used, there are some problems to be solved, such as insufficient water solubility, biocompatibility, etc., and most of the nano materials are difficult to achieve a good degradation process in vivo, causing unnecessary living body injury.
The tumor microenvironment has the characteristics of low pH value, high expression of glutathione and hydrogen peroxide, and the like, and researches show that the damage of the tumor microenvironment to normal tissues can be reduced by modifying the nano probe to enable the nano probe to have the response degradation performance of the tumor microenvironment.Based on the factors of toxicity, degradability, stability, synthesis process and the like, a novel rod-shaped mesoporous silica (FMSN) nano particle is designed and developed, and fluorescent molecules CQ4T and MnO are loaded on the basis of the novel rod-shaped mesoporous silica (FMSN) nano particle2Construction of FMSN-MnO2BSA-CQ4T nanoprobe. The method is expected to solve the safety problem, and can fully utilize the characteristics of the structure and the performance of endogenous substances to construct diagnosis and treatment integrated nanoprobes with better clinical transformation prospect.
Disclosure of Invention
In order to overcome the defects in the prior art, the invention provides a tumor microenvironment response degradation type diagnosis and treatment integrated nanoprobe and a preparation method thereof2The reaction is carried out, so that the nano probe is rapidly degraded, and the toxic and side effects of the material on normal tissues are reduced.
In order to solve the technical problems, the technical scheme adopted by the invention is as follows:
the utility model provides a tumour microenvironment response degradation type integration nanoprobe of diagnosing which characterized in that: the nano probe takes rod-shaped mesoporous silicon dioxide nano particles as a carrier, and MnO is loaded on the nano probe by utilizing potassium permanganate2Then coating bovine serum albumin through electrostatic adsorption, and coupling fluorescent micromolecule CQ4T on the bovine serum albumin, wherein the rod-shaped mesoporous silica nano particles account for 90-93 wt% of the nano probe, and MnO25-8 wt% of the nano probe, and the fluorescent molecule CQ4T accounts for 1-2.5 wt% of the weight of the nano probe. Among them, the fluorescent molecule CQ4T is a fluorescent molecule disclosed In the literature Monitoring the Real-Time circulation System-Related physical and medical Processes In Vivo use a multifunctionality NIR-II Probe.
Preferably, the long diameter of the crystal grain of the nano probe is 80-90 nm, and the short diameter of the crystal grain of the nano probe is 12-20 nm.
A preparation method of a tumor microenvironment response type diagnosis and treatment integrated nanoprobe comprises the following steps:
s1, mixing deionized water: surfactant (b): the albumin is prepared according to the following steps of 277.778-555.556: 0.12-0.29: 1.057.10-3～1.820·10-3Is prepared from (A) and (B)Preparing a mixed solution by a molar ratio, and stirring at room temperature for 5-30 min;
s2, dropwise adding a sodium hydroxide solution with the concentration of 2mol/L into the mixed solution in the S1, adjusting the pH value of the mixed solution to 12, and stirring at the constant temperature of 37 ℃ for 5-15 hours;
s3, according to the molar ratio of ethyl orthosilicate to bis- [3- (triethoxysilyl) propyl ] -tetrasulfide of 1.296-6.480: 0.12-0.29, slowly dropwise adding a mixture of ethyl orthosilicate and bis- [3- (triethoxysilyl) propyl ] -tetrasulfide into the mixed solution in S2, sealing, and stirring at the constant temperature of 37 ℃ for 10-30 h;
s4, washing the mixed solution in the S3 with deionized water, centrifuging, roasting at 450-600 ℃, and drying to obtain the rodlike mesoporous silica nano material FMSN without the template agent;
s5, according to deionized water: FMSN: KMnO40.3-2: 5-10: 0.5-3 mass ratio, KMnO is added into the water solution mixed with the rod-shaped mesoporous silica4Stirring for 1-5 h at room temperature, centrifuging, and freeze-drying to obtain FMSN-MnO2Powder;
s6, according to FMSN-MnO2: 3-aminopropyltriethoxysilane: anhydrous ethanol: 100-200 parts of deionized water: 1.67-3.05: 1356 to 2372: 1.5-3.0, adding the mixed solution of 3-aminopropyltriethoxysilane and deionized water into FMSN-MnO2Stirring the mixed solution with absolute ethyl alcohol for 8-15 hours at room temperature, centrifuging, and mixing the solution: albumin is 0.5 to 1: 5-25, adding albumin, reacting for 1-10 h at room temperature, and centrifuging to obtain FMSN-MnO2-BSA；
S7, FMSN-MnO2CQ4T solution with concentration of 2mg/mL was added to BSA solution, wherein FMSN-MnO was2-BSA: the mass ratio of CQ4T is 5-25: 0.5-2, mixing the solution evenly by vortex, bathing for 2-20 min at 60 ℃, centrifuging, freezing and drying to obtain FMSN-MnO2BSA-CQ4T nanoprobe.
Preferably, the albumin is bovine serum albumin.
Preferably, the surfactant in step S1 is cetyltrimethylammonium bromide.
Preferably, the FMSN-MnO2The BSA-CQ4T nanoprobe has the capability of responding and degrading by a tumor microenvironment.
Compared with the prior art, the invention has the beneficial effects that:
the invention provides a tumor microenvironment response degradation type diagnosis and treatment integrated nanoprobe and a preparation method thereof, the nanoprobe utilizes the interaction of a surfactant and albumin nanoparticles, and modulates the addition amounts of the surfactant, ethyl orthosilicate and albumin in a synthesis system so as to synthesize rod-shaped mesoporous silica nanoparticles FMSN with uniform dispersion and uniform particle size, and KMnO is utilized4On which MnO is loaded2By electrostatic adsorption on FMSN-MnO2The fluorescent molecule CQ4T is coupled on the surface to construct a nano probe with multi-modal imaging and treatment, and the material is acted by glutathione in the tumor microenvironment, so that FMSN and MnO are enabled to be connected2Rapid degradation, reduced damage of nanoprobe to normal tissue, partial GSH consumption due to degradation of FMSN, and increased MnO content2The mediated chemodynamic therapy effectively improves the imaging and treatment performance of the nanoprobe. The invention prepares a simple, rapid and controllable tumor microenvironment response type diagnosis and treatment integrated nanoprobe, the long diameter of the nanoprobe crystal grain is 80-90 nm, the short diameter is 12-20 nm, and the purity of the product reaches 99.9%.
Drawings
Fig. 1 is a transmission electron microscope image of the integrated diagnosis and treatment nanoprobe synthesized in example 1 of the present invention.
Fig. 2 is an X-ray photoelectron spectrum of Mn element in the integrated diagnosis and treatment nanoprobe synthesized in example 1 of the present invention.
Fig. 3 shows the degradation performance of the diagnosis and treatment integrated nanoprobe synthesized in example 1 of the present invention.
Fig. 4 is a hydroxyl radical generation performance study of the diagnosis and treatment integrated nanoprobe synthesized in example 1 of the present invention.
Fig. 5 is a graph showing the cell survival rate of the diagnosis and treatment integrated nanoprobe synthesized in example 1 according to the present invention after the cytochemical dynamic therapy of different concentrations.
FIG. 6 is an NIR-II fluorescence image of a nude mouse living body with the integrated nano probe for diagnosis and treatment synthesized in example 1 of the present invention.
Fig. 7 is an MRI image of a nude mouse living body of the diagnosis and treatment integrated nanoprobe synthesized in example 1 of the present invention.
FIG. 8 is a tumor volume graph showing the anti-tumor treatment effect of the diagnosis and treatment integrated nanoprobe synthesized in example 1 of the present invention on a living nude mouse.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious 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.
The utility model provides a tumour microenvironment response degradation type integration nanoprobe of diagnosing which characterized in that: the nano probe takes rod-shaped mesoporous silicon dioxide nano particles as a carrier, and MnO is loaded on the nano probe by utilizing potassium permanganate2Then coating bovine serum albumin through electrostatic adsorption, and coupling fluorescent micromolecule CQ4T on the bovine serum albumin, wherein the rod-shaped mesoporous silica nano particles account for 90-93 wt% of the nano probe, and MnO25-8 wt% of the nano probe, and the fluorescent molecule CQ4T accounts for 1-2.5 wt% of the weight of the nano probe.
Preferably, the long diameter of the crystal grain of the nano probe is 80-90 nm, and the short diameter of the crystal grain of the nano probe is 12-20 nm.
A preparation method of a tumor microenvironment response type diagnosis and treatment integrated nanoprobe comprises the following steps:
s1, mixing deionized water: surfactant (b): the albumin is prepared according to the following steps of 277.778-555.556: 0.12-0.29: 1.057.10-3～1.820·10-3Preparing a mixed solution according to the molar ratio, and stirring for 5-30 min at room temperature;
s2, dropwise adding a sodium hydroxide solution with the concentration of 2mol/L into the mixed solution in the S1, adjusting the pH value of the mixed solution to 12, and stirring at the constant temperature of 37 ℃ for 5-15 hours;
s3, according to the molar ratio of ethyl orthosilicate to bis- [3- (triethoxysilyl) propyl ] -tetrasulfide of 1.296-6.480: 0.12-0.29, slowly dropwise adding the mixture of ethyl orthosilicate and bis- [3- (triethoxysilyl) propyl ] -tetrasulfide into the mixed solution in S2, sealing, and stirring at the constant temperature of 37 ℃ for 10-30 h;
s4, washing the mixed solution in the S3 with deionized water, centrifuging, roasting at 450-600 ℃, and drying to obtain the rodlike mesoporous silica nano material FMSN without the template agent;
s5, according to deionized water: FMSN: KMnO40.3-2: 5-10: 0.5-3 mass ratio, KMnO is added into the water solution mixed with the rod-shaped mesoporous silica4Stirring for 1-5 h at room temperature, centrifuging, and freeze-drying to obtain FMSN-MnO2Powder;
s6, according to FMSN-MnO2: 3-aminopropyltriethoxysilane: anhydrous ethanol: 100-200 parts of deionized water: 1.67-3.05: 1356 to 2372: 1.5-3.0, adding the mixed solution of 3-aminopropyltriethoxysilane and deionized water into FMSN-MnO2Stirring the mixed solution with absolute ethyl alcohol for 8-15 hours at room temperature, centrifuging, and mixing the solution: albumin is 0.5 to 1: 5-25, adding albumin, reacting for 1-10 h at room temperature, and centrifuging to obtain FMSN-MnO2-BSA；
S7, FMSN-MnO2CQ4T solution with concentration of 2mg/mL was added to BSA solution, wherein FMSN-MnO was2-BSA: the mass ratio of CQ4T is 5-25: 0.5-2, mixing the solution evenly by vortex, bathing for 2-20 min at 60 ℃, centrifuging, freezing and drying to obtain FMSN-MnO2BSA-CQ4T nanoprobe.
In this embodiment, the albumin is bovine serum albumin. The surfactant in step S1 is cetyltrimethylammonium bromide.
Preferably, the FMSN-MnO2The BSA-CQ4T nanoprobe has the capability of responding and degrading by a tumor microenvironment.
Example 1
Taking 83.33g of sodium hydroxide and 1L of deionized water, adding the sodium hydroxide and the deionized water into a beaker, fully mixing, transferring the mixed solution into a volumetric flask, and preparing a sodium hydroxide solution with the concentration of 2moL/L for later use;
taking 120mL of deionized water, 2.750g of bovine serum albumin and 1.05g of hexadecyl trimethyl ammonium bromide, adding the deionized water, the bovine serum albumin and the hexadecyl trimethyl ammonium bromide into a beaker together, placing the beaker into an ultrasonic dispersion instrument for dissolution and dispersion, wherein the frequency is 59KHz, and stirring the mixture for 30min at room temperature to form a transparent solution; adjusting the pH value of the mixed solution to 12 by using a prepared sodium hydroxide solution, heating to 37 ℃, and stirring at constant temperature for 12 hours;
fully mixing 10mL of ethyl orthosilicate and 5mL of bis- [3- (triethoxysilyl) propyl ] -tetrasulfide, slowly dripping the mixture into the solution, sealing, and stirring at the constant temperature of 37 ℃ for 12 hours; washing, centrifuging and drying the product by deionized water, placing the dried solid powder in a roasting furnace, and roasting at 550 ℃ for 300min to obtain the rod-shaped mesoporous silica nano particle FMSN.
Dissolving 1.0g of FMSN nano material in 90.7mL of deionized water, fully dissolving, adding 297.5mg of KMnO4Stirring for 4h at room temperature, washing with deionized water, centrifuging, and freeze-drying to obtain FMSN-MnO2And (3) powder.
Taking 700mL of absolute ethyl alcohol and FMSN-MnO21.50g was added to a beaker, 1mL of APTES (3-aminopropyltriethoxysilane) was dissolved in 0.7mL of deionized water, and the FMSN-MnO described above was added rapidly2Reacting for 10 hours at room temperature in the ethanol solution, washing with deionized water, centrifuging for three times, and keeping FMSN-MnO in the centrifuged solution2Adding 10g of bovine serum albumin into the solution at the concentration of 10g/L, reacting for 6h at room temperature, washing with deionized water, centrifuging for three times, and keeping FMSN-MnO in the centrifuged solution2Adding 0.1g of CQ4T prepared in advance into 10g/L solution, mixing the solution by vortex uniformly, bathing for 15min at 60 ℃, washing with deionized water, centrifuging, and freeze-drying to obtain FMSN-MnO2-BSA-CQ4T nanomaterial.
Example 2
Taking 83.33g of sodium hydroxide and 1L of deionized water, adding the sodium hydroxide and the deionized water into a beaker, fully mixing, transferring the mixed solution into a volumetric flask, and preparing a sodium hydroxide solution with the concentration of 2moL/L for later use;
taking 75mL of deionized water, 1.688g of bovine serum albumin and 0.655g of hexadecyl trimethyl ammonium bromide, adding the deionized water, the bovine serum albumin and the hexadecyl trimethyl ammonium bromide into a beaker together, placing the beaker into an ultrasonic dispersion instrument for dissolution and dispersion, wherein the frequency is 59KHz, and stirring the mixture at room temperature for 30min to form a transparent solution; adjusting the pH value of the mixed solution to 12 by using a prepared sodium hydroxide solution, heating to 37 ℃, and stirring for 5 hours at constant temperature;
fully mixing 7mL of ethyl orthosilicate and 2.3mL of bis- [3- (triethoxysilyl) propyl ] -tetrasulfide, slowly dripping the mixture into the solution, sealing, and stirring at the constant temperature of 37 ℃ for 16 hours; washing, centrifuging and drying the product by deionized water, placing the dried solid powder in a roasting furnace, and roasting at 550 ℃ for 300min to obtain the rod-shaped mesoporous silica nano particle FMSN.
Dissolving 0.6g of the FMSN nano material in 60mL of deionized water, fully dissolving, and adding 156.3mg of KMnO4Stirring for 1h at room temperature, washing with deionized water, centrifuging, and freeze-drying to obtain FMSN-MnO2And (3) powder.
Taking 375mL of absolute ethyl alcohol and FMSN-MnO20.750g was added to a beaker, 0.4mL of APTES (3-aminopropyltriethoxysilane) was dissolved in 0.5mL of deionized water, and the FMSN-MnO described above was added rapidly2Reacting for 8 hours at room temperature in the ethanol solution, washing with deionized water, centrifuging for three times, and keeping FMSN-MnO in the centrifuged solution2Adding 9.6g of bovine serum albumin into the solution with the concentration of 10g/L, reacting for 2 hours at room temperature, washing with deionized water, centrifuging for three times, and keeping FMSN-MnO in the centrifuged solution2Adding 50mg of CQ4T with concentration of 10g/L, mixing the solution by vortex, bathing at 60 deg.C for 3min, washing with deionized water, centrifuging, and freeze drying to obtain FMSN-MnO2-BSA-CQ4T nanomaterial.
Example 3
Taking 83.33g of sodium hydroxide and 1L of deionized water, adding the sodium hydroxide and the deionized water into a beaker, fully mixing, transferring the mixed solution into a volumetric flask, and preparing a sodium hydroxide solution with the concentration of 2moL/L for later use;
adding 160mL of deionized water, 3.75g of bovine serum albumin and 1.43g of hexadecyl trimethyl ammonium bromide into a beaker together, placing the beaker into an ultrasonic dispersion instrument for dissolution and dispersion, wherein the frequency is 59KHz, and stirring the mixture at room temperature for 30min to form a transparent solution; adjusting the pH value of the mixed solution to 12 by using a prepared sodium hydroxide solution, heating to 37 ℃, and stirring for 15 hours at constant temperature;
fully mixing 15mL of ethyl orthosilicate and 5mL of bis- [3- (triethoxysilyl) propyl ] -tetrasulfide, slowly dripping the mixture into the solution, sealing, and stirring at the constant temperature of 37 ℃ for 28 hours; washing, centrifuging and drying the product by deionized water, placing the dried solid powder in a roasting furnace, and roasting at 550 ℃ for 300min to obtain the rod-shaped mesoporous silica nano particle FMSN.
Dissolving 1.5g of the FMSN nano material in 150mL of deionized water, fully dissolving, adding 478.6mg of KMnO4Stirring for 5h at room temperature, washing with deionized water, centrifuging, and freeze-drying to obtain FMSN-MnO2And (3) powder.
Taking 800mL of absolute ethyl alcohol and FMSN-MnO21.8g was added to a beaker, 1mL of APTES (3-aminopropyltriethoxysilane) was dissolved in 2mL of deionized water, and the FMSN-MnO described above was added rapidly2Reacting for 15h at room temperature, washing with deionized water, centrifuging for three times, and keeping FMSN-MnO in the centrifuged solution2Adding 16g of bovine serum albumin into the solution at the concentration of 10g/L, reacting for 10 hours at room temperature, washing with deionized water, centrifuging for three times, and keeping FMSN-MnO in the centrifuged solution2Adding prepared CQ4T into 10g/L solution at 150mg, mixing the solution by vortex, bathing at 60 deg.C for 20min, washing with deionized water, centrifuging, and freeze drying to obtain FMSN-MnO2-BSA-CQ4T nanomaterial.
Example 4
Taking 83.33g of sodium hydroxide and 1L of deionized water, adding the sodium hydroxide and the deionized water into a beaker, fully mixing, transferring the mixed solution into a volumetric flask, and preparing a sodium hydroxide solution with the concentration of 2moL/L for later use;
taking 100mL of deionized water, 2.52g of bovine serum albumin and 0.70g of hexadecyl trimethyl ammonium bromide, adding the deionized water, the bovine serum albumin and the hexadecyl trimethyl ammonium bromide into a beaker together, placing the beaker into an ultrasonic dispersion instrument for dissolution and dispersion, wherein the frequency is 59KHz, and stirring the mixture at room temperature for 30min to form a transparent solution; adjusting the pH value of the mixed solution to 12 by using a prepared sodium hydroxide solution, heating to 37 ℃, and stirring for 7 hours at a constant temperature;
fully mixing 15mL of ethyl orthosilicate and 5mL of bis- [3- (triethoxysilyl) propyl ] -tetrasulfide, slowly dripping the mixture into the solution, sealing, and stirring at the constant temperature of 37 ℃ for 24 hours; washing, centrifuging and drying the product by deionized water, placing the dried solid powder in a roasting furnace, and roasting at 550 ℃ for 300min to obtain the rod-shaped mesoporous silica nano particle FMSN.
Dissolving 0.8g of the FMSN nano material in 90mL of deionized water, fully dissolving, and adding 226.8mg of KMnO4Stirring for 4h at room temperature, washing with deionized water, centrifuging, and freeze-drying to obtain FMSN-MnO2And (3) powder.
Taking 500mL of absolute ethyl alcohol and FMSN-MnO20.750g was added to a beaker, 0.4mL of APTES (3-aminopropyltriethoxysilane) was dissolved in 0.8mL of deionized water, and the FMSN-MnO described above was added rapidly2Reacting for 10 hours at room temperature in the ethanol solution, washing with deionized water, centrifuging for three times, and keeping FMSN-MnO in the centrifuged solution2Adding 7.1g bovine serum albumin into the solution with the concentration of 10g/L, reacting for 5h at room temperature, washing with deionized water, centrifuging for three times, and keeping FMSN-MnO in the centrifuged solution2Adding 50mg of CQ4T prepared in advance into 10g/L solution, mixing the solution by vortex uniformly, bathing for 6min at 60 ℃, washing with deionized water, centrifuging, and freeze-drying to obtain FMSN-MnO2-BSA-CQ4T nanomaterial.
Example 5
Taking 83.33g of sodium hydroxide and 1L of deionized water, adding the sodium hydroxide and the deionized water into a beaker, fully mixing, transferring the mixed solution into a volumetric flask, and preparing a sodium hydroxide solution with the concentration of 2moL/L for later use;
taking 150mL of deionized water, 2.750g of bovine serum albumin and 1.40g of hexadecyl trimethyl ammonium bromide, adding the deionized water, the bovine serum albumin and the hexadecyl trimethyl ammonium bromide into a beaker together, placing the beaker into an ultrasonic dispersion instrument for dissolution and dispersion, wherein the frequency is 59KHz, and stirring the mixture at room temperature for 30min to form a transparent solution; adjusting the pH value of the mixed solution to 12 by using a prepared sodium hydroxide solution, heating to 37 ℃, and stirring at constant temperature for 12 hours;
fully mixing 15mL of ethyl orthosilicate and 5mL of bis- [3- (triethoxysilyl) propyl ] -tetrasulfide, slowly dripping the mixture into the solution, sealing, and stirring at the constant temperature of 37 ℃ for 30 hours; washing, centrifuging and drying the product by deionized water, placing the dried solid powder in a roasting furnace, and roasting at 550 ℃ for 300min to obtain the rod-shaped mesoporous silica nano particle FMSN.
Dissolving 0.8g of the FMSN nano material in 100mL of deionized water, fully dissolving, and adding 300.3mg of KMnO4Stirring for 5h at room temperature, washing with deionized water, centrifuging, and freeze-drying to obtain FMSN-MnO2And (3) powder.
Taking 700mL of absolute ethyl alcohol and FMSN-MnO21.50g was added to a beaker, 0.8mL of APTES (3-aminopropyltriethoxysilane) was dissolved in 0.5mL of deionized water, and the FMSN-MnO described above was added rapidly2Reacting for 13 hours at room temperature in the ethanol solution, washing with deionized water, centrifuging for three times, and keeping FMSN-MnO in the centrifuged solution2Adding 12.0g bovine serum albumin into the solution with the concentration of 10g/L, reacting for 8h at room temperature, washing with deionized water, centrifuging for three times, and keeping FMSN-MnO in the centrifuged solution2Adding 120mg of CQ4T prepared in advance into 10g/L solution, mixing the solution by vortex uniformly, bathing for 15min at 60 ℃, washing with deionized water, centrifuging, and freeze-drying to obtain FMSN-MnO2-BSA-CQ4T nanomaterial.
Example 6
Taking 83.33g of sodium hydroxide and 1L of deionized water, adding the sodium hydroxide and the deionized water into a beaker, fully mixing, transferring the mixed solution into a volumetric flask, and preparing a sodium hydroxide solution with the concentration of 2moL/L for later use;
taking 120mL of deionized water, 1.750g of bovine serum albumin and 1.05g of hexadecyl trimethyl ammonium bromide, adding the deionized water, the bovine serum albumin and the hexadecyl trimethyl ammonium bromide into a beaker together, placing the beaker into an ultrasonic dispersion instrument for dissolution and dispersion, wherein the frequency is 59KHz, and stirring the mixture for 30min at room temperature to form a transparent solution; adjusting the pH value of the mixed solution to 12 by using a prepared sodium hydroxide solution, heating to 37 ℃, and stirring for 8 hours at a constant temperature;
fully mixing 15mL of ethyl orthosilicate and 5mL of bis- [3- (triethoxysilyl) propyl ] -tetrasulfide, slowly dripping the mixture into the solution, sealing, and stirring at the constant temperature of 37 ℃ for 18 hours; washing, centrifuging and drying the product by deionized water, placing the dried solid powder in a roasting furnace, and roasting at 550 ℃ for 300min to obtain the rod-shaped mesoporous silica nano particle FMSN.
Dissolving 0.6g of the FMSN nano material in 30mL of deionized water, fully dissolving, and adding 234.5mg of KMnO4Stirring for 2h at room temperature, washing with deionized water, centrifuging, and freeze-drying to obtain FMSN-MnO2And (3) powder.
Taking 280mL of absolute ethyl alcohol and FMSN-MnO20.750g was added to a beaker, 0.5mL of APTES (3-aminopropyltriethoxysilane) was dissolved in 0.5mL of deionized water, and the FMSN-MnO described above was added rapidly2Reacting for 10 hours at room temperature in the ethanol solution, washing with deionized water, centrifuging for three times, and keeping FMSN-MnO in the centrifuged solution2Adding 10g of bovine serum albumin into the solution at the concentration of 10g/L, reacting for 6h at room temperature, washing with deionized water, centrifuging for three times, and keeping FMSN-MnO in the centrifuged solution2Adding 50mg of CQ4T prepared in advance into 10g/L solution, mixing the solution by vortex uniformly, carrying out water bath at 60 ℃ for 8min, washing with deionized water, centrifuging, and freeze-drying to obtain FMSN-MnO2-BSA-CQ4T nanomaterial.
The diagnosis and treatment integrated nanoprobe prepared by the method is dissolved in PBS buffer solution, and administration is carried out through rat tail intravenous injection, so that the imaging performance and the treatment effect of the nanoprobe are detected.
Fig. 1 is a transmission electron microscope image of the diagnosis and treatment integrated nanoprobe synthesized in example 1 of the present invention, and it can be seen from the image that the synthesized diagnosis and treatment integrated nanoprobe has a unique rod-like structure, and it can be seen from the image that the long diameter of the nanoprobe crystal grain is about 88nm and the short diameter is about 18 nm.
FIG. 2 is an X-ray photoelectron spectrum of Mn element in the integrated nanoprobe synthesized in example 1 of the present invention, wherein it can be seen that 2p corresponds to Mn in the graph3/2And 2p2/1Peak is MnO2The peak corresponding to the medium Mn element.
Fig. 3 shows the degradation performance of the integrated diagnosis and treatment nanoprobe synthesized in example 1, and as can be seen from the transmission electron microscope images of the integrated diagnosis and treatment nanoprobe in a simulated tumor microenvironment glutathione solution (10mM) at different times, the nanoprobe starts to degrade within 5 hours and completely degrades within 160 hours.
Fig. 4 is a performance study of the diagnosis and treatment integrated nanoprobe synthesized in embodiment 1 of the present invention on generation of hydroxyl radicals at different times, and it can be seen from the figure that the ultraviolet-visible spectrum of the diagnosis and treatment integrated nanoprobe in the presence of methylene blue shows that the hydroxyl radical generation capacity is increased with time.
Fig. 5 is a graph showing the cell survival rate of the diagnosis and treatment integrated nanoprobe synthesized in example 1 according to the present invention after the cytochemical dynamic therapy of different concentrations. As can be seen, the cell survival rate after the chemodynamic treatment decreased with the increase of the administration concentration, and was 37.8% when the administration concentration was 800. mu.g/mL.
FIG. 6 is an NIR-II fluorescence image of a nude mouse living body with the integrated nano probe for diagnosis and treatment synthesized in example 1 of the present invention. As can be seen from the figure, the fluorescence of the tumor part is gradually enhanced 2h after the administration of the drug to the tail vein of the nude mouse, the fluorescence signal of the tumor part is strongest 6h, and then the fluorescence intensity is gradually weakened along with the increase of time.
Fig. 7 is an MRI image of a nude mouse living body of the diagnosis and treatment integrated nanoprobe synthesized in example 1 of the present invention. As shown in the figure, the tumor site showed strong MRI signal 6h after the administration of the tail vein in the nude mice.
FIG. 8 is a tumor volume graph showing the anti-tumor treatment effect of the diagnosis and treatment integrated nanoprobe synthesized in example 1 of the present invention on a living nude mouse. As shown in the figure, the nude mice are treated by chemodynamic therapy, the nude mice are injected with diagnosis and treatment integrated nanoprobes and PBS respectively in tail veins, after 14d injection, the tumor volume of the nude mice injected with the nanoprobes is far lower than that of the nude mice injected with the PBS, and the treatment effect is good.
Although only the preferred embodiments of the present invention have been described in detail, the present invention is not limited to the above embodiments, and various changes can be made without departing from the spirit of the present invention within the knowledge of those skilled in the art, and all changes are encompassed in the scope of the present invention.
Claims (6)
1. The utility model provides a tumour microenvironment response degradation type integration nanoprobe of diagnosing which characterized in that: the nanoprobe is in a rod shapeMesoporous silica nano particle is used as carrier, and MnO is loaded on the mesoporous silica nano particle by potassium permanganate2Then coating bovine serum albumin through electrostatic adsorption, and coupling fluorescent micromolecule CQ4T on the bovine serum albumin, wherein the rod-shaped mesoporous silica nano particles account for 90-93 wt% of the nano probe, and MnO25-8 wt% of the nano probe, and the fluorescent molecule CQ4T accounts for 1-2.5 wt% of the weight of the nano probe.
2. The tumor microenvironment response degradation type diagnosis and treatment integrated nanoprobe according to claim 1, wherein: the long diameter of the crystal grain of the nano probe is 80-90 nm, and the short diameter of the crystal grain of the nano probe is 12-20 nm.
3. A preparation method of a tumor microenvironment response degradation type diagnosis and treatment integrated nanoprobe is characterized by comprising the following steps:
s1, mixing deionized water: surfactant (b): the albumin is prepared according to the following steps of 277.778-555.556: 0.12-0.29: 1.057.10-3～1.820·10-3Preparing a mixed solution according to the molar ratio, and stirring for 5-30 min at room temperature;
s2, dropwise adding a sodium hydroxide solution with the concentration of 2mol/L into the mixed solution in the S1, adjusting the pH value of the mixed solution to 12, and stirring at the constant temperature of 37 ℃ for 5-15 hours;
s3, according to the molar ratio of ethyl orthosilicate to bis- [3- (triethoxysilyl) propyl ] -tetrasulfide of 1.296-6.480: 0.12-0.29, slowly dropwise adding a mixture of ethyl orthosilicate and bis- [3- (triethoxysilyl) propyl ] -tetrasulfide into the mixed solution in S2, sealing, and stirring at the constant temperature of 37 ℃ for 10-30 h;
s4, washing the mixed solution in the S3 with deionized water, centrifuging, roasting at 450-600 ℃, and drying to obtain the rodlike mesoporous silica nano material FMSN without the template agent;
s5, according to deionized water: FMSN: KMnO40.3-2: 5-10: 0.5-3 mass ratio, KMnO is added into the water solution mixed with the rod-shaped mesoporous silica4Stirring for 1-5 h at room temperature, centrifuging, and freeze-drying to obtain FMSN-MnO2Powder;
s6, pressAs in FMSN-MnO2: 3-aminopropyltriethoxysilane: anhydrous ethanol: 100-200 parts of deionized water: 1.67-3.05: 1356 to 2372: 1.5-3.0, adding the mixed solution of 3-aminopropyltriethoxysilane and deionized water into FMSN-MnO2Stirring the mixed solution with absolute ethyl alcohol for 8-15 hours at room temperature, centrifuging, and mixing the solution: albumin is 0.5 to 1: 5-25, adding albumin, reacting for 1-10 h at room temperature, and centrifuging to obtain FMSN-MnO2-BSA；
S7, FMSN-MnO2CQ4T solution with concentration of 2mg/mL was added to BSA solution, wherein FMSN-MnO was2-BSA: the mass ratio of CQ4T is 5-25: 0.5-2, mixing the solution evenly by vortex, bathing for 2-20 min at 60 ℃, centrifuging, freezing and drying to obtain FMSN-MnO2BSA-CQ4T nanoprobe.
4. The preparation method of the tumor microenvironment response degradation type diagnosis and treatment integrated nanoprobe according to claim 3, which is characterized in that: the surfactant in step S1 is cetyltrimethylammonium bromide.
5. The preparation method of the tumor microenvironment response degradation type diagnosis and treatment integrated nanoprobe according to claim 3, which is characterized in that: the albumin is bovine serum albumin.
6. The preparation method of the tumor microenvironment response degradation type diagnosis and treatment integrated nanoprobe according to claim 3, which is characterized in that: the FMSN-MnO2The BSA-CQ4T nanoprobe has the capability of responding and degrading by a tumor microenvironment.
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