CN115252776A - Preparation of up-conversion-metal phenolic network composite nano material and application thereof in tumor treatment - Google Patents
Preparation of up-conversion-metal phenolic network composite nano material and application thereof in tumor treatment Download PDFInfo
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- CN115252776A CN115252776A CN202210583052.0A CN202210583052A CN115252776A CN 115252776 A CN115252776 A CN 115252776A CN 202210583052 A CN202210583052 A CN 202210583052A CN 115252776 A CN115252776 A CN 115252776A
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Abstract
The invention relates to the field of biomedical nano materials, and discloses a preparation method of an up-conversion-metal phenolic network composite nano material. The method comprises the following steps: (1) Synthesizing rare earth up-conversion nanoparticles by adopting a thermal decomposition method; (2) Coating a layer of mesoporous silica on the surface of UCNPs to ensure that the UCNPs have water solubility, and loading a photosensitizer and chemotherapeutic drug DOX to the UCNPs @ mSiO2In the pore canal; (3) Coupling UCNPs @ mSiO2And containing TA and Fe3+Mixing the aqueous solution of (1), inducing UCNPs @ mSiO2Rapid formation of MPN film on the surface to obtainA nanocomposite material. The invention also discloses a preparation method of the composite material and application of the composite material in tumor treatment. The MPN film has pH response performance and photothermal performance and is used for PTT treatment; MPN is gradually decomposed to realize DOX controllable release, and is used for chemotherapy; MC540 generates ROS in response to green emission for PDT.
Description
Technical Field
The invention relates to the field of biological nano material medicine, in particular to an upconversion-metal phenolic network composite nano material for synergistic PTT/PDT/chemotherapy in tumor treatment.
Background
Due to the complexity of the tumor microenvironment, the therapeutic effect of monotherapy is often unsatisfactory. Therefore, cancer treatment has shifted from monotherapy to combination therapy to achieve the best therapeutic effect of synergistic treatment. Chemotherapy relies on chemotherapeutic drugs (e.g., doxorubicin (DOX), paclitaxel, etc.) to kill cancer cells. However, these drugs can be absorbed by cancer cells and normal cells, which has a certain adverse effect on normal cells, and in addition, the drug delivery process to the tumor site can face the drug premature ejaculation, which leads to the problem of insufficient drug concentration at the cancer site, so the development of a controllable drug release system has guiding significance in the field of cancer treatment.
Photodynamic therapy (PDT) is a non-invasive, low-toxicity and side-effect treatment modality, with promising promise in cancer therapy. The photodynamic therapy can not be separated from three conditions of photosensitizer, excitation light source and oxygen. The most used photosensitizer molecules at present mainly absorb light in an ultraviolet or visible light region, but have certain limitation on tumor treatment at deep tissues due to the limited penetration depth of light with short wavelength.
Therefore, it is a problem to be solved by researchers in this field to develop a novel material that can achieve both controlled drug release and solve the problem of tissue penetration depth of the excitation light source in PDT.
Disclosure of Invention
Aiming at the defects in the prior art, the invention provides the preparation method of the up-conversion-metal phenolic network composite nano material, which is simple and easy to operate, and the prepared material has uniform appearance; the synthesized composite material after modification can meet the requirements of clinical diagnosis and treatment integration, and a PTT/PDT/chemotherapy combined treatment platform under the guidance of imaging is constructed under the irradiation of near infrared light.
In order to realize the purpose of the invention, the invention adopts the following technical scheme:
a preparation method of a composite nano material based on an up-conversion-metal phenolic network is characterized by comprising the following steps:
(1) Preparation of NaYF4Yb, er, nd nanoparticles as core: by adopting a thermal decomposition method, the oleic acid is prepared in the solution containing 6mL
100mL three-neck flasks of (OA) and 15mL Octadecene (ODE) were charged with Y (CH) in varying proportions3CO2)3，Yb(CH3CO2)3，Er(CH3CO2)3And Nd (CH)3CO2)3(1mmol, y. Placing the mixture on a heating sleeve, then heating to 160 ℃, uniformly stirring (rpm is approximately equal to 700), and keeping the temperature for five minutes until the acetate powder is completely dissolved to form a rare earth-oleic acid complex, namely a light yellow clear transparent solution; the heating is then turned off and the solution is cooled to below 60C. Weighing 0.1g sodium hydroxide and 0.15g ammonium fluoride, dissolving in 5mL methanol solution, carrying out ultrasonic dissolution, slowly adding the mixed solution into a three-mouth flask drop by drop, heating to 110 ℃, reacting for about 30 minutes so as to evaporate methanol, vacuumizing the environment in the three-mouth flask by using a vacuum system for about 30 minutes, then exchanging and ventilating air for 3 times, every time for 30 seconds, heating the reactant to 300 ℃ in an argon environment, and preserving heat to 1h. After the reaction was complete, the solution was cooled to room temperature and the product (NaYF) was precipitated with absolute ethanol4Yb, er and Nd upconversion nanometer particles), washing with cyclohexane and ethanol for multiple times respectively to obtain an upconversion nanometer material with uniform particles, and storing in cyclohexane;
(2) Preparation of NaYF4:Yb,Er@NaYF4Core-shell upconversion nanoparticles: weighing Metal-acetate salt Y (CH)3CO2)3And Nd (CH)3CO2)3(1 mmol, Y; then cooling to below 80 deg.C (boiling point of cyclohexane), adding 5mL above NaYF4Heating Yb, er and Nd cyclohexane solution to 150 deg.c to eliminate cyclohexane solvent until no liquid flows down and no bubble is produced in the solution, and lowering the temperature to below 60 deg.c; 0.0674g NaOH and 0.0374g NH were taken4F is added into 5mL methanol solvent, is added into the reaction solution drop by drop slowly after ultrasonic dissolution, is heated to 110 ℃, and is removed until no mist and no bubbles exist; then vacuumizing for 30min, exchanging and introducing argon for 3 times, heating to 300 ℃, and reacting for 1h. Purification steps such as NaYF4Yb, er and Nd nano particles. Final purified NaYF4:Yb,Er,Nd@NaYF4Nd (core-shell) nanoparticles are dispersed in 15mL cyclohexane;
(3) Water-soluble mesoporous silica coated NaYF4:Yb,Er,Nd@NaYF4Preparing Nd nano particles: firstly, weighing 0.1g CTAB in a beaker, adding 20mL ultrapure water, heating to 70 ℃, and clarifying the solution under strong stirring; the heating was turned off and 5mL NaYF was added at room temperature4:Yb,Er,Nd@NaYF4Nd (approximatively 15 mg) cyclohexane solution, stirring overnight until the solution is clarified again; after overnight, the water is evaporated to reduce the solvent, then water is added to 20mL, the solution is transferred to a 250mL three-neck flask, 40mL ultrapure water, 6mL absolute ethyl alcohol and 300 mu L (2 mol/L) NaOH aqueous solution are added, the solution is placed under an oil bath pan at 70 ℃ for condensation and reflux for 30min (the rotating speed is maximum), 400 mu L TEOS is slowly added dropwise by a 200 mu L liquid transfer gun, after stirring reaction of 1h, the solution is cooled to the room temperature, precipitates are obtained by centrifugation, the absolute ethyl alcohol is washed for 3 times, free silicon is removed, and the UCNPs coated with the mesoporous silicon dioxide are obtained. To remove the CTAB template, a mesoporous structure is obtained. The precipitate was dissolved in 40mL acidic ethanol solution (pH =1.4 to 1.5), and reacted at 60 ℃ with stirring under reflux for 1h. Centrifuging to obtain precipitate, washing with anhydrous ethanol for 2~3 times, dispersing the final product in 20mL anhydrous ethanol, and repeating the reflux process for 2-3 times to remove CTAB and reduce biological toxicity;
（4）UCNPs@mSiO2preparation of MC540/DOX nanocomposites: preparing 0.2mg/mL DOX aqueous solution and 0.2mg/mL MC540 aqueous solution, then adding UCNPs @ mSiO2Centrifuging the aqueous solution to obtain a solid precipitate, collecting 4mg UCNPs @ mSiO2Soaking in 2mL of a mixture of DOX and MC540In the solution, the solution is firstly put in an ultrasonic machine for ultrasonic treatment for 30min, and then 24h is rapidly stirred on a magnetic stirring heating sleeve at room temperature in a dark environment. After physical adsorption is finished, centrifuging to remove supernatant and leave precipitate, then dissolving with ultrapure water, centrifuging again to leave precipitate, washing for three times, and removing free DOX and MC540;
（5）UCNPs@mSiO2preparation of @ MPN-MC540/DOX nanocomposite: under vigorous stirring, 40. Mu.L TA and 40. Mu.L FeCl were added3(24 mM) solution was added to UCNPs @ mSiO at 2mL2-MC540/DOX in aqueous solution. Finally, the collected UCNPs @ mSiO is obtained by centrifugal separation and washing three times by deionized water2@ MPN-MC540/DOX nanocomposite.
The step (1) comprises the following specific steps:
(1) A100 mL three-neck flask containing 6mL Oleic Acid (OA) and 15mL Octadecene (ODE) was charged with Y (CH) in various ratios3CO2)3，Yb(CH3CO2)3，Er(CH3CO2)3And Nd (CH)3CO2)3(1mmol, y. Putting the mixture on a heating sleeve, then heating to 160 ℃, uniformly stirring, and keeping the temperature for five minutes until the acetate powder is completely dissolved to form a rare earth-oleic acid complex, namely a light yellow clear transparent solution;
(2) And then, turning off heating, and cooling the solution to below 60 ℃. Weighing 0.1g sodium hydroxide and 0.15g ammonium fluoride, dissolving in 5mL methanol solution, carrying out ultrasonic dissolution, then gradually adding the mixed solution into a three-mouth flask drop by drop, heating to 110 ℃, reacting for about 30 minutes to evaporate methanol, then vacuumizing the environment in the three-mouth flask by using a vacuum system for about 30 minutes, then exchanging the vacuumizing and ventilating for 3 times, each time for 30 seconds, heating the reactant to 300 ℃ in an argon environment, and carrying out heat preservation for 1h. After the reaction was complete, the solution was cooled to room temperature and the product (NaYF) was precipitated with absolute ethanol4Yb, er, nd upconversion nanoparticles), washing with cyclohexane and ethanol for multiple times respectively to obtain upconversion nanoparticles with uniform particles, and storing in cyclohexane。
The rotating speed of the heating sleeve in the step (1) is 700rpm.
And (3) performing a reaction for 1 hour at 300 ℃ in an argon environment in the step (2).
The step (3) comprises the following specific steps:
(1) Firstly, weighing 0.1g CTAB in a beaker, adding 20mL ultrapure water, heating to 70 ℃, and clarifying the solution under strong stirring; the heating was turned off and 5mL NaYF was added at room temperature4:Yb,Er,Nd@NaYF4Nd (approximatively 15 mg) cyclohexane solution, stirring overnight until the solution is clarified again;
(2) After overnight, the water is evaporated to reduce the solvent, then water is added to 20mL, the solution is transferred to a 250mL three-neck flask, 40mL ultrapure water, 6mL absolute ethyl alcohol and 300 mu L (2 mol/L) NaOH aqueous solution are added, the solution is placed under an oil bath pan at 70 ℃ for condensation and reflux for 30min (the rotating speed is maximum), 400 mu L TEOS is slowly added dropwise by a 200 mu L liquid transfer gun, after stirring reaction of 1h, the solution is cooled to the room temperature, precipitates are obtained by centrifugation, the absolute ethyl alcohol is washed for 3 times, free silicon is removed, and UCNPs coated by mesoporous silicon dioxide are obtained;
(3) To remove the CTAB template, a mesoporous structure is obtained. The precipitate was dissolved in 40mL acidic ethanol solution (pH =1.4 to 1.5), and reacted at 60 ℃ with stirring under reflux for 1h. Centrifuging to obtain precipitate, washing with anhydrous ethanol for 2~3 times, dispersing the final product in 20mL anhydrous ethanol, and repeating the refluxing process for 2-3 times to remove CTAB and reduce biological toxicity.
The heating and stirring temperature in the step (3) is 70 ℃, and the rotating speed is 1250rpm.
Adding NaYF into the step (3)4:Yb,Er,Nd@NaYF4The Nd cyclohexane solution was about 15mg and the overnight solution was clarified before the next experiment was performed.
In the step (3), the CTAB template is removed by refluxing in an acidic ethanol solution with pH =1.4 to 1.5, and the process can be repeated for 2-3 times to sufficiently remove CTAB and reduce biological toxicity.
The step (4) comprises the following specific steps:
(1) Prepare 0.2mg/mL DOX in waterThe solution and an aqueous solution of 0.2mg/mL MC540, then UCNPs @ mSiO2Centrifuging the aqueous solution to obtain a solid precipitate, collecting 4mg UCNPs @ mSiO2Soaking in 2mL of mixed solution of DOX and MC540, firstly placing in an ultrasonic machine for ultrasonic treatment for 30min, and then rapidly stirring on a magnetic stirring heating sleeve at room temperature in a dark environment for 24h;
(2) After the physical adsorption was completed, the supernatant was removed by centrifugation to leave a precipitate, and then dissolved in ultrapure water, centrifuged again to leave a precipitate, and washed three times to remove free DOX and MC540.
In the step (5), 40. Mu.L of TA and 40. Mu.L of FeCl are added under vigorous stirring3(24 mM) solution to 2mL UCNPs @ mSiO2-MC540/DOX in aqueous solution. Finally, the collected UCNPs @ mSiO is obtained by centrifugal separation and washing three times by deionized water2@ MPN-MC540/DOX nanocomposite.
The preparation method of the up-conversion-metal phenolic network composite nanomaterial is characterized in that the up-conversion-metal phenolic network composite nanomaterial is synthesized by a thermal decomposition method, and has uniform size, good biocompatibility, excellent photo-thermal performance and excellent pH response performance.
The preparation method of the up-conversion-metal phenolic network composite nano material is characterized in that the in-vitro cell therapy experiment and the mouse in-vivo tumor therapy experiment prove that the composite material realizes the combined treatment of the PTT/PDT/chemotherapy tumor and has higher combined treatment effect.
The invention has the advantages that:
(1) The preparation method of the up-conversion-metal phenolic network composite nano material provided by the invention is characterized in that UCNPs are synthesized by adopting a thermal decomposition method. The synthetic process is simple and convenient to operate. The preparation process of the composite nano material has high and stable repetition rate. The invention can realize the stability, uniformity and good biocompatibility of the nano-scale structure.
(2) The up-conversion-metal phenolic network composite nanomaterial provided by the invention is characterized in that a layer of mesoporous silica is coated on the surface of UCNPs, so that the UCNPs become water-soluble and are used for subsequent biological experiments. Mesoporous structure using silicaLoading photosensitizer MC540 and chemotherapeutic drug DOX to UCNPs @ mSiO2In the pore canal. Finally, UCNPs @ mSiO is assembled by a simple assembly method2And containing TA and Fe3+The strong adhesion of TA and the complexation of metal ions induce UCNPs @ mSiO2Rapid formation of surface MPN films.
(3) The up-conversion-metal phenolic network composite nano material provided by the invention is characterized in that as MPN has dual properties (photo-thermal property and pH response property), UCNPs @ mSiO is irradiated by 808 nm laser2The @ MPN-MC540/DOX has good photothermal performance, the photothermal conversion efficiency is as high as 35.13%, and photothermal therapy (PTT) can be realized; meanwhile, MPN can be gradually decomposed under the weak acid condition of a tumor microenvironment to realize the controllable release of DOX, and the MPN is used for chemotherapy, and the influence of photo-heat on the DOX release is researched, so that the photo-heat can promote 5% of drug release; the photosensitizer MC540 responds to 808 nm and excites an emission peak of 545 nm of UCNPs to realize photodynamic therapy, and the synergistic effect can achieve the aim of killing tumor cells.
(4) The up-conversion-metal phenolic network composite nano material provided by the invention is characterized in that the result in the anti-cancer experiment of Hela cells and tumor-bearing mice shows that UCNPs @ mSiO2Under the excitation of 808 nm, the @ MPN-MC540/DOX nano composite material is cooperated with PTT/PDT/chemotherapy, so that the lethality rate of cancer cells is obviously increased compared with single PTT treatment or PDT/chemotherapy (PTT/chemotherapy) cooperation treatment, and the composite material has a good effect of inhibiting the growth of tumors. The present invention will be described in further detail with reference to the accompanying drawings and embodiments.
Drawings
FIG. 1 is a schematic representation of the preparation of nanomaterial N in example 12Adsorption/desorption isotherms and pore size distribution profiles.
FIG. 2 is an electron micrograph of the nanomaterial prepared in example 1.
FIG. 3 is the UV absorption diagram of the nanomaterial prepared in example 1.
FIG. 4 is a photothermal graph of the nanomaterial prepared in example 2.
FIG. 5 is a graph of the time-dependent release of DOX in PBS buffer at different pH values (7.4 and 6.0,5.0) for nanomaterials prepared in example 3.
FIG. 6 is the ROS release curve of the nanomaterial prepared in example 4 under different pH (pH =7.4, pH =6.0 and pH = 5.0) environments
FIG. 7 is a graph showing the cytotoxicity and therapeutic effects of the nanomaterials prepared in example 5 in vitro.
FIG. 8 is the body weight change curve and tumor growth curve of mice in the experiment of inhibiting Hela cell tumor-bearing mice tumor by preparing the nanomaterial of example 6.
Detailed Description
Referring to fig. 1-8, the technical solution of the present invention is explained in detail by embodiments and drawings.
Example 1
The preparation method of the up-conversion-metal phenolic network composite nanomaterial provided by the embodiment comprises the following steps:
(1) Preparation of NaYF4Yb, er, nd nanoparticles as core: by adopting a thermal decomposition method, the oleic acid is prepared in the solution containing 6mL
100mL three-neck flasks of (OA) and 15mL Octadecene (ODE) were charged with Y (CH) in varying proportions3CO2)3，Yb(CH3CO2)3，Er(CH3CO2)3And Nd (CH)3CO2)3(1mmol, y. Placing the mixture on a heating sleeve, then heating to 160 ℃, uniformly stirring (rpm is approximately equal to 700), and keeping the temperature for five minutes until the acetate powder is completely dissolved to form a rare earth-oleic acid complex, namely a light yellow clear transparent solution; the heating is then turned off and the solution is cooled to below 60C. Weighing 0.1g sodium hydroxide and 0.15g ammonium fluoride, dissolving in 5mL methanol solution, carrying out ultrasonic dissolution, slowly adding the mixed solution into a three-mouth flask drop by drop, heating to 110 ℃, reacting for about 30 minutes so as to evaporate methanol, vacuumizing the environment in the three-mouth flask by using a vacuum system for about 30 minutes, then exchanging and ventilating air for 3 times, every time for 30 seconds, heating the reactant to 300 ℃ in an argon environment, and preserving heat to 1h. After the completion of the reaction, the reaction mixture is stirred,the solution was cooled to room temperature and the product (NaYF) was precipitated with absolute ethanol4Yb, er and Nd upconversion nanometer particles), washing with cyclohexane and ethanol for multiple times respectively to obtain an upconversion nanometer material with uniform particles, and storing in cyclohexane;
(2) Preparation of NaYF4:Yb,Er@NaYF4Core-shell upconversion nanoparticles: weighing metal-acetate Y (CH)3CO2)3And Nd (CH)3CO2)3(1 mmol, Y; then cooling to below 80 deg.C (boiling point of cyclohexane), adding 5mL above NaYF4Heating Yb, er and Nd cyclohexane solution to 150 deg.c to eliminate cyclohexane solvent until no liquid flows down and no bubble is produced in the solution, and lowering the temperature to below 60 deg.c; 0.0674g NaOH and 0.0374g NH were taken4F is added into 5mL methanol solvent, is added into the reaction solution drop by drop slowly after ultrasonic dissolution, is heated to 110 ℃, and is removed until no mist and no bubbles exist; then vacuumizing for 30min, exchanging and introducing argon for 3 times, heating to 300 ℃, and reacting for 1h. Purification steps such as NaYF4Yb, er and Nd nano particles. Final purified NaYF4:Yb,Er,Nd@NaYF4Nd (core-shell) nanoparticles dispersed in 15mL cyclohexane;
(3) Water-soluble mesoporous silica coated NaYF4:Yb,Er,Nd@NaYF4Preparing Nd nano particles: firstly, weighing 0.1g CTAB in a beaker, adding 20mL ultrapure water, heating to 70 ℃, and clarifying the solution under strong stirring; the heating was turned off and 5mL NaYF was added at room temperature4:Yb,Er,Nd@NaYF4Nd (approximatively 15 mg) cyclohexane solution, stirring overnight until the solution is clarified again; after overnight, the water evaporation causes the solvent to reduce, then water to 20mL, the solution is transferred to 250mL three-mouth flask, then 40mL ultrapure water, 6mL absolute ethyl alcohol and 300 muL (2 mol/L) NaOH aqueous solution are added, the solution is placed under an oil bath pan at 70 ℃ for condensation and reflux for 30min (the rotating speed is maximum), 400 muL TEOS is slowly added dropwise by a 200 muL liquid transfer gun, after stirring reaction of 1h, the solution is cooled to room temperature, and the precipitate is obtained by centrifugation, the anhydrous water is addedWashing with ethanol for 3 times to remove free silicon to obtain mesoporous silica coated UCNPs. To remove the CTAB template, a mesoporous structure is obtained. The precipitate was dissolved in 40mL acidic ethanol solution (pH =1.4 to 1.5), and reacted at 60 ℃ with stirring under reflux for 1h. Centrifuging to obtain precipitate, washing with anhydrous ethanol for 2~3 times, dispersing the final product in 20mL anhydrous ethanol, and repeating the reflux process for 2-3 times to remove CTAB and reduce biological toxicity;
（4）UCNPs@mSiO2preparation of MC540/DOX nanocomposites: preparing 0.2mg/mL DOX aqueous solution and 0.2mg/mL MC540 aqueous solution, then adding UCNPs @ mSiO2Centrifuging the aqueous solution to obtain a solid precipitate, collecting 4mg of UCNPs @ mSiO2Soaking in 2mL of mixed solution of DOX and MC540, firstly putting in an ultrasonic machine for ultrasonic treatment for 30min, and then rapidly stirring on a magnetic stirring heating sleeve at room temperature in a dark environment for 24h. After physical adsorption is finished, centrifuging to remove supernatant and leave precipitate, then dissolving with ultrapure water, centrifuging again to leave precipitate, washing for three times, and removing free DOX and MC540;
（5）UCNPs@mSiO2preparation of @ MPN-MC540/DOX nanocomposite: under vigorous stirring, 40. Mu.L TA and 40. Mu.L FeCl were added3(24 mM) solution to 2mL UCNPs @ mSiO2-MC540/DOX in aqueous solution. Finally, the collected UCNPs @ mSiO is obtained by centrifugal separation and washing three times by deionized water2@ MPN-MC540/DOX nanocomposite.
The step (1) comprises the following specific steps:
(1) A100 mL three-neck flask containing 6mL Oleic Acid (OA) and 15mL Octadecene (ODE) was charged with Y (CH) in various ratios3CO2)3，Yb(CH3CO2)3，Er(CH3CO2)3And Nd (CH)3CO2)3(1mmol, y. Putting the mixture on a heating sleeve, then heating to 160 ℃, uniformly stirring, and keeping the temperature for five minutes until the acetate powder is completely dissolved to form a rare earth-oleic acid complex, namely a light yellow clear transparent solution;
(2) Then closeHeating, and cooling the solution to below 60 ℃. Weighing 0.1g sodium hydroxide and 0.15g ammonium fluoride, dissolving in 5mL methanol solution, carrying out ultrasonic dissolution, slowly adding the mixed solution into a three-mouth flask drop by drop, heating to 110 ℃, reacting for about 30 minutes so as to evaporate methanol, vacuumizing the environment in the three-mouth flask by using a vacuum system for about 30 minutes, then exchanging and ventilating air for 3 times, every time for 30 seconds, heating the reactant to 300 ℃ in an argon environment, and preserving heat to 1h. After the reaction was complete, the solution was cooled to room temperature and the product (NaYF) was precipitated with absolute ethanol4Yb, er, nd upconversion nanoparticles), washed with cyclohexane and ethanol respectively for multiple times to obtain upconversion nanomaterials with uniform particles, and then stored in cyclohexane.
The rotating speed of the heating sleeve in the step (1) is 700rpm.
And (3) carrying out a reaction for 1 hour at 300 ℃ in an argon environment in the step (2).
The step (3) comprises the following specific steps:
(1) Firstly, weighing 0.1g CTAB in a beaker, adding 20mL ultrapure water, heating to 70 ℃, and clarifying the solution under strong stirring; the heating was turned off and 5mL NaYF was added at room temperature4:Yb,Er,Nd@NaYF4Nd (approximatively 15 mg) cyclohexane solution, stirring overnight until the solution is clarified again;
(2) After overnight, the water is evaporated to reduce the solvent, then water is added to 20mL, the solution is transferred to a 250mL three-neck flask, 40mL ultrapure water, 6mL absolute ethyl alcohol and 300 mu L (2 mol/L) NaOH aqueous solution are added, the solution is placed under an oil bath pan at 70 ℃ for condensation and reflux for 30min (the rotating speed is maximum), 400 mu L TEOS is slowly added dropwise by a 200 mu L liquid transfer gun, after stirring reaction of 1h, the solution is cooled to the room temperature, precipitates are obtained by centrifugation, the absolute ethyl alcohol is washed for 3 times, free silicon is removed, and UCNPs coated by mesoporous silicon dioxide are obtained;
(3) To remove the CTAB template, a mesoporous structure is obtained. The precipitate was dissolved in 40mL acidic ethanol solution (pH =1.4 to 1.5), and reacted at 60 ℃ with stirring under reflux for 1h. Centrifuging to obtain precipitate, washing with anhydrous ethanol for 2~3 times, dispersing the final product in 20mL anhydrous ethanol, and repeating the refluxing process for 2-3 times to remove CTAB and reduce biological toxicity.
The heating and stirring temperature in the step (3) is 70 ℃, and the rotating speed is 1250rpm.
Adding NaYF into the step (3)4:Yb,Er,Nd@NaYF4The Nd cyclohexane solution was about 15mg and the overnight solution was clarified before the next experiment was performed.
In the step (3), the CTAB template is removed by refluxing in an acidic ethanol solution with pH =1.4 to 1.5, and the process can be repeated for 2-3 times to sufficiently remove CTAB and reduce biological toxicity.
The step (4) comprises the following specific steps:
(1) Preparing 0.2mg/mL DOX aqueous solution and 0.2mg/mL MC540 aqueous solution, then adding UCNPs @ mSiO2Centrifuging the aqueous solution to obtain a solid precipitate, collecting 4mg of UCNPs @ mSiO2Soaking in 2mL of mixed solution of DOX and MC540, firstly placing in an ultrasonic machine for ultrasonic treatment for 30min, and then rapidly stirring on a magnetic stirring heating sleeve at room temperature in a dark environment for 24h;
(2) After the physical adsorption was completed, the supernatant was removed by centrifugation to leave a precipitate, and then dissolved in ultrapure water, centrifuged again to leave a precipitate, and washed three times to remove free DOX and MC540.
In the step (5), under vigorous stirring, 40. Mu.L of TA and 40. Mu.L of FeCl are added3(24 mM) solution to 2mL UCNPs @ mSiO2-MC540/DOX in aqueous solution. Finally, the collected UCNPs @ mSiO is obtained by centrifugal separation and washing three times by deionized water2@ MPN-MC540/DOX nanocomposite.
The preparation method of the up-conversion-metal phenolic network composite nano material is characterized in that the up-conversion-metal phenolic network composite nano material is synthesized by adopting a thermal decomposition method, has uniform size, good biocompatibility and excellent photo-thermal performance and pH response performance.
The preparation method of the up-conversion-metal phenolic network composite nano material is characterized in that the in-vitro cell therapy experiment and the mouse in-vivo tumor therapy experiment prove that the composite material realizes the combined treatment of the PTT/PDT/chemotherapy tumor and has higher combined treatment effect.
The up-conversion-metal phenolic network composite nano material prepared by the method is synthesized by a thermal decomposition method.
FIG. 1 is a pore size analysis diagram of the mesoporous nanomaterial prepared in this example 1. Nitrogen adsorption-desorption mode they were tested. As can be seen from the nitrogen adsorption-desorption isotherm curve, the mesoporous nano material shows a typical type IV isotherm, the pore diameter of the synthesized mesoporous nano material is calculated to be about 2.2 nm according to the nitrogen adsorption-desorption isotherm curve by using a Brunauer-Emmett-Teller (BET) method, and the pore diameter basically accords with the specification of mesoporous size (2-50 nm); the specific surface area of the mesoporous nano-particles is 979 m2/g。
FIG. 2 is a TEM photograph of the upconversion-metal phenolic network composite nanomaterial prepared in this example 1, and it can be seen from the observation that UCNPs @ mSiO coated with MPN2Has good monodispersity, the average grain diameter is about 101 nm, and the method has important significance for circulation in organisms.
FIG. 3 shows the UV absorption spectrum of the upconversion-metal phenolic network composite nanomaterial prepared in this example 1. As can be seen from the figure, UCNPs @ mSiO2@ MPN has a broad absorption peak at 560 nm due to Fe3+Formation of the TA complex is accompanied by charge transfer from tannic acid to iron ions.
Example 2
The preparation method and application of the upconversion-metal phenolic network composite nanomaterial provided in this embodiment are basically the same as those in embodiment 1, and the difference is that:
the method for applying the up-conversion-metal phenolic network composite nanomaterial prepared in example 1 to a photo-thermal experiment specifically comprises the following steps:
(1) Respectively preparing the nano materials with the nano particle concentration of 0.1,0.2,0.4 and 0.8 mg/mL by using ultrapure water;
(2) Each sample was taken at 1 mL in a cuvette at 2W/cm using a 808 nm laser2Performing 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. 4 is a photothermal graph of the nanomaterial prepared in example 2. The observation shows that the temperature of the sample is gradually increased along with the increase of the concentration of the sample, and the prepared nano material is proved to have good photo-thermal effect and high photo-stability.
Example 3
The preparation method and application of the upconversion-metal phenolic network composite nanomaterial provided in this embodiment are basically the same as those in embodiments 1-2, except that:
the nanometer material loaded with anticancer DOX is further used as a therapeutic agent and applied to a chemotherapy method, and comprises the following steps:
(1)2 mg UCNP@mSiO2adding 2mL doxorubicin hydrochloride solution (0.2 mg/mL), stirring in the dark for adsorption for 24 hr to obtain UCNPs @ mSiO2-the DOX product is separated by centrifugation and washed with water;
(2) Mixing 2 mLUCNPs @ mSiO2The @ MPN-DOX (1 mg/mL) solution was added to a dialysis bag with a molecular weight cut-off of 8000 Da, and both ends were tied with a thread to prevent leakage of the solution. The dialysis bags were immersed in beakers containing Phosphate Buffered Saline (PBS) at different pH values (pH 7.4, pH 6.0 and pH 5.0) of 10 mL without or with NIR laser irradiation (2W/cm)2) Slowly stirring under the condition;
(3) The dialysate was aspirated and collected at different time points, and then an equal amount of fresh buffer solution was added rapidly as a supplement. The time-dependent release of DOX in PBS buffer solutions of different pH with and without laser irradiation was determined by uv-vis absorption spectroscopy at 480 nm.
FIG. 5 is a graph of the time-dependent release of DOX from the upconversion-metal phenolic network composite nanomaterial prepared in example 3 in PBS buffers at different pH values (7.4 and 6.0,5.0). As can be seen, the loading amount of DOX is 10.03 wt%, the release curve of DOX is related to the pH value, and the release rate is increased under the acidic condition. In addition, under the irradiation of near-infrared light, photothermal promotes 5% of DOX to be released, so that the photothermal effect accelerates the Brownian motion of DOX molecules and promotes the drug permeation.
Example 4
The preparation method and application of the upconversion-metal phenolic network composite nanomaterial provided in this embodiment are basically the same as those in embodiments 1 to 3, except that:
the in-vitro photodynamic therapy method for the MC 540-loaded nano diagnosis and treatment agent composite material comprises the following steps:
(1) 2mL UCNPs @ mSiO2-MC540 aqueous solution in cuvette, 10. Mu.L DPBF (10 mM) ethanol solution was added. In the dark, an 808 nm laser (1W/cm)2) The solution was irradiated for 30min and the absorbance at the maximum absorption wavelength (-417 nm) was recorded every 5 min. The solution can be uniformly irradiated by continuously stirring in the irradiation process. The control group is UCNPs @ mSiO without laser irradiation2-MC540 aqueous solution and pure water solution to exclude the effects of laser and DPBF natural degradation.
(2) In addition, UCNPs @ mSiO is made2Release experiments of ROS at different pH values (pH =7.4, pH =6.0 and pH = 5.0) for @ MPN-MC540/DOX, briefly speaking, ucnps @ msio synthesized first2@ MPN-MC540/DOX was left in solution at various pH values (pH =7.4, pH =6.0 and pH = 5.0) for a period of time until the release experiment of ROS was performed after the MPN had decomposed, as specified above.
FIG. 6 is UCNPs @ mSiO prepared in example 42@ MPN-MC540/DOX release profile of ROS in different pH environments (pH =7.4, pH =6.0 and pH = 5.0). As can be seen from the figure, in the solutions of pH =5.0 and pH =6.0, UCNPs @ mSiO2@ MPN-MC540/DOX has a binding affinity with UCNPs @ mSiO2-MC540 is similar1O2The generation ability can prove UCNPs @ mSiO2@ MPN-MC540/DOX has great potential for achieving PDT in a tumor microenvironment. But at pH =7.4, UCNPs @ mSiO2@ MPN-MC540/DOX Generation1O2May be due to the outer MPN film absorbing light at 808 nm, converting the light into heat, and achieving PTT.
Example 5
The preparation method and application of the upconversion-metal phenolic network composite nanomaterial provided in this embodiment are basically the same as those in embodiments 1 to 4, except that:
the method is characterized in that a DOX and MC540 loaded nano diagnosis and treatment agent composite material is applied to in vitro toxicity evaluation, and comprises the following steps:
(1) Cervical cancer HeLa cells were cultured at 1.5X 105Individual cells/well density were plated in 96-well plates, CO-incubated with DMEM containing 10% FBS and 1% penicillin/streptomycin at 37 ℃ in 5% CO2Culturing 24h in an incubator with concentration;
(2) Old medium was aspirated off with a pipette, 100. Mu.L of fresh medium containing different concentrations of material (0, 25, 50, 100. Mu.g/mL) was added, and the mixture was placed in an incubator to incubate 24h.
(3) The culture medium mixed solution containing the nano-materials was aspirated by a pipette and washed 3-4 times with PBS in order to remove the free materials, and then new culture medium was added to place the cells in 808 nm (2W/cm)2) Irradiating with laser for 5 min. After the irradiation is completed, the culture medium is placed in a constant temperature incubator again to culture 24h. After the time, a quantitative CCK-8 reagent was added and the absorbance of each well was measured using a microplate reader. The control group is set to control other variables to be consistent, and no 808 nm laser irradiation is added.
Fig. 7 shows that in the preparation of the nano material in example 5, the material without the drug DOX added has no obvious toxicity to cells, which indicates that the material has no obvious toxicity to cells and has good biocompatibility. When the DOX-containing nanocomposite was added, the cell viability decreased significantly with increasing concentration of the nanocomposite. Notably, the irradiation of the 808 nm laser will trigger the sample material ucnps @ msio for PTT treatment2Sample material UCNPs @ mSiO for @ MPN, PTT/PDT treatment2@ MPN-MC540, sample Material for PTT/chemotherapy treatment UCNPs @ mSiO2Sample material UCNPs @ mSiO of @ MPN-DOX and combined PTT/PDT/chemotherapy2@ MPN-MC540/DOX. After 808 nm laser irradiation is carried out for 5 minutes, the single PTT treatment effect is not obvious, and the survival rate of cells can still reach about 60 percent even if the concentration reaches 100 mug/mL; in addition, when Hela cells and 100 mug/mL UCNPs @ mSiO2Cell viability during @ MPN-MC540/DOX incubation and UCNPs @ mSiO of 100 μ g/mL2@MPN-MC540 or UCNPs @ mSiO2Cell viability decreased to less than 10% after @ MPN-DOX incubation, which fully suggests that PDT/PTT/chemotherapy combination therapy has a better effect in inhibiting cancer cell growth than PTT or PTT/PDT (PTT/chemotherapy) alone.
Example 6
The preparation method and application of the upconversion-metal phenolic network composite nanomaterial provided in this embodiment are basically the same as those in embodiments 1 to 5, except that:
the method for applying the DOX and MC540 loaded nano diagnosis and treatment agent composite material to in-vivo tumor photothermal/photodynamic/chemotherapy treatment comprises the following steps:
(1) In female BALB/c mice, 5X 10 subcutaneous injection is performed in the right axilla6HeLa cells, after the tumor volume grows to 100 mm3Left and right;
(2) Hela tumor-bearing mice were randomly divided into five groups: (1) PBS +808 nm, (2) UCNPs @ mSiO2@ MPN (10 mg/mL,100 μ L) +808 nm laser, (3) UCNPs @ mSiO2@ MPN-MC540 (10 mg/mL,100 μ L) +808 nm laser, (4) UCNPs @ mSiO2@ MPN-DOX (10 mg/mL,100 μ L) +808 nm laser, (5) UCNPs @ mSiO2The laser is @ MPN-MC540/DOX (10 mg/mL,100 mu L) +808 nm. 1 hour after injection of the material, the mouse tumor site was exposed to 808 nm laser at a power density of 2.5W/cm2The irradiation treatment was carried out for 15 minutes, but in order to avoid overheating which caused skin tissue burns in the mice, the irradiation was continued after 3 minutes of pause every 5 minutes of irradiation. Treatment was performed every other day. During the treatment period, changes in body weight and tumor volume of the mice were recorded daily.
FIG. 8 is a tumor growth curve diagram in the experiment of inhibiting the tumor of mice with Hela cell tumor by preparing the nano material in example 6. The body weight of the group mice did not change much from the initial body weight, indicating that the material had no significant effect on the health of the mice. We also recorded changes in tumor size for each group: (1) The volume of the tumor has obvious growth trend, which shows that the growth of the tumor is not inhibited by laser and no material; (2) The group was photothermal, and swelling was observedThe tumor is reduced; (3) The group is a photo-thermal treatment group and a photodynamic treatment group, and the growth volume of the tumor can be seen to be slow; (4) The group is a photothermal and drug combination treatment group, and the tumor volume is obviously smaller than that of the group (2); (5) The group is a photo-thermal, photodynamic and drug combined treatment group, the tumor volume is obviously smaller than that of other groups, which indicates UCNPs @ mSiO2The @ MPN-MC540/DOX composite nano material has good tumor combined treatment effect. The tumor pictures of the dissected mice in each group are consistent with the results, and the tumor inhibition effect on the tumors is more visually reflected, wherein the tumor volumes of the groups (3), (4) and (5) are obviously smaller than those of the former two groups, and the volume of the group (5) in combined treatment is the minimum.
The method provided by the invention is the synthesized NaYF4:Yb,Er,Nd@NaYF4Nd upconversion nano particles are coated on a silicon dioxide layer to form UCNPs @ mSiO2Improving the hydrophilicity and enabling the material to have the capability of loading materials by using UCNPs @ mSiO2The mesoporous of (A) supports DOX and MC540 to form UCNPs @ mSiO2the-MC 540/DOX nano composite material is finally coated with a complex (MPN) formed by Fe-TA on the outermost layer, and UCNPs @ mSiO is finally formed2@ MPN-MC540/DOX nanocomposite.
The key point of the invention is that the photo-thermal performance and the pH response performance of MPN are utilized, and UCNPs @ mSiO is irradiated under 808 nm laser2The @ MPN-MC540/DOX shows good photo-thermal performance, and photo-thermal treatment is realized; meanwhile, under the weak acid condition of the tumor microenvironment, the MPN membrane is gradually decomposed, so that the controllable release of DOX is realized, and the composition is used for chemotherapy; and the photosensitizer MC540 responds to 808 nm and excites an emission peak of 545 nm of UCNPs, so that photodynamic therapy is realized. The synergistic effect can achieve the purpose of killing tumor cells. UCNPs @ mSiO2Under the excitation of 808 nm, the @ MPN-MC540/DOX nano composite material has obviously higher cancer cell lethality compared with single PTT or PDT/PTT (PTT/chemotherapy) synergistic treatment due to the synergistic PTT/PDT/chemotherapy treatment effect, and has obvious tumor growth inhibition effect.
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 (12)
1. A preparation method of an up-conversion-metal phenolic network composite nano material is characterized by comprising the following steps:
(1) Preparation of NaYF4Yb, er, nd nanoparticles as core: using the "thermal decomposition" method, Y (CH) was added in different proportions to a 100mL three-necked flask containing 6mL Oleic Acid (OA) and 15mL Octadecene (ODE)3CO2)3，Yb(CH3CO2)3，Er(CH3CO2)3And Nd (CH)3CO2)3(1mmol, y. Placing the mixture on a heating sleeve, then heating to 160 ℃, uniformly stirring (rpm is approximately equal to 700), and keeping the temperature for five minutes until the acetate powder is completely dissolved to form a rare earth-oleic acid complex, namely a light yellow clear transparent solution; the heating was then turned off and the solution cooled to below 60 ℃. 0.1g of sodium hydroxide and 0.15g of ammonium fluoride were weighed and dissolved in 5mL of a methanol solution, ultrasonically dissolved, then the mixed solution was slowly added dropwise to a three-necked flask, the temperature was raised to 110 ℃ and the reaction was carried out for about 30 minutes, thereby evaporating the methanol, then the atmosphere in the three-necked flask was evacuated using a vacuum system for about 30 minutes, then the atmosphere was exchanged and ventilated 3 times each for 30 seconds, and the reaction was raised to 300 ℃ in an argon atmosphere and kept warm for 1 hour. After the reaction was complete, the solution was cooled to room temperature and the product (NaYF) was precipitated with absolute ethanol4Yb, er and Nd upconversion nanometer particles), washing for multiple times by cyclohexane and ethanol respectively to obtain an upconversion nanometer material with uniform particles, and storing in cyclohexane;
(2) Preparation of NaYF4:Yb,Er@NaYF4Core-shell upconversion nanoparticles: weighing metal-acetate Y (CH)3CO2)3And Nd (CH)3CO2)3(1mmol, Y; then, the temperature is reduced to below 80 ℃ (cyclohexane boiling point), and 5mL of the NaYF is added4Heating Yb, er and Nd cyclohexane solution to 150 deg.c to eliminate cyclohexane solvent until no liquid flows down and no bubble is produced in the solution, and lowering the temperature to below 60 deg.c; 0.0674g NaOH and 0.0374g NH were taken4F is added into 5mL of methanol solvent, is added into the reaction solution drop by drop slowly after ultrasonic dissolution, is heated to 110 ℃, and is removed until no mist and no bubbles exist; then vacuumizing for 30min, introducing argon for 3 times, heating to 300 ℃, and reacting for 1h. Purification steps such as NaYF4Yb, er and Nd nano particles. Final purified NaYF4:Yb,Er,Nd@NaYF4Nd (core-shell) nanoparticles dispersed in 15mL cyclohexane;
(3) Water-soluble mesoporous silica coated NaYF4:Yb,Er,Nd@NaYF4Preparing Nd nano particles: firstly, weighing 0.1g of CTAB in a beaker, adding 20mL of ultrapure water, heating to 70 ℃, and clarifying the solution under strong stirring; heating was turned off and 5mL of NaYF was added at room temperature4:Yb,Er,Nd@NaYF4Nd (about 15 mg) cyclohexane solution is stirred overnight until the solution is clarified again; after overnight, the solvent is reduced due to water evaporation, water is added to 20mL, the solution is moved to a 250mL three-neck flask, 40mL of ultrapure water, 6mL of absolute ethyl alcohol and 300 muL (2 mol/L) of NaOH aqueous solution are added, the mixture is placed under an oil bath pan at 70 ℃ for condensation reflux for 30min (the rotating speed is maximum), 400 muL of TEOS is slowly added dropwise by a 200 muL liquid transfer gun, the mixture is stirred for reaction for 1h, cooled to the room temperature, centrifuged to obtain precipitates, and the precipitates are washed by the absolute ethyl alcohol for 3 times to remove free silicon, so that the mesoporous silicon dioxide coated UCNPs are obtained. To remove the CTAB template, a mesoporous structure is obtained. The precipitate was dissolved in 40mL of an acidic ethanol solution (pH =1.4 to 1.5), and reacted at 60 ℃ for 1 hour with stirring under reflux. Centrifuging to obtain a precipitate, washing with absolute ethyl alcohol for 2-3 times, and dispersing the final product in 20mL of waterIn the water ethanol, the reflux process can be repeated for 2-3 times so as to fully remove CTAB and reduce the biological toxicity;
(4)UCNPs@mSiO2preparation of MC540/DOX nanocomposites: preparing 0.2mg/mLDOX aqueous solution and 0.2mg/mLMC540 aqueous solution, and then adding UCNPs @ mSiO2Centrifuging the aqueous solution to obtain solid precipitate, and collecting 4mgUCNPs @ mSiO2Soaking in a mixed solution of 2mLDOX and MC540, firstly placing in an ultrasonic machine for ultrasonic treatment for 30min, and then rapidly stirring on a magnetic stirring heating sleeve for 24h at room temperature in a dark environment. After physical adsorption is finished, centrifuging to remove supernatant liquid and leave precipitate, then dissolving the precipitate by using ultrapure water, centrifuging again and leaving precipitate, washing for three times, and removing free DOX and MC540;
(5)UCNPs@mSiO2preparation of @ MPN-MC540/DOX nanocomposite: 40 μ LTA and 40 μ LFeCl were mixed under vigorous stirring3(24 mM) solution was added to 2mL of UCNPs @ mSiO2-MC540/DOX in aqueous solution. Finally, the collected UCNPs @ mSiO is obtained by centrifugal separation and washing three times by deionized water2@ MPN-MC540/DOX nanocomposite.
2. The method for preparing the upconversion-metal phenolic network composite nanomaterial according to claim 1, wherein the step (1) comprises the following specific steps:
(1) To a 100mL three-necked flask containing 6mL Oleic Acid (OA) and 15mL Octadecene (ODE) was added Y (CH) in varying proportions3CO2)3，Yb(CH3CO2)3，Er(CH3CO2)3And Nd (CH)3CO2)3(1mmol, y. Placing the mixture on a heating sleeve, then heating to 160 ℃, stirring at a constant speed, and preserving heat for five minutes until acetate powder is completely dissolved to form a rare earth-oleic acid complex, namely a light yellow clear transparent solution;
(2) The heating was then turned off and the solution cooled to below 60 ℃. 0.1g of sodium hydroxide and 0.15g of ammonium fluoride were weighed out and dissolved in 5mL of a methanol solution, and dissolved by sonication, and then the mixed solution was slowly added dropwise to a three-necked flask,the temperature was raised to 110 ℃ for about 30 minutes to evaporate the methanol, and then the atmosphere in the three-necked flask was evacuated using a vacuum system for about 30 minutes, and then the evacuation was exchanged 3 times each for 30 seconds, and the temperature of the reaction was raised to 300 ℃ in an argon atmosphere and maintained for 1 hour. After the reaction was complete, the solution was cooled to room temperature and the product (NaYF) was precipitated with absolute ethanol4Yb, er, nd upconversion nanoparticles), washed with cyclohexane and ethanol respectively for multiple times to obtain upconversion nanomaterials with uniform particles, and then stored in cyclohexane.
3. The method for preparing up-conversion-metal phenolic network composite nanomaterial of claim 1, wherein the rotation speed of the heating jacket in the step (1) is 700rpm.
4. The method for preparing up-conversion-metal phenolic network composite nanomaterial according to claim 1, wherein the step (2) is carried out in an argon atmosphere at 300 ℃ for 1 hour.
5. The method for preparing the upconversion-metal phenolic network composite nanomaterial according to claim 1, wherein the step (3) comprises the following specific steps:
(1) Firstly, weighing 0.1g of CTAB in a beaker, adding 20mL of ultrapure water, heating to 70 ℃, and clarifying the solution under strong stirring; heating was turned off and 5mL of NaYF was added at room temperature4:Yb,Er,Nd@NaYF4Nd (about 15 mg) cyclohexane solution is stirred overnight until the solution is clarified again;
(2) After overnight, evaporating water to reduce the solvent, then replenishing water to 20mL, transferring the solution into a 250mL three-neck flask, adding 40mL of ultrapure water, 6mL of absolute ethanol and 300 mu L (2 mol/L) of NaOH aqueous solution, placing the solution under an oil bath pan, condensing and refluxing at 70 ℃ for 30min (the rotating speed is maximum), dropwise and slowly adding 400 mu L of TEOS by using a 200 mu L liquid transfer gun, stirring and reacting for 1h, cooling to room temperature, centrifuging to obtain a precipitate, washing for 3 times by using absolute ethanol, and removing free silicon to obtain mesoporous silica-coated UCNPs;
(3) To remove the CTAB template, a mesoporous structure is obtained. The precipitate was dissolved in 40mL of an acidic ethanol solution (pH =1.4 to 1.5), and reacted at 60 ℃ for 1 hour with stirring under reflux. Centrifuging to obtain a precipitate, washing with absolute ethyl alcohol for 2-3 times, dispersing the final product in 20mL of absolute ethyl alcohol, and repeating the reflux process for 2-3 times to fully remove CTAB and reduce biological toxicity.
6. The method for preparing up-conversion-metal phenolic network composite nanomaterial of claim 1, wherein the temperature of heating and stirring in the step (3) is 70 ℃ and the rotation speed is 1250rpm.
7. The method for preparing up-conversion-metal phenolic network composite nanomaterial of claim 1, wherein NaYF is added in the step (3)4:Yb,Er,Nd@NaYF4The Nd cyclohexane solution was about 15mg, and the overnight solution was clarified and subjected to the next experiment.
8. The method for preparing the upconversion-metal phenol aldehyde network composite nanomaterial according to claim 1, wherein in the step (3), the CTAB template is removed by refluxing in an acidic ethanol solution with pH = 1.4-1.5, and the process can be repeated for 2-3 times, so that CTAB is sufficiently removed and the biotoxicity is reduced.
9. The method for preparing the upconversion-metal phenolic network composite nanomaterial according to claim 1, wherein the step (4) comprises the following specific steps:
(1) Preparing an aqueous solution of 0.2mg/mL DOX and an aqueous solution of 0.2mg/mL MC540, and then adding UCNPs @ mSiO2Centrifuging the aqueous solution to obtain solid precipitate, and collecting 4mg UCNPs @ mSiO2Soaking in a mixed solution of 2mLDOX and MC540, firstly putting in an ultrasonic machine for ultrasonic treatment for 30min, and then quickly stirring on a magnetic stirring heating sleeve for 24h at room temperature in a dark environment;
(2) After the physical adsorption was completed, the supernatant was removed by centrifugation to leave a precipitate, and then dissolved in ultrapure water, centrifuged again to leave a precipitate, and washed three times to remove free DOX and MC540.
10. The method for preparing up-conversion-metal phenolic network composite nanomaterial of claim 1, wherein in the step (5), 40 μ L TA and 40 μ L FeCl are stirred vigorously3(24 mM) solution was added to 2mL of UCNPs @ mSiO2-MC540/DOX in aqueous solution. Finally, the collected UCNPs @ mSiO is obtained by centrifugal separation and washing three times by deionized water2@ MPN-MC540/DOX nanocomposite.
11. An upconversion-metal phenolic network composite nanomaterial prepared by the method of any one of claims 1 to 10, characterized in that the composite nanomaterial is synthesized by a thermal decomposition method, and the composite nanomaterial is uniform in size, good in biocompatibility, and excellent in photothermal property and pH response property.
12. The method for preparing up-conversion-metal phenolic network composite nanomaterial of claim 11, wherein the composite material is proved to realize combined treatment of tumor by PTT/PDT/chemotherapy through in vitro cell therapy experiment and in vivo tumor therapy experiment of mouse, and has higher combined treatment effect.
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