CN112641759B - Redox-enhanced drug sensitive release mesoporous silica nanoparticle and preparation method thereof - Google Patents

Abstract

The invention belongs to the technical field of nano materials and preparation thereof, and particularly discloses a redox enhanced drug sensitive release mesoporous silica nanoparticle and a preparation method thereof. The nano-particles are prepared by self-assembling curcumin derivatives with surfaces being pegylated, mesoporous silica nano-particles with surfaces being amino-carboxylated and internally bridged with double tellurium bonds and anticancer drugs. The preparation conditions of the nano particles are mild, toxic and harmful substances are not introduced, the process is simple, and the repeatability is good; the prepared anti-tumor nano particles have strong oxidation-reduction sensitive release performance, are easy to degrade matrixes and control drug release, effectively avoid adverse effects such as burst release, drug leakage and the like in normal physiological environment, and the carrier has ultra-large pores due to the introduction of the mesoporous silica nano particles and can load anti-tumor drugs; the introduction of PEG-CCM avoids the leakage of mesoporous silicon dioxide nano particle drugs, improves the water solubility and stability of the nano particles, provides an anticancer synergistic effect, and has wide application prospects.

Description

Redox-enhanced drug sensitive release mesoporous silica nanoparticle and preparation method thereof

Technical Field

The invention relates to the technical field of nano materials and preparation thereof, in particular to a redox enhanced drug sensitive release mesoporous silica nano particle and a preparation method thereof.

Background

The nano particles are three-dimensional network structures which are nano-sized (10-1000nm) and formed by chemically or physically crosslinking macromolecules. The nano particles are used as a drug carrier, therapeutic drugs are loaded in an adsorption or embedding mode, and the drug carrier with active or passive targeting performance is designed through the combination between a targeting ligand and a receptor or the difference between normal tissues and the difference between the inside and the outside of cells and tumors. The EPR effect of the tumor part is combined, the larger cell gap and the looser structure of the tumor part are utilized to promote the nanometer carrier to pass through, so that the tumor part can be better enriched at the focus part, the bioavailability of the medicine and the conveying and releasing performance of the medicine in the body can be obviously improved, and the system is a safe system with potential biomedical application value.

Over the past decade, stimulus-responsive drug delivery systems have rapidly evolved in the search for cancer diagnosis and therapy. As is known, tumor cells are generally in an oxidative stress state, the sensitivity to ROS is higher than that of normal cells, and simultaneously, an antioxidant system is activated by up-regulating the level of glutathione GSH to adapt to oxidative stress, so that the GSH value of the environment outside the tumor cells is 2-10 mu M, and the GSH values of endosomes and lysosomes are 1-10 mM. Therefore, designing a nano-delivery system with redox responsiveness, such as a structure containing cleavable chemical bonds such as disulfide bond, diselenide bond, selenothio bond, and telluriothio bond, has been widely developed and applied in the treatment of cancer.

The polyethylene glycol series products have no toxicity, no irritation, slightly bitter taste, good water solubility, good intermiscibility with a plurality of organic matter components, convenient chemical modification of terminal hydroxyl, and stability, solubility and safety required by medicinal auxiliary materials, are widely applied to industries of foods, medicines, daily necessities and the like, and are good medicinal carriers.

Therefore, the preparation of the silica-based nano-drug carrier with high drug availability, which has good repeatability, low toxic and side effects and easy matrix biodegradation, can avoid the premature release and burst release of the drug in systemic circulation and normal tissues and the massive and rapid release of the drug in a tumor tissue environment, is one of the problems which need to be solved in the application of the current chemotherapeutic drugs.

Disclosure of Invention

Aiming at the defects in the prior art, the invention aims to solve the problem that the existing single stimulation responsive material cannot achieve the drug treatment effect due to the limitations such as poor stability, small release amount in cells, slow biodegradability and the like, and provides the redox enhanced mesoporous silica nanoparticle based on the double tellurium bonds and the preparation method thereof.

In order to achieve the purpose, the technical scheme adopted by the invention is as follows:

a redox-enhanced drug sensitive release mesoporous silica nanoparticle is characterized in that the nanoparticle is prepared from (0.5-1) by mass: 1: (1-2) preparing a curcumin derivative (PEG-CCM) with polyethylene glycol 2000 on the surface, mesoporous silica nanoparticles with amino carboxyl on the surface and double tellurium bonds bridged inside and anticancer drugs;

the optimal mass ratio is 1: 1: 1;

further, the PEG-CCM is prepared by the following method steps:

1) dissolving curcumin, 4-Dimethylaminopyridine (DMAP) and triethylamine in tetrahydrofuran, stirring at room temperature and activating;

the dosage proportion of the curcumin, the 4-dimethylaminopyridine and the triethylamine is 1 g: (50-60) mg: (0.6-0.7) mL;

2) dissolving citric anhydride in tetrahydrofuran, then dropwise adding the solution obtained in the step 1), then carrying out reflux stirring for more than 10 hours under the protection of nitrogen in the whole process, dissolving 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride and 4-dimethylaminopyridine in a mixed solvent (preferably equal-volume mixing) of tetrahydrofuran and dichloromethane to obtain an EDC/DMAP mixed solution, then dropwise adding the EDC/DMAP mixed solution into the citrated curcumin solution under the protection of nitrogen, and stirring and activating at room temperature;

the dosage proportion of the citric acid anhydride, the curcumin in the step 1), the 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride and the 4-dimethylaminopyridine is 0.6 g: 2 g: (350-400) mg: (18-20) mg;

3) dissolving polyethylene glycol 2000 in a mixed solution of tetrahydrofuran and dichloromethane in the same volume, then dropwise adding the mixed solution into the solution obtained in the step 2), stirring for more than 3 hours, after the reaction is finished, evaporating the reaction solution under reduced pressure, adjusting the pH to 3-4 with hydrochloric acid, extracting with dichloromethane, drying with anhydrous magnesium sulfate, filtering, performing rotary evaporation, finally performing recrystallization at least twice with excessive cold ethyl ether to obtain a yellow solid, then dissolving with ultrapure water, dialyzing in the ultrapure water with an MWCO 1000Da dialysis bag for more than two days, and performing freeze drying to obtain a yellow PEG-CCM solid;

the mass ratio of the polyethylene glycol 2000 to the curcumin in the solution obtained in the step 2) is 1.6 g: 2g of the total weight of the mixture; the mesoporous silica nanoparticle with the surface amino-carboxylated and internally bridged double tellurium bonds is prepared by the following method steps:

1) synthesis of 3, 3' -ditellurodipropyltriethoxysilane (DTETePD):

dissolving tellurium powder and sodium borohydride in ice water, stirring at room temperature until the tellurium powder is completely dissolved, heating to 70 ℃ under the protection of nitrogen in the whole process, and continuing to react for more than 20min until the color of the solution is reddish brown; dropwise adding 3-chloropropyltriethoxysilane into the reddish brown solution, stirring overnight at 50 ℃ under the condition of nitrogen, filtering the reaction solution after the reaction is finished, extracting twice with dichloromethane, drying with anhydrous magnesium sulfate, filtering, performing rotary evaporation, and finally passing through a silica gel column to obtain DTETePD;

the using proportion of the tellurium powder, the sodium borohydride and the 3-chloropropyltriethoxysilane is 5 g: (1.4-1.6) g: 10g of a mixture;

2) weighing hexadecyl trimethyl ammonium chloride and triethanolamine into a three-neck flask filled with ultrapure water under the conditions of 80 ℃ and nitrogen protection, adding the hexadecyl trimethyl ammonium chloride and the triethanolamine into the three-neck flask filled with the ultrapure water, stirring to dissolve the hexadecyl trimethyl ammonium chloride and the triethanolamine to obtain a solution, then weighing tetraethyl orthosilicate and DTETePD to mix together, injecting the mixture into the solution, stirring to react for more than 3 hours under the reaction condition of 80 ℃, refluxing the obtained reaction product in an ethanol solution of ammonium nitrate (1% w/v) for more than 10 hours under the condition of 80 ℃, washing and centrifuging for more than two times by using absolute ethanol, and drying to obtain mesoporous silica nanoparticles with double tellurium bonds bridged inside;

the dosage proportion of the hexadecyl trimethyl ammonium chloride, the triethanolamine, the tetraethyl orthosilicate and the DTETePD is 0.6 g: 1 g: 0.15 g: 4g of the total weight of the mixture;

3) dissolving the mesoporous silica nanoparticles with internal bridged double tellurium bonds prepared in the step 2) in absolute ethyl alcohol, stirring for more than 2h at the temperature of 80 ℃, then cooling to room temperature, dropwise adding 3-aminopropyltriethoxysilane into the solution, stirring and reacting for at least 0.5h at the temperature of room temperature, then refluxing for 12h at the temperature of 80 ℃, then washing with absolute ethyl alcohol, centrifuging for more than two times, and drying to obtain aminated double tellurium bond mesoporous silica nanoparticles; weighing aminated double-tellurium-bond mesoporous silica nanoparticles, dissolving the aminated double-tellurium-bond mesoporous silica nanoparticles in dimethylformamide, adding succinic anhydride and triethylamine into the solution, stirring and reacting for more than 18 hours at 50 ℃, washing and centrifuging for more than two times by using absolute ethyl alcohol, and drying to obtain surface-aminated double-tellurium-bond mesoporous silica nanoparticles (DTeMSN);

the dosage proportion of the mesoporous silica nanoparticles with the internal bridged double tellurium bonds and the 3-aminopropyltriethoxysilane prepared in the step 2) is 1 mg: 1 mu L of the solution;

the dosage proportion of the aminated double-tellurium-bond mesoporous silica nano particle, succinic anhydride and triethylamine is 200 mg: 1.2 g: (70-90). mu.L.

The anticancer drug is adriamycin hydrochloride.

The preparation method of the redox enhanced drug sensitive release mesoporous silica nanoparticle comprises the following steps:

weighing DTeMSN and transferring the DTeMSN into a reaction container filled with ultrapure water; weighing adriamycin hydrochloride in ultrapure water, and then dropwise adding the adriamycin hydrochloride into the reaction container; finally, adjusting the pH value to 7.4 by using a sodium hydroxide solution, stirring for more than 3 hours at room temperature, taking light-proof measures in the whole process, centrifuging after the reaction is finished, re-dissolving in ultrapure water, and adjusting the pH value to 7.2-7.4 by using the sodium hydroxide solution; weighing PEG-CCM, dissolving the PEG-CCM in ultrapure water, then dropwise adding the PEG-CCM into the solution obtained by re-dissolving, adjusting the pH value of the solution to 7.4 by using a sodium hydroxide solution, stirring the solution for more than 10 hours, centrifuging the solution after the reaction is finished, re-dissolving the PEG-CCM in the ultrapure water, and adjusting the pH value of the solution to 7.4 by using the sodium hydroxide solution to obtain the redox-enhanced drug sensitive release mesoporous silica nanoparticles.

Compared with the prior art, the invention has the advantages and beneficial effects that:

the nano-particle preparation reaction conditions are mild, the toxic and side effects of the raw materials are low, the entrapment of the drug can be realized in an electrostatic interaction mode, the double tellurium bonds are introduced into the internal structure of the silicon dioxide nano-particle, the silicon dioxide nano-particle has strong redox sensitivity, the rapid release of a large amount of the drug in a cancer cell environment is controlled, and the substrate biodegradation is easy to realize; the introduction of PEG-CCM effectively avoids adverse effects such as drug leakage of mesoporous silica nanoparticles, improves the water solubility and stability of the nanoparticles, provides an anticancer synergistic effect, and has low toxic and side effects and high-efficiency treatment effect.

Drawings

FIG. 1 is a representation of redox-responsive silica nanoparticles prepared in example 1 of the present invention, and (a) and (c) of DTETePD and PEG-CCM, respectively¹H spectrum, (b) and (d) are mass spectra of DTETePD and PEG-CCM respectively.

Fig. 2 is a transmission electron microscope image (b) and a particle size distribution diagram (a) of the redox-responsive silica nano-drug carrier prepared in example 1 of the present invention.

Fig. 3 is a drug release curve diagram of the redox-responsive silica nano-drug carrier prepared in example 1 of the present invention under different environments.

Fig. 4 is a graph showing the degradation levels of the redox-responsive silica nano-drug carrier prepared in example 1 of the present invention under different degradation times and redox conditions.

Fig. 5 is a cytotoxicity graph of the redox-responsive silica nanoparticles prepared in example 1 of the present invention.

Fig. 6 is a biological evaluation of the redox-responsive silica nano-drug loaded mice prepared in example 1 of the present invention, a tumor volume change map (a), a tumor tap (b), a mouse body weight change map (c) and a tumor weight map (d).

Detailed Description

The applicant further illustrates the present invention in connection with specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the claimed invention.

Example 1

A preparation method of redox enhanced drug sensitive release mesoporous silica nanoparticles comprises the following steps:

1. curcumin derivatives (PEG-CCM) with surface polyethylene glycol (PEG 2000) conversion were prepared in one step based on the literature (Research Journal of pharmaceutical Biological & Chemical Sciences,2010,1,28-34), (Nature Communications,2018,9,2785) and the like, and optimized in preparation conditions. The method comprises the following specific steps:

1) dissolving 2.01g of curcumin, 112mg of 4-Dimethylaminopyridine (DMAP) and 1.33mL of triethylamine in 100mL of tetrahydrofuran, and stirring and activating at room temperature for 30 min;

2) 0.601g of citric anhydride was dissolved in 5ml of tetrahydrofuran, and then added dropwise to the solution obtained in step 1), followed by stirring under reflux for 12 hours all over under nitrogen, 383mg of 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC) and 19mg of 4-Dimethylaminopyridine (DMAP) were dissolved in tetrahydrofuran and dichloromethane in this order (v/v, 1:1, 5ml each) to obtain EDC/DMAP mixed solution, dropwise adding the EDC/DMAP solution into the citrated curcumin solution under the protection of nitrogen, and stirring and activating at room temperature for 30 min;

3) dissolving 1.6g of polyethylene glycol 2000 in a mixed solution of 5mL of tetrahydrofuran and 5mL of dichloromethane, then dropwise adding the solution obtained in the step 2), stirring for 4 hours, after the reaction is finished, evaporating the reaction solution under reduced pressure, adjusting the pH value to 3-4 with 1.0mol/L hydrochloric acid, extracting twice with dichloromethane, drying with anhydrous magnesium sulfate, filtering, performing rotary evaporation, finally dissolving and precipitating three times with excessive cold ether to obtain a yellow solid, then dissolving with ultrapure water, dialyzing in ultrapure water with a dialysis bag (MWCO 1000Da) for three days, and performing freeze drying to obtain a yellow solid, namely PEG-CCM.

2. Preparing mesoporous silica nanoparticles with amino-carboxylated surfaces and double-tellurium-bond bridged interiors. The method comprises the following specific steps:

1) 3, 3' -ditellurodipropyltriethoxysilane (DTETePD) was synthesized by methods such as references (Soft Material, 2012,8,1460), (ACS Applied Materials & Interfaces,2017,9,30253-302578), (advanced Materials,2018,30, 1801198).

Dissolving 5.09g of tellurium powder and 1.5g of sodium borohydride in 30mL of ice water, stirring for 10 minutes at room temperature until the tellurium powder is completely dissolved, then heating to 70 ℃ under the protection of nitrogen in the whole process, and continuing to react for 30 minutes until the color of the solution becomes reddish brown; and (2) dropwise adding 10g of 3-chloropropyltriethoxysilane into the reddish brown solution, stirring overnight at 50 ℃ under the condition of nitrogen, filtering the reaction solution after the reaction is finished, extracting twice by using dichloromethane, drying by using anhydrous magnesium sulfate, filtering, performing rotary evaporation, and finally passing through a silica gel column (n-hexane: dichloromethane, 10:1-1:1) to obtain liquid 3, 3' -ditellurodipropyltriethoxysilane (DTETePD).

2) Weighing 0.6g of hexadecyl trimethyl ammonium chloride and 0.15g of triethanolamine as reaction media at 80 ℃ under the protection of nitrogen, adding the hexadecyl trimethyl ammonium chloride and the triethanolamine into a three-neck flask filled with 40mL of ultrapure water, stirring for half an hour to dissolve the hexadecyl trimethyl ammonium chloride and the triethanolamine, weighing 4.0g of TEOS (tetraethyl orthosilicate) and 1.0g of DTETePD, mixing the TEOS and the TEETePD together, injecting the mixture into the solution, stirring the mixture for reaction for 4 hours at the reaction condition of 80 ℃, washing the reaction product in an ethanol solution of ammonium nitrate (1% w/v) at the temperature of 80 ℃ for 12 hours, washing the reaction product with absolute ethanol, centrifuging the reaction product for three times, and drying the washing product to obtain the mesoporous silica nano particles with the double tellurium bonds bridged inside.

3) Methods in references (Advanced Materials,2018,30,1801198) and the like:

dissolving 200mg of mesoporous silica nanoparticles with double tellurium bonds bridged inside prepared in the step 2) in 80mL of absolute ethanol, stirring for 3h at 80 ℃, cooling to room temperature, dropwise adding 200 mu L of 3-aminopropyltriethoxysilane into the solution, stirring for reaction for 1h at room temperature, transferring into an oil bath kettle, refluxing for 12h at 80 ℃, washing with absolute ethanol for three times, centrifuging, and drying to obtain aminated double tellurium bond mesoporous silica nanoparticles; weighing 200mg of aminated double-tellurium-bond mesoporous silica nanoparticles, dissolving in 80mL of dimethylformamide, adding 1.2g of succinic anhydride and 80 mu L of triethylamine into the solution, stirring and reacting at 50 ℃ for 24h, washing with absolute ethyl alcohol, centrifuging for three times, and drying to obtain the mesoporous silica nanoparticles (DTeMSN) with amino carboxylated surfaces and internally bridged double-tellurium bonds.

3. Weigh 4.0mg of the DTeMSN prepared in step 2 and transfer it to a three-neck flask containing 2.0mL of ultrapure water; weighing 4.0mg of doxorubicin hydrochloride into 2.0mL of ultrapure water, dropwise adding the doxorubicin hydrochloride into the three-neck flask, finally adjusting the pH to 7.4 by using 0.1mol/L of sodium hydroxide, stirring for 5 hours at room temperature, taking light-shielding measures in the whole process, centrifuging after the reaction is finished, re-dissolving the doxorubicin hydrochloride into the three-neck flask filled with 2.0mL of ultrapure water, and adjusting the pH value to 7.2-7.4 by using 1.0mol/L of sodium hydroxide solution; weighing 4.0mg of PEG-CCM prepared in the step 1, dissolving the PEG-CCM in 2.0mL of ultrapure water, then dropwise adding the PEG-CCM into the solution obtained by redissolution, adjusting the pH value of the solution to 7.4 by using 1.0mol/L of sodium hydroxide solution, stirring the solution for 12 hours, centrifuging the solution after the reaction is finished, redissolving the solution in the ultrapure water, and adjusting the pH value of the solution to 7.4 by using 1.0mol/L of sodium hydroxide solution to obtain the redox-enhanced drug sensitive release mesoporous silica nanoparticles (DTeMSN @ DOX @ PEG-CCM). The aqueous solution of the nanoparticles obtained was stored at 4 ℃. The content of encapsulated DOX in the nanoparticles was measured with a fluorescence spectrophotometer at an excitation wavelength of 480nm and under an emission condition of 590nm, and the drug loading of the resulting nanoparticles was calculated to be 25.2% (drug loading: mass of encapsulated DOX/mass of lyophilized nanoparticles × 100%).

In addition, the nanoparticles obtained without adding PEG-CCM in the preparation steps are marked as DTeMSN @ DOX; the nanoparticles obtained without adding DOX in the above preparation steps are labeled as DTeMSN @ PEG-CCM.

Example 2 instrumental characterization of the product of each step in example 1 and determination of the properties of the nanoparticles obtained:

and characterizing the prepared molecules by adopting nuclear magnetic resonance imaging and a mass spectrum analyzer. Preparation of 3, 3' -ditellurodipropyltriethoxysilane (DTETePD) as shown in FIGS. 1a and b¹The H spectrum shows four chemical shifts of 3.72nm, 3.08nm, 1.76nm, 1.11nm and 0.61nm, and the mass spectrum result shows that the molecular weight is 684.09(M + NH)₄ ⁺) And the DTETePD is successfully prepared. In addition, of PEG-CCM¹The H-nmr spectrum (fig. 1C) showed three characteristic signals of CCM at 7.6ppm, 6.5-7.2ppm and 5.35ppm, respectively-CH ═ C (2H), Ar (6H) and-OH (1H) protons, the mass spectrum of PEG-CCM (fig. 1d) showed a molecular weight of 2389.679, and was successfully preparedPEG-CCM was prepared.

The particle size of the DTeMSN @ DOX @ PEG-CCM nanoparticles prepared in example 1 was measured using a Malvern Nano-ZS90 laser particle sizer. Dissolving 2mg of DTeMSN @ DOX @ PEG-CCM nano particles in 4mL of ultrapure water, carrying out ultrasonic treatment for 5min, putting 1.2mL of the solution in a quartz cuvette, and placing the cuvette in a Malvern laser particle size analyzer to measure the particle size. As shown in FIG. 2, the DTeMSN @ DOX @ PEG-CCM nanoparticles had a particle size (size) of 104. + -.10 nm and a dispersity (PDI) of 0.163. .

The drug-loaded nanoparticles DTeMSN @ DOX prepared in example 1 have significant redox response release characteristics, as shown in FIG. 3, 2mL of 1mg/mL DTeMSN @ DOX solution was added to a dialysis bag (MWCO 3500Da) and then immersed in a dialysis bag containing 18mL of 5mM GSH or 100. mu. M H₂O₂Or taking out 2mL of solution in a 50mL centrifugal tube of ultrapure water in a specific time period, adding the corresponding 2mL of solution, and measuring the content of DOX at different time points by using a fluorescence spectrophotometer under the excitation wavelength of 480nm and the emission condition of 590 nm. After releasing for 48 hours, the release amount of the DTeMSN @ DOX nano particles in the environment of 5mM GSH is up to 82.5%; at 100 μ M H₂O₂Under the environmental condition of (3), the cumulative release amount is 40.2%; the cumulative release was 24.3% under the environmental conditions of ultrapure water. The prepared carrier DTeMSN has obvious redox sensitivity.

Example 1 the prepared nanoparticle DTeMSN was evaluated for its degradation effect by simulating intracellular GSH and ROS concentrations. DTeMSN (100. mu.g/mL) was placed in GSH (5mM) and H, respectively₂O₂Samples were collected at predetermined time points (0, 1,2 and 3day) in a centrifuge tube (100. mu.M) with continuous rotation at 37 ℃ and Si concentration was measured by ICP-OES after centrifugation. The quantitative measurement results show (FIG. 4) that DTeMSN is in the presence of H₂O₂And degradation in GSH media over time. These phenomena should be due to the breakdown of ditellurium bonds under oxidizing and reducing conditions.

The nanoparticles prepared in example 1 were evaluated cytologically using mouse embryonic cells (NIH3T3 cells, Cat No: CL-0171) as a model. First of all, resuscitateThawing NIH3T3 cells, centrifuging at 1000rpm for 3min, discarding supernatant, resuspending cells in DMEM medium containing 10% fetal calf serum and 1% double antibody (streptomycin/penicillin), inoculating in T25 flask, and placing in CO₂Incubator (37 ℃, 5% CO)₂Under the condition), when the cell fusion degree reaches more than 80%, subculturing for two generations, making NIH3T3 cell into 1 × 10⁴Perml cell suspension and 100. mu.L per well were planted in 96-well plates and then CO was added₂5% CO at 37 ℃ in an incubator₂The culture was carried out under conditions overnight. The DMEM medium was removed, high, medium, low, 6 concentration gradient DTeMSN solutions prepared with the DMEM medium were added to the cells for 24h, and then 10 μ L CCK-8 reagent was added to each well according to the method of using a CCK-8 kit (cell proliferation and toxicity detection kit, Dojindo (japan syngen chemical), CK04-01), incubation was performed at room temperature for 1.0h, absorbance of each well was measured at a wavelength of 450nm using a fluorescence microplate reader (SpectraMax M2, molecular beacons, Sunnyvale, CA), and the survival rate of cells was calculated according to the formula ═ a experimental group-a (% control)/(a control group-a blank control group) × 100%, blank control group was blank well of non-inoculated cells, experimental group was drug-added well of inoculated cells, control group was blank well of inoculated cells, and control group was survival rate of DTeMSN to NIH3T3 cells was calculated. The result is shown in fig. 5, when the concentration of the DTeMSN nanoparticles reaches 200 μ g/ml, the survival rate of NIH3T3 cells is higher than 90%, so the DTeMSN nanoparticles have good biocompatibility and low toxicity.

The nanoparticles prepared in example 1 were subjected to biological evaluation using an experimental mouse as a model, as shown in fig. 6. Firstly, cervical cancer cells (HeLa cells, CatNo: CL-0349) are implanted into mice subcutaneously until tumors grow to 80mm³On the left and right, mice were divided into a blank control group (saline control group), an Doxorubicin (DOX) control group, a DTeMSN @ PEG-CCM group, a DTeMSN @ DOX group, and a (DTeMSN @ DOX @ PEG-CCM) group. By tail vein injection, the amounts of Doxorubicin (DOX) control group, DTeMSN @ PEG-CCM group, DTeMSN @ DOX group and (DTeMSN @ DOX @ PEG-CCM) group injected were all 5.0mgDOX/kg mice every three days, as compared to the drug-free saline control group, in which DT @ DOX @ PEG-CCM was usedThe mass concentration of the nano-particles of the eMSN @ DOX @ PEG-CCM group is consistent with that of the nano-particles of the DTeMSN @ DOX @ PEG-CCM group. Upon observation for 21 days, the body weight of the mice treated with Doxorubicin (DOX) control group, DTeMSN @ PEG-CCM group, DTeMSN @ DOX group and (DTeMSN @ DOX @ PEG-CCM) group did not change significantly, while the body weight of the mice in the saline control group decreased significantly at day 15 (FIG. 6-c). In subsequent observations, the body weight of mice in the doxorubicin control group increased more slowly than in the normal saline control group, while the body weight of mice in the DTeMSN @ PEG-CCM, DTeMSN @ DOX, and (DTeMSN @ DOX @ PEG-CCM) groups differed little, indicating that they had less toxic side effects. On the other hand, the tumor volume growth of the mice in the DTeMSN @ PEG-CCM group, the DTeMSN @ DOX group and the (DTeMSN @ DOX @ PEG-CCM) group is obviously slower than that of the mice in the adriamycin control group (FIGS. 6-a and b), the tumor inhibition rate of the DTeMSN @ PEG-CCM is 24.5% (the tumor inhibition rate is calculated as 1, the tumor weight of the experimental group/the tumor weight of the control group x 100%, the same applies below), the tumor inhibition rate of the DOX is 41.2%, the tumor inhibition rate of the DTeMSN @ DOX is 59.8%, and the tumor inhibition rate of the DTeMSN @ DOX @ PEG-CCM is 70.6% (FIG. 6-d). The result shows that the prepared drug-loaded nano particle DTeMSN @ DOX @ PEG-CCM has better tumor inhibition effect than free adriamycin, DTeMSN @ PEG-CCM and DTeMSN @ DOX, and generates less toxic and side effects.

Claims (5)

1. A redox-enhanced drug sensitive release mesoporous silica nanoparticle is characterized in that: the nano particles are prepared from the following components in percentage by mass (0.5-1): 1: and (1-2) preparing the curcumin derivative PEG-CCM subjected to surface pegylation, the mesoporous silica nanoparticles subjected to surface aminocarboxylation and internally bridged double-tellurium bonds and the adriamycin hydrochloride.

2. The redox-enhanced drug sensitive release mesoporous silica nanoparticles as claimed in claim 1, wherein: the mass ratio is 1: 1: 1.

3. the redox-enhanced drug-sensitive release mesoporous silica nanoparticles according to claim 1 or 2, wherein: the preparation method of the redox enhanced drug sensitive release mesoporous silica nanoparticle comprises the following steps:

weighing mesoporous silica nanoparticles with amino carboxylated surfaces and bridged double tellurium bonds inside into a reaction vessel filled with ultrapure water; weighing anticancer drugs in ultrapure water, and then dripping the anticancer drugs into the reaction container; finally, adjusting the pH value to 7.4 by using a sodium hydroxide solution, stirring for more than 3 hours at room temperature, taking light-shielding measures in the whole process, centrifuging after the reaction is finished, re-dissolving in ultrapure water, and adjusting the pH value to 7.2-7.4 by using the sodium hydroxide solution; weighing PEG-CCM, dissolving the PEG-CCM in ultrapure water, then dropwise adding the PEG-CCM into the solution obtained by re-dissolving, adjusting the pH value of the solution to 7.4 by using a sodium hydroxide solution, stirring the solution for more than 10 hours, centrifuging the solution after the reaction is finished, re-dissolving the PEG-CCM in the ultrapure water, and adjusting the pH value of the solution to 7.4 by using the sodium hydroxide solution to obtain the redox-enhanced drug sensitive release mesoporous silica nanoparticles.

4. The redox-enhanced drug-sensitive release mesoporous silica nanoparticles according to claim 3, wherein: the PEG-CCM is prepared by the following method steps:

1) dissolving curcumin, 4-dimethylaminopyridine and triethylamine in tetrahydrofuran, stirring at room temperature and activating;

the dosage proportion of the curcumin, the 4-dimethylaminopyridine and the triethylamine is 1 g: (50-60) mg: (0.6-0.7) mL;

2) dissolving citric anhydride in tetrahydrofuran, then dropwise adding the solution obtained in the step 1), then refluxing and stirring for more than 10 hours under the protection of nitrogen in the whole process, dissolving 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride and 4-dimethylaminopyridine in the mixed solution of tetrahydrofuran and dichloromethane in the same volume to obtain an EDC/DMAP mixed solution, then dropwise adding the EDC/DMAP mixed solution into the citrated curcumin solution under the protection of nitrogen, and stirring and activating at room temperature;

the dosage proportion of the citric acid anhydride, the curcumin in the step 1), the 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride and the 4-dimethylaminopyridine is 0.6 g: 2 g: (350-: (18-20) mg;

3) dissolving polyethylene glycol 2000 in a mixed solution of tetrahydrofuran and dichloromethane in the same volume, then dropwise adding the mixed solution into the solution obtained in the step 2), stirring for more than 3 hours, after the reaction is finished, evaporating the reaction solution under reduced pressure, adjusting the pH to 3-4 with hydrochloric acid, extracting with dichloromethane, drying with anhydrous magnesium sulfate, filtering, performing rotary evaporation, finally performing recrystallization at least twice with excessive cold ethyl ether to obtain a yellow solid, then dissolving with ultrapure water, dialyzing in the ultrapure water with an MWCO 1000Da dialysis bag for more than two days, and performing freeze drying to obtain a yellow PEG-CCM solid;

the mass ratio of the polyethylene glycol 2000 to the curcumin in the solution obtained in the step 2) is 1.6 g: 2g of the total weight.

5. The redox-enhanced drug-sensitive release mesoporous silica nanoparticles according to claim 3, wherein: the mesoporous silica nanoparticle with the surface amino-carboxylated and internally bridged double tellurium bonds is prepared by the following method steps:

1) synthesizing 3, 3' -ditellurodipropyltriethoxysilane DTETePD:

dissolving tellurium powder and sodium borohydride in ice water, stirring at room temperature until the tellurium powder is completely dissolved, heating to 70 ℃ under the protection of nitrogen in the whole process, and continuing to react for more than 20min until the color of the solution is reddish brown; dropwise adding 3-chloropropyltriethoxysilane into the reddish brown solution, stirring overnight at 50 ℃ under the condition of nitrogen, filtering the reaction solution after the reaction is finished, extracting twice with dichloromethane, drying with anhydrous magnesium sulfate, filtering, performing rotary evaporation, and finally passing through a silica gel column to obtain DTETePD;

the using proportion of the tellurium powder, the sodium borohydride and the 3-chloropropyltriethoxysilane is 5 g: (1.4-1.6) g: 10g of a mixture;

2) weighing hexadecyl trimethyl ammonium chloride and triethanolamine into a three-neck flask filled with ultrapure water under the conditions of 80 ℃ and nitrogen protection, adding the hexadecyl trimethyl ammonium chloride and the triethanolamine into the three-neck flask filled with the ultrapure water, stirring to dissolve the hexadecyl trimethyl ammonium chloride and the triethanolamine to obtain a solution, then weighing tetraethyl orthosilicate and DTETePD to mix together, injecting the mixture into the solution, stirring to react for more than 3 hours under the reaction condition of 80 ℃, refluxing the obtained reaction product in an ethanol solution of 1% w/v ammonium nitrate at the temperature of 80 ℃ for more than 10 hours, washing with absolute ethanol, centrifuging for more than two times, and drying to obtain mesoporous silica nanoparticles with double tellurium bonds bridged inside;

the dosage proportion of the hexadecyl trimethyl ammonium chloride, the triethanolamine, the tetraethyl orthosilicate and the DTETePD is 0.6 g: 1 g: 0.15 g: 4g of the total weight of the mixture;

3) dissolving the mesoporous silica nanoparticles with the bridged double tellurium bonds inside prepared in the step 2) in absolute ethyl alcohol, stirring for more than 2h at the temperature of 80 ℃, cooling to room temperature, dropwise adding 3-aminopropyltriethoxysilane into the solution, stirring and reacting for at least 0.5h at the temperature of room temperature, refluxing for 12h at the temperature of 80 ℃, washing and centrifuging for more than two times by using absolute ethyl alcohol, and drying to obtain aminated double tellurium bond mesoporous silica nanoparticles; weighing aminated double-tellurium-bond mesoporous silica nanoparticles, dissolving the aminated double-tellurium-bond mesoporous silica nanoparticles in dimethylformamide, adding succinic anhydride and triethylamine into the solution, stirring and reacting for more than 18 hours at 50 ℃, washing and centrifuging for more than two times by using absolute ethyl alcohol, and drying to obtain surface-aminated double-tellurium-bond mesoporous silica nanoparticles;

the dosage proportion of the mesoporous silica nanoparticles with the internal bridged double tellurium bonds and the 3-aminopropyltriethoxysilane prepared in the step 2) is 1 mg: 1 mu L of the solution;

the dosage proportion of the aminated double-tellurium-bond mesoporous silica nano particle, succinic anhydride and triethylamine is 200 mg: 1.2 g: (70-90) μ L.

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