CN114906874A - Hafnium oxide nano-particles and preparation method and application thereof - Google Patents

Hafnium oxide nano-particles and preparation method and application thereof Download PDF

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CN114906874A
CN114906874A CN202210687761.3A CN202210687761A CN114906874A CN 114906874 A CN114906874 A CN 114906874A CN 202210687761 A CN202210687761 A CN 202210687761A CN 114906874 A CN114906874 A CN 114906874A
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谷战军
汪诚艳
刘瑞雪
闫海丽
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Institute of High Energy Physics of CAS
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Abstract

The invention discloses a hafnium oxide nano-particle and a preparation method thereof, belongs to the technical field of hafnium oxide, and solves the problems of complex synthesis method and irregular shape of the existing hafnium oxide nano-particle. The preparation method takes hafnium tetrachloride as a hafnium source and oleic acid and octadecene as solvents to generate the hafnium oxide nano-particles of the oil phase under the conditions of the oil phase system and anhydrous alkaline. The preparation method is simple, and the prepared hafnium oxide nanoparticles are small in particle size and regular in shape and can be used for diagnosis and treatment integration of tumor treatment.

Description

Hafnium oxide nano-particles and preparation method and application thereof
Technical Field
The invention belongs to the technical field of hafnium oxide, and particularly relates to hafnium oxide nanoparticles and a preparation method and application thereof.
Background
Malignant tumors are one of the important causes of human death, and ionizing radiation, one of the most commonly used non-surgical treatment means, is widely used for the diagnosis and treatment of clinical tumors due to its high permeability to tissues. The radiotherapy mainly causes free radical damage of cells or DNA double-chain breakage through free photoelectrons generated by high-energy X rays and the like, causes apoptosis of the cells to kill tumor tissues, and then reduces or disappears the tumor tissues. However, the radiation resistance of tumor tissue due to various reasons has to be increased during the treatment process to achieve the therapeutic effect. However, tissue unselectivity of radiation therapy results in the fragmentation of the normal tissue's DNA double strand causing radiation damage to the normal tissue. Thus, depositing a radiation dose at the tumor site, reducing radiation damage to surrounding healthy tissue is an effective strategy to address this problem.
Radiation dose deposition in tissue is related to the tissue's ability to interact with or absorb X-rays, and thus, intervention with substances containing high electron density can increase the radiation dose deposition of X-rays at the tumor tissue site, an effect known as radiosensitization. Hafnium has an atomic number of 72 and a density of 9.7g/cm 3 Has good X-ray deposition capability, and is used for radiotherapy sensitization. Hafnium oxide or hafnium oxide nanoparticles have been investigated for various applications. The compounds are physically and chemically inert and have beneficial properties from a biosafety perspective. Once the hafnium oxide nanoparticles accumulate in tumor cells, the hafnium oxide nanoparticles generate a large amount of electrons under x-ray irradiation, which can enhance the killing ability of cancer cells and reduce the damage to healthy tissues.
However, the existing synthesis method of hafnium oxide nanoparticles is complex, irregular in shape, and poor in dispersibility and stability.
Disclosure of Invention
In view of the above analysis, the present invention aims to provide hafnium oxide nanoparticles, and a preparation method and applications thereof. The method is used for providing a simple preparation method of the hafnium oxide nano-particles, and the prepared hafnium oxide nano-particles have small particle size, regular shape and good stability.
The purpose of the invention is mainly realized by the following technical scheme:
the invention provides a preparation method of hafnium oxide nanoparticles, which takes hafnium tetrachloride as a hafnium source and oleic acid and octadecene as solvents to generate the hafnium oxide nanoparticles of an oil phase under the conditions of an oil phase system and anhydrous alkalinity.
Furthermore, octadecene is used as a solvent in the oil phase system, and sodium hydroxide provides an alkaline condition.
Further, the preparation method comprises the following steps:
step 1, adding hafnium tetrachloride, oleic acid and octadecene into a container, stirring and heating the mixture in a vacuum state, and stirring the mixture until the solution is clear; then naturally cooling to room temperature to obtain a first mixture;
step 2, adding a methanol solution containing sodium hydroxide into the first mixture, and stirring at room temperature to obtain a second mixture;
step 3, heating the second mixture, and vacuumizing to remove methanol to obtain a third mixture;
step 4, heating the third mixture to 320-340 ℃ under the protection of inert gas for reaction;
and 5, naturally cooling the reaction system to room temperature, adding excessive ethanol into the reaction system, and centrifugally collecting to obtain the hafnium oxide nanoparticles.
Further, the preparation method also comprises the following steps:
and 6, modifying the surface of the hafnium oxide nano particles obtained in the step 5 by adopting a surfactant to increase the water solubility of the hafnium oxide nano particles.
Further, step 6 comprises:
s601, dissolving a surfactant in water, and performing ultrasonic treatment to uniformly disperse the surfactant in the water to obtain an aqueous solution of the surfactant;
s602, dispersing the hafnium oxide nanoparticles obtained in the step 5 into cyclohexane to obtain a hafnium oxide cyclohexane suspension;
s603, adding the aqueous solution of the surfactant into the hafnium oxide cyclohexane suspensionObtaining a fourth mixture, and carrying out ultrasonic stirring treatment on the fourth mixture until the cyclohexane is completely volatilized, and the hafnium oxide is completely converted into a water phase; washing for many times by using deionized water after centrifugation to obtain HfO modified by surfactant 2 And (3) nanoparticles.
Further, in the step 1, controlling the dosage ratio of hafnium tetrachloride to oleic acid to octadecene to be 0.5-1.5 mmol: 5-7 ml: 12-18 ml.
Further, in the step 1, the heating is controlled to be 150-170 ℃.
Further, in the step 2, the ratio of the amount of the hafnium tetrachloride to the amount of the sodium hydroxide is controlled to be 0.5-1.5 mmol: 2-3 mmol.
Further, in the step 2, the ratio of the amount of sodium hydroxide to the amount of methanol is controlled to be 2-3 mmol: 8-13 ml.
The invention also provides hafnium oxide nano-particles prepared by the preparation method.
The invention also provides application of the hafnium oxide nanoparticles in preparation of tumor radiotherapy medicines, and the hafnium oxide nanoparticles can be used as carriers of the tumor radiotherapy medicines.
Compared with the prior art, the invention can realize at least one of the following beneficial effects:
a) according to the preparation method, uniform hafnium hydroxide is generated in an oil phase under an alkaline condition, hafnium oxide nanoparticles of the oil phase are generated under an anhydrous condition, water is not added in the whole process, the particle size of the synthesized hafnium oxide nanoparticles is small (the average particle size is 4-6 nm), the shape is regular, the hafnium oxide nanoparticles can be spherical, rod-shaped, flaky and other shapes, can also be in a nanoflower shape, and are good in stability, uniform in size, short in preparation time, free of special pretreatment process and simple in process.
b) Surfactant modified HfO prepared by the preparation method of the invention 2 In the nanoparticles, the surfactant forms a hydrophilic layer on the surface of the hafnium oxide nanoparticles by the principle of electrostatic adsorption, so that the dispersibility of the hafnium oxide nanoparticles in aqueous solution and physiological solution is increased, and the bioavailability of tumor tissues is facilitated. Surfactant modified hafnium oxide sodiumThe rice granule has good biocompatibility and safety.
c) The hafnium oxide nanoparticles after surface modification spontaneously form aggregates with the particle size of about 50nm, and have better cell uptake effect.
d) The hafnium oxide nano-particles prepared by the method have good CT imaging effect and diagnosis and treatment integration property.
e) The hafnium oxide nanoparticles prepared by the invention can load common tumor radiotherapy medicines, such as: taxanes, vinca alkaloids, metallic platins, anthracyclines, antifolates, nitrogen mustards, podophyllum alkaloids, etc., so that the composition can be used for the synergistic treatment of radiotherapy and chemotherapy; can be combined with protein antibody and inhibitor by electrostatic adsorption for synergistic treatment of radiotherapy and immunity. Wherein, preferably, the adriamycin and the protein inhibitor VE-822 are combined with the hafnium oxide nano-particles to synergistically enhance the tumor killing.
f) The hafnium oxide nano-particles prepared by the method can be suitable for radiation therapy of different light sources, including neutron sources, gamma ray sources, X ray sources, alpha and beta ray radiation sources, and have good tumor killing effect in the use of different radiation sources.
Additional features and advantages of the invention will be set forth in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention. The objectives and other advantages of the invention will be realized and attained by the structure particularly pointed out in the written description.
Drawings
The drawings are only for purposes of illustrating the particular invention and are not to be construed as limiting the invention, wherein like reference numerals are used to designate like parts throughout the figures.
FIG. 1 is a transmission electron micrograph of hafnium oxide nanoparticles of example 1;
FIG. 2 is an XRD pattern of hafnium oxide nanoparticles of example 1;
FIG. 3 is TPGS-HfO of example 1 2 Transmission electron microscopy of nanoparticles;
FIG. 4 is a dispersion diagram of hafnium oxide nanoparticles of example 1 in cyclohexane;
FIG. 5 is TPGS-HfO of example 1 2 Dispersion profile of nanoparticles in different physiological solutions;
FIG. 6 is TPGS-HfO of example 1 2 Pictures of nanoparticle uptake by cancer cells;
FIG. 7 is TPGS-HfO of example 1 2 Nanoparticle to doxorubicin loading curve;
FIG. 8 is TPGS-HfO of example 1 2 Nanoparticle load curve for protein inhibitor VE-822;
FIG. 9 TPGS-HfO at various concentrations in example 1 2 Cytotoxicity of nanoparticles in normal and tumor cells, respectively;
FIG. 10 is TPGS-HfO of example 1 2 The hemolytic properties of the nanoparticles;
FIG. 11 is TPGS-HfO of example 1 2 The radiosensitizing ability of the nanoparticles;
FIG. 12 is TPGS-HfO of example 1 2 The radiotherapy sensitization effect of the nano particles;
FIG. 13 is TPGS-HfO of example 1 2 CT imaging effect of nanoparticles.
Detailed Description
The following is a detailed description of a hafnium oxide nanoparticle, its preparation and use, in conjunction with specific examples, which are provided for purposes of comparison and explanation only and to which the present invention is not limited.
The invention provides a preparation method of hafnium oxide nanoparticles, which takes hafnium tetrachloride as a hafnium source and oleic acid and octadecene as solvents to generate the hafnium oxide nanoparticles of an oil phase under the conditions of an oil phase system and anhydrous alkalinity.
Specifically, the raw materials comprise hafnium tetrachloride, oleic acid, octadecene and sodium hydroxide; mixing hafnium tetrachloride, oleic acid and octadecene, stirring and heating in a vacuum state until the solution is clear, cooling to room temperature, adding a methanol solution containing sodium hydroxide, stirring and mixing at room temperature, heating, vacuumizing to remove methanol, heating to 320-340 ℃ in an inert gas protection state, and reacting to obtain the hafnium oxide nanoparticles.
Wherein the dosage ratio of the hafnium tetrachloride to the oleic acid to the octadecene is 0.5-1.5 mmol: 5-7 ml: 12-18 ml; the amount ratio of the hafnium tetrachloride to the sodium hydroxide is 0.5-1.5 mmol: 2-3 mmol; the ratio of the amount of sodium hydroxide to the amount of methanol is 2-3 mmol: 8-13 ml.
Wherein, hafnium tetrachloride, oleic acid and octadecene are mixed, stirred and heated in a vacuum state, and then heated to 150-170 ℃.
In the preparation process, hafnium tetrachloride reacts with sodium oleate to generate hafnium oleate, hafnium oleate reacts with sodium hydroxide to obtain hafnium hydroxide, and the hafnium hydroxide generates oil-phase hafnium oxide nanoparticles under anhydrous condition.
Specifically, the preparation method of the hafnium oxide nanoparticles comprises the following steps:
step 1, adding hafnium tetrachloride, oleic acid and octadecene into a container, stirring and heating under a vacuum state, and stirring until a solution is clear; then naturally cooling to room temperature to obtain a first mixture;
step 2, adding a methanol solution containing sodium hydroxide into the first mixture, and stirring at room temperature to obtain a second mixture;
step 3, heating the second mixture, and vacuumizing to remove methanol to obtain a third mixture;
step 4, heating the third mixture to 320-340 ℃ under the protection of inert gas for reaction;
step 5, naturally cooling the reaction system to room temperature, adding excessive ethanol into the reaction system, centrifugally collecting to obtain hafnium oxide nanoparticles, washing the hafnium oxide nanoparticles with ethanol for multiple times, and then suspending the hafnium oxide nanoparticles in cyclohexane for storage for later use;
and 6, modifying the surface of the hafnium oxide nano particles obtained in the step 5 by adopting a surfactant to increase the water solubility of the hafnium oxide nano particles.
Specifically, in step 6, the surfactant is a surfactant commonly used in the medical field, and includes an anionic surfactant: stearic acid, sodium dodecylbenzenesulfonate, etc.; cationic surfactant: quaternary ammonium surfactants; zwitterionic surfactant: lecithin, soybean lecithin, betaine type, etc.; also nonionic surfactants: alkyl glucosides, fatty acid glycerides, span, TPGS (vitamin E polyethylene glycol succinate), polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), or tween.
Preferably, the surfactant is selected from TPGS.
Specifically, the step 6 includes the following steps: s601, dissolving a surfactant in water, and dispersing the surfactant uniformly by using ultrasound to obtain an aqueous solution of the surfactant;
s602, dispersing the hafnium oxide nanoparticles obtained in the step 5 into cyclohexane to obtain a hafnium oxide cyclohexane suspension;
s603, adding the aqueous solution of the surfactant into the hafnium oxide cyclohexane suspension to obtain a fourth mixture, and carrying out ultrasonic stirring treatment on the fourth mixture until the cyclohexane is completely volatilized, and the hafnium oxide is completely converted into a water phase; washing with deionized water for several times after centrifuging to remove excessive surfactant to obtain surfactant modified HfO 2 Nanoparticles, surfactant modified HfO 2 Dispersing the nano particles in deionized water for storage for later use.
Specifically, steps 1 to 4 are all performed under the protection of an inert gas, and the inert gas may be argon.
Specifically, in the whole preparation process of the hafnium oxide nanoparticles, hafnium tetrachloride is used as a hafnium source, oleic acid is used as a complexing agent and a stabilizing agent to coordinate with hafnium ions in a reaction system, octadecene is used as a reaction solvent, so that in a synthesis system, if the amount of hafnium chloride is controlled to be unchanged, oleic acid is used as a ligand, and the use amount of oleic acid is inversely proportional to the particle size of hafnium oxide; if other variables are controlled to be constant, too much hafnium tetrachloride results in incomplete reaction and too little results in low yield. Therefore, in the step 1, the usage ratio of the hafnium tetrachloride to the oleic acid to the octadecene is controlled to be 0.5-1.5 mmol: 5-7 ml: 12-18 ml.
Specifically, in the step 1, too high stirring and heating temperature affects the subsequent reaction, which may cause experimental failure, and too low temperature is not favorable for the formation of hafnium oleate; too short stirring time is not beneficial to the formation of hafnium oleate, and too long stirring time only can prolong the whole synthesis time. Therefore, the heating is controlled to 150-170 ℃, such as 155 ℃, 160 ℃ and 165 ℃; stirring for 20-40 min under vacuum.
Specifically, in the step 2, sodium hydroxide is used as a mineralizer in the reaction system, and has the function of promoting the reaction to proceed, and reacts with the hafnium oleate formed in the previous step to generate hafnium hydroxide, the excessive amount of sodium hydroxide can cause the excessive alkalinity in the reaction system to influence the experimental reaction, and the insufficient amount of sodium hydroxide can cause the incomplete reaction. Therefore, the amount ratio of the hafnium tetrachloride to the sodium hydroxide is controlled to be 0.5 to 1.5 mmol: 2-3 mmol.
Specifically, because the pyrolysis reaction in the preparation method of the present invention is a high temperature oil phase reaction, oxygen-free and water-free in the whole system is ensured, and therefore, in step 2, methanol is used as a solvent of sodium hydroxide, so that methanol can be volatilized during the temperature raising process, so that the volatilization time is increased due to excessive amount of methanol in the system, and the dissolution of sodium hydroxide is not facilitated due to too little amount of methanol. Therefore, in the step 2, the ratio of the amount of the sodium hydroxide to the amount of the methanol is controlled to be 2-3 mmol: 8-13 ml.
Specifically, in step 2, a peristaltic pump may be used to add the methanol solution containing sodium hydroxide dropwise into the reaction system, and the dropping rate is too fast, which results in too large particle size of the hafnium oxide to be formed later, and if too slow, the whole reaction time may be prolonged. Therefore, the dropping rate is controlled to be 12-17 mm/min (mm is the scale on the syringe on the peristaltic pump and represents mm), and the mixture is stirred for 20-40 min at room temperature.
Specifically, in the step 3, the temperature is increased to 70-90 ℃, and the vacuum-pumping treatment is carried out for 20-40 min.
Specifically, in the steps 1 to 4, the reactions involved are as follows:
HfCl 4 +4(C 17 H 33 CO 2 Na)＝(C 17 H 33 CO 2 ) 4 Hf+4NaCl (1)
(C 17 H 33 CO 2 ) 4 Hf+NaOH＝Hf(OH) 4 +4(C 17 H 33 CO 2 Na) (2)
Hf(OH) 4 ＝HfO 2 +2H 2 O (3)
specifically, in the step 4, the reaction time is controlled to be 0.5-2 h.
Specifically, in the step 5, the rotating speed of the centrifugation is controlled to be 11500-12500 rpm, and the centrifugation processing time is 1-5 min.
Specifically, in step 6, when TPGS is selected as the surfactant, too small amount of TPGS may deteriorate dispersibility of the hafnium oxide nanoparticles in water, but too large amount of TPGS may not increase water solubility of the hafnium oxide, but may increase subsequent washing time; therefore, the mass ratio of TPGS to hafnium oxide nanoparticles is controlled to be 0.5-1.5: 0.5 to 1.5; the volume ratio of the TPGS aqueous solution to the hafnium oxide cyclohexane suspension is 0.5-1.5: 0.5 to 1.5.
Specifically, in order to reduce the impurity contamination, ultrapure water may be used as the water in S601.
Specifically, in the step S603, the fourth mixture is subjected to ultrasonic stirring treatment at 60 to 80 ℃.
Specifically, in the step S603, the rotation speed of the centrifugation is controlled to be 11500 to 12500rpm, and the centrifugation time is 3 to 10 min.
Specifically, the hafnium oxide nanoparticles obtained in the step 5 have a small particle size and a regular shape, and may be in the shape of a sphere, a rod, a sheet, or a nanoflower, and have a uniform particle size with an average particle size of 4 to 6 nm. The product has good dispersibility and stability in cyclohexane; for example, 70mg of hafnium oxide nanoparticles are dispersed in 1ml of cyclohexane, and after standing for one week, no obvious precipitation is observed in the solution, as shown in FIG. 4, which shows that the hafnium oxide nanoparticles have good dispersibility and stability in cyclohexane.
Specifically, in step S603, TPGS forms a hydrophilic layer on the surface of the hafnium oxide nanoparticle by the principle of electrostatic adsorption, so as to increase the dispersibility of the hafnium oxide nanoparticle in aqueous solution and physiological solution, and facilitate the bioavailability of tumor tissue.
Specifically, in step S603, TPGS-HfO 2 The average particle size of the nanoparticles is about 10-50 nm, and the nanoparticles have a better cell uptake effect.
In particularIn the step S603, TPGS-HfO 2 The nanoparticles have good dispersibility and stability, for example, 10 mg of TPGS-HfO 2 The nanoparticles are dispersed in physiological solution such as 1mL of aqueous solution, phosphate buffer solution and the like, and after standing for one week, no obvious precipitation appears, as shown in FIG. 5, which illustrates TPGS-HfO 2 The nano-particles have good dispersibility and stability in physiological solution.
The hafnium oxide nanoparticles prepared by the invention can load common tumor radiotherapy medicines, such as: taxanes, vinca alkaloids, metallic platins, anthracyclines, antifolates, nitrogen mustards, podophyllum alkaloids, etc., so that the composition can be used for the synergistic treatment of radiotherapy and chemotherapy; can be combined with protein antibody and inhibitor by electrostatic adsorption for synergistic treatment of radiotherapy and immunity. Wherein, preferably, the adriamycin and the protein inhibitor VE-822 are combined with the hafnium oxide nano-particles to synergistically enhance the tumor killing; the hafnium oxide nano-particles have good CT imaging effect and diagnosis and treatment integration property.
Compared with the prior art, the preparation method generates uniform hafnium hydroxide in the oil phase under the alkaline condition, generates the hafnium oxide nano-particles in the oil phase under the anhydrous condition, and has no water in the whole process, so that the synthesized hafnium oxide nano-particles have small and uniform particle size and good stability.
The preparation method has short preparation time, does not need a special pretreatment process and has simple process.
Surfactant modified HfO prepared by the preparation method of the invention 2 In the nanoparticles, the surfactant forms a hydrophilic layer on the surface of the hafnium oxide nanoparticles by the principle of electrostatic adsorption, so that the dispersibility of the hafnium oxide nanoparticles in aqueous solution and physiological solution is increased, and the bioavailability of tumor tissues is facilitated. Hafnium oxide nanoparticles and surfactant modified HfO 2 The nanoparticles have good biocompatibility and safety.
The hafnium oxide nano-particles prepared by the method have the function of CT radiography and can be used for diagnosis and treatment integration of tumor treatment.
The invention is madeThe hydrophilic surfactant-modified HfO thus obtained 2 The nanoparticles can be loaded with commonly used tumor radiotherapy drugs, such as: taxanes, vinca alkaloids, metallic platins, anthracyclines, antifolates, nitrogen mustards, podophyllum alkaloids, etc., and thus can be used for the synergistic treatment of radiotherapy and chemotherapy; can be combined with protein antibody and inhibitor by electrostatic adsorption for synergistic treatment of radiotherapy and immunity. Wherein, preferably, the adriamycin and the protein inhibitor VE-822 are combined with the hafnium oxide nano-particles to synergistically enhance the tumor killing; and the system also has good CT imaging effect and diagnosis and treatment integration property.
The hafnium oxide nano-particles prepared by the method can be suitable for radiation therapy of different light sources, including neutron sources, gamma ray sources, X ray sources, alpha and beta ray radiation sources, and have good tumor killing effect in the use of different radiation sources.
Example 1
The embodiment provides a preparation method of hafnium oxide nanoparticles, which comprises the following steps:
1. adding 1mmol of hafnium tetrachloride, 6mL of oleic acid and 15mL of octadecene into a three-neck flask, stirring and heating to 160 ℃, and maintaining for 30min under a vacuum state until the solution is clear;
2. naturally cooling to room temperature under the state of inert gas (argon);
adding 10mL of methanol solution containing 2.5mmol of sodium hydroxide into the reaction system by using a peristaltic pump, dropwise adding at the speed of 15mm/min, and stirring at room temperature for 30 min;
3. slowly heating the reaction system to 80 ℃, and vacuumizing for 30min to remove methanol;
4. heating to 330 ℃ under the condition of inert gas (argon) and maintaining for 1 h;
5. naturally cooling to room temperature, adding excessive ethanol into the reaction system, centrifuging at 12000rpm for 2min, collecting materials, washing with ethanol for three times, and then suspending in cyclohexane for storage;
6. surface modification to increase its water solubility:
1) dissolving 20mg of TPGS in 10mL of ultrapure water, and performing ultrasonic treatment to uniformly disperse the TPGS;
2) taking 20mg of oil phase HfO 2 Dispersing the nanoparticles into cyclohexane to 10 mL;
3) adding TPGS aqueous solution to HfO 2 Performing ultrasound for 3 min;
4) placing the beaker in a constant temperature water bath at 70 ℃, stirring until the cyclohexane is completely volatilized, and HfO 2 All are converted into water phase;
5) centrifuging (12000rpm, 5min), washing with deionized water for 5 times, and washing to remove excessive TPGS to obtain TPGS-HfO 2 TPGS-HfO 2 Dispersing in deionized water and storing for later use.
Example 2
The embodiment provides a preparation method of hafnium oxide nanoparticles, which comprises the following steps:
1. adding 0.8mmol of hafnium tetrachloride, 6mL of oleic acid and 15mL of octadecene into a three-neck flask, stirring and heating to 165 ℃, and maintaining for 30min under a vacuum state until the solution is clear;
2. naturally cooling to room temperature under the condition of inert gas (argon);
adding 10mL of methanol solution containing 2.5mmol of sodium hydroxide into the reaction system by using a peristaltic pump, dropwise adding at the speed of 16mm/min, and stirring at room temperature for 30 min;
3. slowly heating the reaction system to 85 ℃, and vacuumizing for 25min to remove methanol;
4. heating to 335 ℃ under the inert gas (argon) state and maintaining for 1 h;
5. naturally cooling to room temperature, adding excessive ethanol into the reaction system, centrifuging at 12000rpm for 2min, collecting materials, washing with ethanol for three times, and then suspending in cyclohexane for storage;
6. surface modification to increase its water solubility:
1) dissolving 20mg of TPGS in 10mL of ultrapure water, and performing ultrasonic treatment to uniformly disperse the TPGS;
2) taking 20mg of oil phase HfO 2 Dispersing into cyclohexane to 10 mL;
3) adding TPGS aqueous solution to HfO 2 Performing ultrasound for 3 min;
4) placing the beaker in a constant temperature water bath at 70 ℃, stirring until the cyclohexane is completely volatilized, and HfO 2 All are converted into water phase;
5) centrifuging (12000rpm, 5min), washing with deionized water for 5 times, and washing to remove excessive TPGS to obtain TPGS-HfO 2 Nanoparticles of TPGS-HfO 2 Dispersing the nano particles in deionized water and storing for later use.
Test 1
The hafnium oxide nanoparticles synthesized in example 1 were observed by transmission electron microscopy.
Fig. 1 is a Transmission Electron Microscope (TEM) image of the hafnium oxide nanoparticles synthesized in example 1, and it can be seen from the TEM image that the average particle size of the hafnium oxide nanoparticles is about 5nm and the particle size is uniform.
Test 2
XRD of the hafnium oxide nanoparticles synthesized in example 1 was examined.
Fig. 2 is an XRD spectrum of the hafnium oxide nanoparticles synthesized in example 1, from which it can be seen that the diffraction peak of the hafnium oxide nanoparticles coincides with the peak position on the standard card, indicating that the hafnium oxide nanoparticles were successfully synthesized.
Test 3
The hafnium oxide nanoparticles of example 1 were tested for dispersibility and stability in cyclohexane.
Fig. 4 is a graph of the dispersibility and stability of the hafnium oxide nanoparticles of example 1 in cyclohexane. Specifically, 70mg of the hafnium oxide nanoparticles of example 1 were dispersed in 1ml of cyclohexane, and the dispersion of the hafnium oxide nanoparticles in cyclohexane was observed after one week. As can be seen from the figure, the hafnium oxide nanoparticles can be stably dispersed in cyclohexane after standing for one week, which shows that the hafnium oxide nanoparticles have good dispersibility and stability in cyclohexane.
Test 4
TPGS-HfO of example 1 was observed by transmission electron microscopy 2 And (3) nanoparticles.
FIG. 3 is TPGS-HfO of example 1 2 Transmission electron microscopy of nanoparticles, from which TPGS-HfO can be seen 2 The average particle size of the nanoparticles is about 50nm, and the particle size is uniform. It is stated that, after surface modification of the hafnium oxide nanoparticles, the hafnium oxide nanoparticles form aggregates,while the gaps between the hafnium oxide nanoparticles provide advantages for drug loading. And researches show that the size of the nano particles is about 50nm and is more favorable for cellular uptake.
Test 5
Testing of TPGS-HfO of example 1 2 Dispersibility and stability of nanoparticles in different physiological solutions.
FIG. 5 is TPGS-HfO of example 1 2 The dispersion and stability of nanoparticles in different physiological solutions. Specifically, 10 mg of TPGS-HfO of example 1 was added 2 The nanoparticles were dispersed in 1ml of different physiological solutions and observed one week later for TPGS-HfO 2 Dispersion of nanoparticles in solution. As can be seen from the figure, TPGS-HfO was found after one week of standing 2 The nano particles can still be stably dispersed in physiological solution, which shows that the nano particles have good dispersibility and stability.
Test 6
TPGS-HfO of example 1 2 TPGS-HfO was performed 2 The DOX (adriamycin) loading experiment method comprises the following steps:
DOX standard curve determination: preparing DOX solutions (6.25/12.5/25/50/100/200 mu g/mL) with different concentrations, measuring the absorbance value at 488.5nm by using an ultraviolet spectrophotometer, and fitting a standard curve of DOX;
2. 2mg of TPGS-HfO was taken 2 Dispersing in a proper amount of deionized water, adding a DOX solution, and adding deionized water to 10mL, wherein the DOX final concentration is 150 mu g/mL;
3. placing the mixed system on a stirring table, stirring at room temperature, sampling at different time points (0.5/1/3/6/9/12/24h), and separating a product and unloaded DOX by a centrifugal method;
4. measuring the supernatant by an ultraviolet spectrophotometer for detection to obtain the absorbance value of DOX at 488.5nm, and calculating TPGS-HfO 2 Load efficiency on DOX;
5. the calculation formula is as follows: DOX loading (%) - (W) DOX /W TPGS-HfO2 ) X 100), wherein W DOX Representing the load to TPGS-HfO 2 Mass of DOX above, W TPGS-HfO2 RepresentTPGS-HfO 2 The quality of (c).
FIG. 7 is TPGS-HfO 2 Nanoparticle to doxorubicin loading curve: as can be seen from the figure, TPGS-HfO 2 The nanoparticles can physically adsorb doxorubicin, and the larger the adsorption of doxorubicin increases with time, the maximum adsorption is 26%.
TPGS-HfO of example 1 2 Nanoparticles were subjected to TPGS-HfO 2 The experimental method of the protein inhibitor-loaded VE-822 comprises the following steps:
VE-822 standard curve determination: preparing VE-822 solutions (1.25/2.5/5/10/20/40/80 mu g/mL) with different concentrations, measuring the absorbance value at 387nm by using an ultraviolet spectrophotometer, and fitting a standard curve of VE-822;
2. taking 2mg of TPGS-HfO 2 Dispersing in a proper amount of deionized water, adding DMSO solutions of VE-822 with different concentrations, and adding deionized water to 10mL, wherein the final concentration of VE-822 is 0, 1, 2, 4, 6, 8, 10, 20, 40 mu mol/mL;
3. placing the mixed system on a stirring table, stirring for 5h, and separating the product and the unloaded VE-822 by a centrifugal method;
4. measuring the supernatant by an ultraviolet spectrophotometer for detection to obtain the absorbance value of VE-822 at 387nm, and calculating TPGS-HfO 2 Load efficiency on VE-822.
FIG. 8 is TPGS-HfO 2 Nanoparticle load curve for inhibitor VE-822: as can be seen from the figure, TPGS-HfO 2 The nanoparticles can physically adsorb VE-822, and the larger the amount of adsorption of VE-822 with increasing time, the maximum amount of adsorption is 8.5%.
Test 7
Observation of cancer cells by inverted microscope TPGS-HfO of example 1 2 Uptake of nanoparticles.
Firstly, cells are planted in a 24-well plate with a cell slide, and after the cells are completely attached to the wall, TPGS-HfO containing 50 mu g/mL is used 2 After the cells were cultured in the complete medium for nanoparticles for 6 hours, the cells were washed 3 times with a phosphate buffer solution, and then allowed to standCells were fixed with paraformaldehyde for 10 minutes, followed by treatment with nuclear stain at room temperature for 15 minutes, and finally imaged using an inverted microscope. Wherein, each group to be detected is treated as follows:
control group: groups of cells not treated with any material.
Hafnium oxide nanoparticle group: a cell panel treated with hafnium oxide nanoparticles.
TPGS-HfO 2 Group of nanoparticles: use of TPGS-HfO 2 Nanoparticle treated cell groups.
As shown in FIG. 6, a large amount of TPGS-HfO could be detected in the cells after 6 hours of material uptake by the cells 2 Nanoparticles, demonstrate that hafnium oxide nanoparticles can increase material uptake by cells after surface modification.
Test 8
TPGS-HfO was studied at various concentrations 2 Cytotoxicity of nanoparticles in normal and tumor cells, respectively.
FIG. 9 shows TPGS-HfO at various concentrations 2 Cytotoxicity of nanoparticles in normal and tumor cells, respectively: as can be seen from the figure, TPGS-HfO was present at various concentrations 2 The nanoparticles were not biotoxic, neither in normal cells nor in tumor cells, indicating that synthetic TPGS-HfO 2 The nanoparticles have good biocompatibility and safety.
Test 9
TPGS-HfO was investigated 2 Hemolytic properties of the nanoparticles.
Shown in FIG. 10 as TPGS-HfO 2 Hemolytic properties of the nanoparticles: as can be seen from the figure, TPGS-HfO 2 The nanoparticles did not cause hemolysis, indicating that TPGS-HfO 2 The nano-particles have good biological safety.
Test 10
TPGS-HfO was investigated 2 The radiosensitization ability of the nanoparticles at the cellular level. Firstly, the cells are planted into a confocal small dish, and after the cells are completely attached to the wall, the corresponding cells are replaced by cells containing TPGS-HfO 2 Complete culture of nanoparticles, followed by 6 h incubationAfter incubation, all groups of cells were replaced with serum-free medium containing DCFH-DA probes, incubated at 37 ℃ for 30 minutes, excess probe solution was removed, and the cells were then subjected to X-ray irradiation. After irradiation, fluorescence intensity in cells was observed using a confocal scanning microscope, and fluorescence intensity statistics were performed using image J software. Wherein the treatment of each group to be detected is as follows:
control group: normal control group.
X-ray group: only the X-ray irradiation group was performed.
HfO 2 Group (2): TPGS-HfO only 2 Nanoparticle treatment group.
HfO 2 + X-ray group: in the process of TPGS-HfO 2 The nanoparticles were treated followed by the X-ray treatment group.
The dose of X-rays was 6Gy, and the irradiation conditions were: 160kV and 25mA current.
FIG. 11 shows TPGS-HfO 2 The radiosensitization capacity of the nanoparticles at the cell level: as can be seen in the figure, TPGS-HfO was used prior to irradiation 2 The nanoparticles show a significant increase in ROS at the cellular level for the prognosis of the stem, indicating that TPGS-HfO 2 Nanoparticles can increase the amount of radiation deposition on cells to generate more ROS to enhance the killing of tumor cells.
Test 11
TPGS-HfO was investigated 2 Radiotherapy sensitization effect of the nanoparticles. Inoculating cells in a 24-well plate with a cell slide, and applying a solution containing TPGS-HfO after the cells are completely attached to the wall 2 The cells were treated with complete medium of nanoparticles, after 6 hours of incubation, the cells were X-rayed, after 3 hours of irradiation, all groups of cells were fixed with 4% paraformaldehyde for 10 minutes, then the cells were treated with a punch (0.2% triton-100X + 99.8% PBS) for 10 minutes, then the cells were treated with a blocking solution (1% triton-100X + 5% FBS + 94% PBS) for 1 hour, then the cells were treated with a gamma-H2 AX antibody (primary antibody) at 4 ℃ for 12 hours, then the cells were treated with an antibody with red fluorescence (secondary antibody) at 37 ℃ for 1 hour, finally the cells were imaged with a confocal scanning microscope and the fluorescence spots were counted with image J softwareAnd (4) counting.
Wherein, each group to be detected is processed as follows:
control group: normal control group.
X-ray group: after the cells are fully adherent, the cells are treated with X-rays.
HfO 2 Group (2): after the cells are completely attached to the wall, TPGS-HfO is used 2 The nanoparticles treated the cells for 6 hours.
HfO 2 + X-ray group: after the cells are completely attached to the wall, TPGS-HfO is used 2 After the nanoparticles treated the cells for 6 hours, the cells were treated with X-rays.
The dose of X-rays was 6Gy, and the irradiation conditions were: 160kV and 25mA current.
FIG. 12 shows TPGS-HfO 2 Radiotherapy sensitization effect of nanoparticles: as can be seen from the figure, TPGS-HfO was used in the irradiation process 2 Nanoparticles, which can cause more severe cellular DNA damage, suggest the use of TPGS-HfO 2 Nanoparticles can enhance the killing of cells by radiation.
Test 12
TPGS-HfO obtained in example 1 was used 2 The nano particles are applied to tumor CT imaging.
Fig. 13 shows the CT imaging effect of TPGS-HfO2 nanoparticles on tumor-bearing mice: as shown, TPGS-HfO was not performed 2 No CT signal was observed at the tumor site of tumor-bearing mice locally injected with nanoparticles, but TPGS-HfO was locally injected 2 After the nanoparticles are added, CT signals of tumor parts of tumor-bearing mice are obvious, which shows that the synthesized TPGS-HfO 2 The nano particles have good CT imaging effect and the property of integration of diagnosis and treatment.
The above description is only for the preferred embodiment of the present invention, but the scope of the present invention is not limited thereto, and any changes or substitutions that can be easily conceived by those skilled in the art within the technical scope of the present invention are included in the scope of the present invention.

Claims (10)

1. The preparation method of the hafnium oxide nanoparticles is characterized in that hafnium tetrachloride is used as a hafnium source, oleic acid and octadecene are used as solvents, and the hafnium oxide nanoparticles in an oil phase are generated under the conditions of an oil phase system and anhydrous alkalinity.
2. The method of claim 1, wherein the oil phase system is alkaline with sodium hydroxide.
3. The method of claim 1, comprising the steps of:
step 1, adding hafnium tetrachloride, oleic acid and octadecene into a container, stirring and heating the mixture in a vacuum state, and stirring the mixture until the solution is clear; then naturally cooling to room temperature to obtain a first mixture;
step 2, adding a methanol solution containing sodium hydroxide into the first mixture, and stirring at room temperature to obtain a second mixture;
step 3, heating the second mixture, and vacuumizing to remove methanol to obtain a third mixture;
step 4, heating the third mixture to 320-340 ℃ under the protection of inert gas for reaction;
and 5, naturally cooling the reaction system to room temperature, adding excessive ethanol into the reaction system, and centrifugally collecting to obtain the hafnium oxide nanoparticles.
4. The method of manufacturing according to claim 3, further comprising:
and 6, modifying the surface of the hafnium oxide nano particles obtained in the step 5 by adopting a surfactant to increase the water solubility of the hafnium oxide nano particles.
5. The method of claim 4, wherein the step 6 comprises:
s601, dissolving a surfactant in water, and performing ultrasonic treatment to uniformly disperse the surfactant in the water to obtain an aqueous solution of the surfactant;
s602, dispersing the hafnium oxide nanoparticles obtained in the step 5 into cyclohexane to obtain a hafnium oxide cyclohexane suspension;
s603, adding the aqueous solution of the surfactant into the hafnium oxide cyclohexane suspension to obtain a fourth mixture, and carrying out ultrasonic stirring treatment on the fourth mixture until the cyclohexane is completely volatilized, and the hafnium oxide is completely converted into a water phase; washing for multiple times by using deionized water after centrifugation to obtain modified HfO 2 And (3) nanoparticles.
6. The preparation method according to claim 3, wherein in the step 1, the ratio of the hafnium tetrachloride to the oleic acid to the octadecene is controlled to be 0.5-1.5 mmol: 5-7 ml: 12-18 ml.
7. The method according to claim 3, wherein the heating is controlled to 150 to 170 ℃ in the step 1.
8. The method according to claim 3, wherein in the step 2, the ratio of the amounts of hafnium tetrachloride and sodium hydroxide is controlled to be 0.5 to 1.5 mmol: 2-3 mmol.
9. A hafnium oxide nanoparticle, wherein the hafnium oxide nanoparticle is prepared by the method of any one of claims 1 to 8.
10. The use of hafnium oxide nanoparticles for the preparation of a medicament for radiotherapy of tumors, wherein said hafnium oxide nanoparticles of claim 9 can be used as a carrier for a medicament for radiotherapy of tumors.
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