CN110787149A

Movatterモバイル変換

Info

Publication number: CN110787149A
Application number: CN201911117322.3A
Authority: CN
Inventors: 黄文飞
Original assignee: Shenzhen Carbon 14 Technology Innovation Co Ltd
Current assignee: Shenzhen Carbon 14 Technology Innovation Co Ltd
Priority date: 2019-11-12
Filing date: 2019-11-12
Publication date: 2020-02-14

Abstract

The invention discloses a double-shell nanoparticle and a preparation method thereof, wherein the double-shell nanoparticle comprises the following components in parts by weight: an inner core, wherein the inner core is an inorganic nanoparticle; a first organic phase shell coated on the surface of the inner core, wherein the first organic phase shell comprises a ligand with the function of identifying tumor tissues; and the second organic phase shell is coated on the surface of the first organic phase shell. The technical scheme of the invention can improve the adsorption rate of the inorganic nanoparticles on the surface of the tumor tissue and improve the tumor treatment effect.

Description

Double-shell nanoparticle and preparation method thereof

Technical Field

The invention relates to the technical field of nano materials and preparation thereof, in particular to double-shell nano particles and a preparation method thereof.

Background

With the development of nanotechnology, nanomaterials provide new possibilities for tumor therapy. In recent years, many researches have found that the nano material has a remarkable effect on the aspects of inhibiting the growth of tumor tissues and the like. In the process of treating the tumor, the nano material is adsorbed on the surface of the tumor tissue to perform specific reaction with tumor cells, so that the effect of treating the tumor is achieved. The nano material is mainly divided into inorganic nano material and organic nano material, and compared with organic nano material, the inorganic nano material has the advantages of good stability, multiple functions, good physicochemical properties and the like. Generally, the surface of the inorganic nanoparticles needs to be coated with an organic layer to solve the biocompatibility problem of the inorganic nanoparticles. On the basis, in order to improve the adsorption rate of the inorganic nanoparticles on tumor tissues, the surface of the organic layer usually contains a specific protein ligand capable of recognizing tumor cells. However, in animal tests, it was found that the inorganic nanoparticles modified with specific protein ligands are recognized as foreign substances by immune macrophages in blood and phagocytosed and eliminated, and thus, even if the corresponding specific protein ligands are modified on the surface of the organic layer, the adsorption rate of the inorganic nanoparticles on the surface of tumor tissue cannot be increased.

Disclosure of Invention

The invention mainly aims to provide double-shell nanoparticles, aiming at improving the adsorption rate of inorganic nanoparticles on the surface of tumor tissues and improving the tumor treatment effect.

In order to achieve the above object, the present invention provides a double-shell nanoparticle, comprising:

an inner core, wherein the inner core is an inorganic nanoparticle;

a first organic phase shell coated on the surface of the inner core, wherein the first organic phase shell comprises a ligand with the function of identifying tumor cells;

and the second organic phase shell is coated on the surface of the first organic phase shell.

Optionally, the ligand comprises a polymer chain with a hydrophilic group and a specific group with a function of recognizing tumor cells, and the specific group is connected to the polymer chain with the hydrophilic group.

Alternatively, the specificity group is a base group that can bind to a particular protein, or alternatively, the specificity group is a charged group.

Optionally, the polymer chain having a hydrophilic group is one of a polyethylene glycol polymer chain, a carboxymethyl cellulose polymer chain, a hyaluronic acid polymer chain, a chitosan polymer chain, and a polyvinyl alcohol polymer chain.

Optionally, the composition of the second organic phase shell comprises a fat-soluble polymer material, and/or the composition of the second organic phase shell comprises a polymer material having hydrophilic groups.

Optionally, the double-shell nanoparticles have a particle size of 10nm to 900 nm.

Optionally, the wall thickness of the second organic phase shell is 5nm to 500nm, and/or the wall thickness of the first organic phase shell is 5nm to 500 nm.

The invention also provides a preparation method of the double-shell nano particle, which comprises the following steps:

preparing a first aqueous phase solution comprising a first precursor and a carrier;

preparing a second aqueous phase solution, wherein the second aqueous phase solution comprises a second precursor;

preparing a first organic phase solution and a second organic phase solution;

mixing the first aqueous phase solution and the first organic phase solution to form a water-in-oil first emulsion;

mixing the second aqueous phase solution and the second organic phase solution to form a water-in-oil second emulsion;

mixing and uniformly dispersing the first emulsion and the second emulsion to form a water-in-oil third emulsion;

preparing a third aqueous phase solution, mixing the third aqueous phase solution with the third emulsion and stirring to react the first precursor and the second precursor and form a fourth oil-in-water emulsion;

and stirring, filtering and drying the fourth emulsion to obtain the double-shell nano particles.

Optionally, the step of "preparing a third aqueous phase solution, mixing the third aqueous phase solution with the third emulsion to react the first precursor with the second precursor and form an oil-in-water fourth emulsion" comprises:

preparing a third aqueous phase solution, adjusting the solution parameters of the third aqueous phase solution, and mixing the third aqueous phase solution and the third emulsion to enable the first precursor and the second precursor to react and form a fourth oil-in-water emulsion.

Optionally, the third aqueous phase solution comprises a surface active polymer.

In the technical scheme of the invention, the inner core is inorganic nano particles, the surface of the inner core is coated with a first organic phase shell, the first organic phase shell comprises a ligand with a function of identifying tumor tissues, and the surface of the first organic phase shell is coated with a second organic phase shell. The surface of the ligand is coated with the second organic phase shell, so that the second organic phase shell effectively prevents immune macrophages from recognizing the ligand, and the probability that inorganic nanoparticles are phagocytosed and eliminated by immune cells is reduced. After dispersing the double-shell nanoparticles to blood, the double-shell nanoparticles flow along with blood circulation, when the double-shell nanoparticles move to the periphery of tumor cells, because the biological environment at the periphery of the tumor tissue is different from the biological environment at the periphery of the healthy cell tissue, the second organic phase shell of the double-shell nanoparticles can be hydrolyzed or degraded at an accelerated speed, so that the ligand modified on the surfaces of the inorganic nanoparticles is exposed, the ligand is identified by the tumor cells and is combined with specific protein on the surfaces of the tumor cells, and the inorganic nanoparticles are adsorbed on the surfaces of the tumor cells. It can be understood that when the double-shell nanoparticles are dispersed in blood, the technical scheme of the invention can improve the adsorption rate of the inorganic nanoparticles on the surface of tumor cells and improve the tumor treatment effect.

Drawings

FIG. 1 is a schematic structural diagram of an embodiment of a double-shell nanoparticle of the present invention;

FIG. 2 is a flow chart of an embodiment of a method for preparing double-shelled nanoparticles of the invention;

FIG. 3 is a schematic diagram of the preparation of inorganic nanoparticles according to the present invention;

the implementation, functional features and advantages of the objects of the present invention will be further explained with reference to the accompanying drawings.

Reference numerals	Name (R)	Name (R)	Reference numerals
				100	Double shell nanoparticles	120	Firstorganic phase shell
110	Secondorganic phase shell	130	Inner core

Detailed Description

In order to make the objects, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially.

The invention provides a double-shell nanoparticle.

Referring to fig. 1, in one embodiment of the present invention, a double-shelled nanoparticle includes:

inner core 130,inner core 130 is inorganic nano particle;

a firstorganic phase shell 120 coated on the surface of theinner core 130, the firstorganic phase shell 120 comprising a ligand having a function of recognizing tumor cells;

the secondorganic phase shell 110 covers the surface of the firstorganic phase shell 120.

In the technical scheme of the present invention, theinner core 130 is an inorganic nanoparticle, the firstorganic phase shell 120 is coated on the surface of theinner core 130, the firstorganic phase shell 120 comprises a ligand having a function of identifying tumor cells, and the secondorganic phase shell 110 is coated on the surface of the firstorganic phase shell 120. Because the surface of the ligand is coated with the secondorganic phase shell 110, the second organic phase shell effectively prevents immune macrophages from recognizing ligand particles, thereby reducing the probability that inorganic nanoparticles are phagocytosed and eliminated by immune cells. After dispersing the double-shell nanoparticles to blood, the double-shell nanoparticles flow along with blood circulation, when the double-shell nanoparticles move to the periphery of tumor cells, because the biological environment at the periphery of the tumor tissue is different from the biological environment at the periphery of the healthy cell tissue, the secondorganic phase shell 110 of the double-shell nanoparticles can be hydrolyzed or degraded at an accelerated speed, so that the ligand modified on the surfaces of the inorganic nanoparticles is exposed, the ligand is identified by the tumor cells and is combined with specific protein on the surfaces of the tumor cells, and the inorganic nanoparticles are adsorbed on the surfaces of the tumor cells. It can be understood that when the double-shell nanoparticles are dispersed in blood, the technical scheme of the invention can improve the adsorption rate of the inorganic nanoparticles on the surface of tumor cells and improve the tumor treatment effect.

The ligand composition of the embodiment of the present invention may be a polymer having a function of recognizing tumor cells, or a composition of a specific substance having a function of recognizing tumor cells and a polymer having a hydrophilic group. For example, the surface of the tumor cell is positively charged, and the ligand can be negatively charged hyaluronic acid; alternatively, the surface of the tumor cell contains the base T, and the ligand may be a combination of carboxymethyl cellulose and base A. The secondorganic phase shell 110 may be made of a fat-soluble polymer material having a hydrophilic group, or a mixture material of a functional substance that prevents immune phagocyte from recognizing and a fat-soluble polymer. In the embodiment of the invention, by arranging the secondorganic phase shell 110, the functional group for avoiding the recognition of the immune phagocyte can be connected with the fat-soluble polymer chain with the hydrophilic group, so that more ligands can be modified on the surface of the firstorganic phase shell 120, and more ligands can be ensured to recognize tumor cells and be specifically combined with the tumor cells, thereby enhancing the adsorption force of the double-shell layer nanoparticles and the tumor cells.

In one embodiment of the present invention, the ligand comprises a polymer chain having a hydrophilic group and a specific group having a function of recognizing tumor cells. The specific group in the embodiment of the invention is connected to the water-soluble polymer chain, thus ensuring that the firstorganic phase shell 120 is tightly combined with the surface of the tumor cell, and improving the adsorption rate of the inorganic nano-particles.

The specificity group is a base group, or the specificity group is a charged group. The polymer chain with the hydrophilic group in the embodiment of the invention is connected with different specific groups to realize the specific recognition of different types of tumor cells. For example, the surface of the tumor cell is positively charged, and the specificity group can be a negatively charged group; alternatively, the surface of the tumor cell contains a base T and the specificity group can be a base A group. Therefore, the embodiment of the invention realizes the specific identification of the double-shell nanoparticles on different tumor cells, and ensures the effective adsorption of the inorganic nanoparticles on the surfaces of different tumor cells.

In an embodiment of the present invention, the polymer chain having a hydrophilic group is one of a polyethylene glycol polymer chain, a carboxymethyl cellulose polymer chain, a hyaluronic acid polymer chain, a chitosan polymer chain, and a polyvinyl alcohol polymer chain. In order to be suitable for different specific groups, the embodiment of the invention can adopt different water-soluble polymer chains, and the connection of different specific groups is realized by adopting different water-soluble polymer chains, so that the tumor cells with different characteristics are identified. Of course, different firstorganic phase shells 120 with polymer chains having hydrophilic groups are adopted, and due to the difference of the polymer chains, the hydrolysis or degradation rates of the firstorganic phase shells 120 are also different, so that the adsorption rates of the inorganic nanoparticles are also different.

In one embodiment of the present invention, the double-shell nanoparticles have a particle size of 10nm to 900 nm. The particle size of the double-shell nanoparticles in the embodiment of the invention is 10nm to 900nm, so that the uniform dispersion performance of the double-shell nanoparticles is ensured, and the double-shell nanoparticles can be uniformly dispersed in blood and can flow along with blood circulation. The embodiment of the invention selects double-shell nanoparticles without particle size, thereby realizing the treatment of different types of tumor cells by the inorganic nanoparticles.

Referring to fig. 2, in an embodiment of the present invention, the thickness of the secondorganic phase shell 110 is 5nm to 500nm, and alternatively, the wall thickness of the firstorganic phase shell 120 is 5nm to 500 nm. According to the embodiment of the invention, the wall thickness of the secondorganic phase shell 110 is controlled, so that the hydrolysis or degradation rate of the secondorganic phase shell 110 is adjusted, the circulation time of the inorganic nanoparticles in blood and the rate of the inorganic nanoparticles adsorbed on tumor cell tissues are controlled, and the effective control of the adsorption rate of the inorganic nanoparticles is realized. Similarly, the present invention adjusts the hydrolysis or degradation rate of the firstorganic phase shell 120 by controlling the wall thickness of the firstorganic phase shell 120, thereby controlling the release rate of the inorganic nanoparticles, and thus, effectively adjusting the adsorption rate of the inorganic nanoparticles.

The present invention further provides a method for preparing a double-shell nanoparticle, including the double-shell nanoparticle, which refers to the above embodiments, and since the double-shell nanoparticle adopts all the technical solutions of all the embodiments, at least all the beneficial effects brought by the technical solutions of the embodiments are achieved, and thus, the details are not repeated herein. The preparation method of the double-shell nanoparticle comprises the following steps:

preparing a first aqueous phase solution, wherein the first aqueous phase solution comprises a first precursor and a carrier;

preparing a first organic phase solution and a second organic phase solution;

preparing a third aqueous phase solution, mixing the third aqueous phase solution with the third emulsion and stirring to enable the first precursor and the second precursor to react and form a fourth oil-in-water emulsion;

and filtering and drying the fourth emulsion to obtain the double-shell nano particles.

In the present embodiment, the first aqueous phase solution and the first organic phase solution are mixed to form a water-in-oil first emulsion; mixing the second aqueous phase solution and the second organic phase solution to form a water-in-oil second emulsion; mixing the first emulsion and the second emulsion to obtain a water-in-oil third emulsion; and then, adding the third emulsion into the third water phase to form a fourth emulsion of water-in-oil-in-water, and preparing the stable double-shell nanoparticles. The invention realizes the synchronous synthesis of the double-shell nanoparticles, simplifies the preparation steps and saves the preparation time. In addition, the double-shell nano particles prepared by the invention are powdery, and compared with a colloidal solution, the double-shell nano particles have long storage time and more stable structure. In addition, the first precursor and the second precursor may be prepared into the inorganic nanoparticles by a redox method, and of course, the first precursor and the second precursor may also be prepared by a non-oxidative epoxy method, including a displacement reaction, a chemical combination reaction, and the like. As shown in fig. 3, after the first emulsion and the second emulsion are mixed, the water-in-oil structure in the first emulsion and the water-in-oil structure in the second emulsion are fused together to form a mixed droplet, and at the same time, the mixed droplet is separated into droplets with specific sizes, and the separated droplets are used as a nano-reaction container for inorganic nanoparticle synthesis, so that the first precursor and the second precursor react therein to generate corresponding inorganic nanoparticles. The embodiment of the invention can realize the preparation of the double-shell nano particles with specific sizes by adjusting the dispersion condition of the mixed liquid drops and controlling the size of the nano reaction vessel. Of course, the first emulsion and the second emulsion in the embodiment of the present invention may be ultrasonically dispersed by using an ultrasonic emulsifier, so that the size of the prepared double-shell nanoparticles can be effectively adjusted by controlling the ultrasonic dispersion conditions of the ultrasonic emulsifier.

In the preparation method of the selenium nanoparticles, the first precursor is sodium selenite, the second precursor is vitamin C, and when the first emulsion containing sodium selenite and the second emulsion containing vitamin C are mixed, the sodium selenite and the vitamin C are subjected to oxidation-reduction reaction to generate the selenium nanoparticles. In the preparation method of the gold nanoparticles, a first precursor is chloroauric acid, a second precursor is sodium borohydride, and when chloroauric acid and first emulsion are mixed with second emulsion containing sodium borohydride, the chloroauric acid and the sodium borohydride generate oxidation-reduction reaction to generate the gold nanoparticles.

Specifically, the preparation method of the double-shell selenium nanoparticle comprises the following steps: mixing a macromolecular solution with hydrophilic groups with a sodium selenite solution to prepare a first aqueous phase solution; preparing a first organic phase solution and preparing a second organic phase solution; dissolving vitamin C in water to prepare a second aqueous phase solution; mixing the first aqueous phase solution and the first organic phase solution to form a water-in-oil first emulsion; mixing the second aqueous phase solution and the second organic phase solution to form a water-in-oil second emulsion; mixing the first emulsion and the second emulsion, uniformly dispersing, and converting into a water-in-oil third emulsion to enable sodium selenite and vitamin C to start oxidation-reduction reaction; preparing a third aqueous phase solution, mixing the third aqueous phase solution with the third emulsion, stirring to form a fourth oil-in-water emulsion, and in the process, continuously carrying out redox reaction on sodium selenite and vitamin C to generate nano selenium; and filtering and drying the fourth emulsion to obtain the double-shell nano particles.

The preparation method of the double-shell gold nanoparticles comprises the following steps: mixing a polymer solution with hydrophilic groups with a chloroauric acid solution to prepare a first aqueous phase solution; preparing a first organic phase solution and preparing a second organic phase solution; dissolving sodium borohydride in water to prepare a second aqueous phase solution; mixing the first aqueous phase solution and the first organic phase solution to form a water-in-oil first emulsion; mixing the second aqueous phase solution and the second organic phase solution to form a water-in-oil second emulsion; mixing the first emulsion and the second emulsion, uniformly dispersing, and converting into a water-in-oil third emulsion to enable chloroauric acid and sodium borohydride to start redox reaction; preparing a third aqueous phase solution, mixing the third aqueous phase solution with the third emulsion, stirring to form a fourth emulsion of oil-in-water, and in the process, continuously carrying out redox reaction on chloroauric acid and sodium borohydride to generate nanogold; and filtering and drying the fourth emulsion to obtain the double-shell nano particles.

It is added that the solvent of the first organic phase solution and the solvent of the second organic phase solution in the embodiment of the present invention are volatile organic solvents, and of course, the solvent of the second organic phase solution may be the same as the solvent of the first organic phase solution or different from the solvent of the first organic phase solution, so that the organic solvent is easily volatilized and removed during the drying process. Preferably, the organic solvent includes at least one of dichloromethane, chloroform, ethyl acetate, pentane, benzene, cyclohexane, tetrahydrofuran, isopropanol, ethylene glycol, ethanol, and methanol. Similarly, for convenience of drying, the solvent of the first aqueous phase solution, the second aqueous phase solution and the third aqueous phase solution may be water, or may be one of polar solvents such as isopropyl alcohol, ethylene glycol, ethanol, butanol, methanol and the like.

In one embodiment of the present invention, the step of preparing the third aqueous solution, and mixing the third aqueous solution and the third emulsion to react the first precursor and the second precursor and form the oil-in-water fourth emulsion comprises: preparing a third aqueous phase solution, adjusting the solution parameters of the third aqueous phase solution, and mixing the third aqueous phase solution and the third emulsion to enable the first precursor and the second precursor to react and form a fourth oil-in-water emulsion. According to the invention, after the solution parameters of the third aqueous phase solution are adjusted, the third aqueous phase solution and the third emulsion are mixed, so that the stability of the prepared double-shell nanoparticles is ensured while the double-shell structure is realized.

In one embodiment of the present invention, the solution parameters include temperature, pressure, and acidity or alkalinity. In the preparation process of the third aqueous phase solution, the temperature, the pressure, the acidity and alkalinity and the like of the third aqueous solution can be adjusted, so that when the third aqueous solution is mixed with the third emulsion, the mixed liquid drops, namely the nano reaction container, can be uniformly dispersed, and the reaction rate of the first precursor and the second precursor is effectively controlled, so that the first precursor and the second precursor react to generate the inorganic nanoparticles.

In an embodiment of the present invention, the third aqueous solution includes a polymer having surface activity. The polymer with surface activity in the embodiment of the invention can be polyvinyl alcohol, and certainly, other hydrophilic polymers can also be used.

Specifically, a self-made ultrasonic emulsifier is adopted in the emulsification process, the frequency of the self-made ultrasonic emulsifier is 10 HZ-10 MHZ, the emulsification time is 5 s-5 min, the volume ratio of the aqueous phase solution to the organic phase solution is 1: 50-50: 1, the concentration of fat-soluble polymers in the organic phase solution is 2 mg/ml-1000 mg/ml, the mass fraction of a first precursor in the first aqueous phase solution is 0.05-10%, the mass fraction of a second precursor in the second aqueous phase solution is 0.05-10%, the concentration of solutes in the first organic phase solution and the second organic phase solution is 1 mg/ml-1000 mg/ml, the mass fraction of polymers with surface activity in the third aqueous phase solution is 0.1-10%, the stirring time of the fourth emulsion is 0.5 h-24 h, and the drying time is 10 min-24 h. In order to prepare double-shell nanoparticles of a specific size, the embodiments of the present invention may adjust the above parameters to prepare double-shell nanoparticles having a particle size of 10nm to 900nm, and may control the wall thickness of the first organic phase shell to be 5nm to 500nm and the wall thickness of the second organic phase shell to be 5nm to 500 nm. The invention is not limited by the above, and the method for preparing the core-shell structure nano structure with a specific size by adjusting the parameters is within the protection scope of the invention.

The technical solution of the present invention is further described below with reference to specific examples. It should be understood that the specific embodiments described herein are merely illustrative of the invention and do not limit the scope of the invention.

Example 1

A preparation method of double-shell selenium nanoparticles comprises the following steps:

mixing 1 volume of citric acid-dissolved chitosan solution (0.48mg/mL) with 1 volume of sodium selenite solution (9.72mmol/L) at room temperature to prepare a first aqueous phase solution (S1); then, the prepared first aqueous phase solution (S1) was added to 10 volumes of a 20mg/ml polyethylene glycol-co-glycolic acid-lactic acid (PLGA-PEG) solution in methylene chloride, and ultrasonic emulsification was performed for 1 minute to obtain a first emulsion (R1); subsequently, 1 volume of a second aqueous phase solution having a vitamin C concentration of 2.4mmol/L was prepared (S2), and the prepared second aqueous phase solution (S2) was added to 5 volumes of a 20mg/mL polyethylene glycol-lactic acid-glycolic acid copolymer in methylene chloride solution and subjected to ultrasonic emulsification for 0.5 minute to obtain a second emulsion (R2); mixing the first emulsion (R1) and the second emulsion (R2), and performing ultrasonic emulsification for 2 minutes to obtain a third emulsion (R3); in the process, sodium selenite and vitamin C start oxidation-reduction reaction; then, adding 1 volume of the third emulsion (R3) into 2 volumes of the third aqueous phase solution (S3), and performing ultrasonic emulsification for 2 minutes to obtain a fourth emulsion (R2) so that the sodium selenite and the vitamin C are subjected to continuous oxidation-reduction reaction to generate nano-selenium; finally, the fourth emulsion (R4) was stirred for 3 hours, filtered and dried to obtain double-shell nanoparticles. Wherein, in the third aqueous phase solution (S3), the pH value of the second aqueous phase solution (S3) is adjusted to 9, the mass fraction of the polyvinyl alcohol is 1.5%, and the mass fraction of the surfactant is 0.5%.

Example 2

A preparation method of double-shell gold nanoparticles comprises the following steps:

On the basis of example 1, the concentrations of the polyethylene glycol-lactic acid-glycolic acid copolymer in the first organic phase solution and the second organic phase solution are adjusted to 20mg/mL, 30mg/mL and 40mg/mL, and the average particle diameter of the prepared double-shell selenium nanoparticles is shown in table 1:

TABLE 1

Concentration of PLGA-PEG	20mg/mL	30mg/mL	40mg/mL
				Average particle diameter (nm)	150	200	260
Standard Deviation (SD)	25	18	22

As can be seen from table 1, adjusting the solute concentrations of the first organic phase solution and the second organic phase solution can effectively adjust the size of the double-shell selenium nanoparticles. The particle size of the double-shell selenium nanoparticles increases as the concentration of the organic phase solvent increases. Thus, the preparation of double-shell selenium nano particles with specific sizes can be realized by controlling the solute concentration of the organic phase.

On the basis of example 1, the ultrasonic emulsification time of the third emulsion added into the third aqueous phase solution is adjusted to be 1 minute, 2 minutes or 3 minutes, and the average particle size of the prepared double-shell selenium nanoparticles is shown in table 2:

TABLE 2

Time of phacoemulsification	1 minute	2 minutes	3 minutes
				Average particle diameter (nm)	250	150	120
Standard Deviation (SD)	25	18	22

As can be seen from Table 2, the size of the double-shell selenium nanoparticles can be effectively adjusted by adjusting the time of adding the third emulsion into the third aqueous phase solution. Also, the particle size of the double-shell selenium nanoparticles decreases with increasing emulsification time. Thus, the double-shell selenium nano-particles with specific sizes can be prepared by controlling the ultrasonic emulsification time.

Because sodium citrate has reducibility, the reduced gold simple substance can be effectively self-assembled to form gold nanoparticles, on the basis of example 2, the concentration of sodium citrate is adjusted to be 0mmol/L, 1.6mmol/L and 3.2mmol/L, and the average particle diameter of the prepared double-shell gold nanoparticles is shown in Table 3:

TABLE 3

Concentration of sodium citrate (mmol/L)	0	1.6	3.2
				Average particle diameter (nm)	143	154	160
Standard Deviation (SD)	20	17	16

As can be seen from table 3, adjusting the concentration of sodium citrate in the first aqueous phase can effectively adjust the size of the double-shell selenium nanoparticles. And, the particle size of the double-shell selenium nanoparticles decreases with increasing sodium citrate concentration. Thus, the preparation of double-shell selenium nano particles with specific sizes can be realized by controlling the concentration of sodium citrate.

The above description is only a preferred embodiment of the present invention, and not intended to limit the scope of the present invention, and all modifications and equivalents of the present invention, which are made by the present specification and directly/indirectly applied to other related technical fields within the spirit of the present invention are included in the scope of the present invention.

Claims

1. A double-shelled nanoparticle comprising:

an inner core, wherein the inner core is an inorganic nanoparticle;

a first organic phase shell coated on the surface of the inner core, wherein the first organic phase shell comprises a ligand with the function of identifying tumor tissues;

2. The double-shell nanoparticle according to claim 1, wherein the ligand comprises a polymer chain having a hydrophilic group and a specificity group having a function of recognizing tumor cells, the specificity group being linked to the polymer chain having a hydrophilic group.

3. The double-shelled nanoparticle of claim 2, where the specificity group is a base group that can bind to a particular protein, or where the specificity group is a charged group.

4. The double-shell nanoparticle according to claim 2, wherein the polymer chain having a hydrophilic group is one of a polyethylene glycol polymer chain, a carboxymethyl cellulose polymer chain, a hyaluronic acid polymer chain, a chitosan polymer chain, and a polyvinyl alcohol polymer chain.

5. The double-shelled nanoparticle according to claim 1, wherein the composition of the second organic phase shell comprises a fat-soluble polymeric material, and/or wherein the composition of the second organic phase shell comprises a polymeric material having hydrophilic groups.

6. The double-shelled nanoparticle of claim 1, wherein the double-shelled nanoparticle has a particle size of 10nm to 900 nm.

7. The double-shelled nanoparticle according to claim 6, wherein the wall thickness of the second organic phase shell is 5nm to 500nm, and/or the wall thickness of the first organic phase shell is 5nm to 500 nm.

8. A method for preparing double-shelled nanoparticles according to any one of claims 1 to 7, comprising the following steps:

preparing a first aqueous phase solution, wherein the first aqueous phase solution comprises a first precursor and a ligand;

preparing a first organic phase solution and a second organic phase solution;

preparing a third aqueous phase solution, mixing the third aqueous phase solution and the third emulsion and stirring to enable the first precursor and the second precursor to react and form a fourth oil-in-water emulsion;

9. The method of preparing double-shelled nanoparticles of claim 8, wherein the step of "preparing a third aqueous phase solution, mixing the third aqueous phase solution with the third emulsion to react the first precursor with the second precursor and form a fourth emulsion of oil-in-water" comprises:

preparing a third aqueous phase solution, adjusting the solution parameters of the third aqueous phase solution, and mixing the third aqueous phase solution and the third emulsion to enable the first precursor and the second precursor to fully react and form a fourth oil-in-water emulsion.

10. The method of claim 8, wherein the third aqueous solution comprises a surface active polymer.