WO2020042397A1

WO2020042397A1 - Thermal sensitive drug-loading organic microgel with shell containing graphene quantum dot and kernel containing magnetic nanoparticle, preparation method therefor and application thereof

Info

Publication number: WO2020042397A1
Application number: PCT/CN2018/117514
Authority: WO
Inventors: 李占锋; 王宗花; 杜晓玉; 龚世达; 陈积世
Original assignee: 青岛大学
Priority date: 2018-08-30
Filing date: 2018-11-26
Publication date: 2020-03-05
Also published as: CN109078195A; CN109078195B

Abstract

A thermal sensitive drug-loading organic microgel with a shell containing graphene quantum dots (GQDs) and a kernel containing Fe3O4 magnetic nanoparticle (Fe3O4 NPs), a preparation method therefor and an application thereof. By means of experiment methods such as ultrasonic radiation and electrostatic adsorption, a microstructure material is obtained by using a composite of a positive ion polyelectrolyte/GQDs/multi-thiol protein or polypeptide as a shell and using an organic gel phase loading Fe3O4 NPs and a hydrophobic drug as a kernel.

Description

Thermosensitive drug-loaded microorganic gel containing graphene quantum dots in the shell and magnetic nanoparticles in the core, and preparation method and application thereof

Technical field

The disclosure particularly relates to a heat-sensitive drug-loaded micro-organic gel containing graphene quantum dots (GQDs) in the shell layer and Fe ₃ O ₄ nanoparticles (Fe ₃ O ₄ NPs) in the core, and a preparation method and application thereof.

Background technique

The statements herein merely provide background information related to the present disclosure and do not necessarily constitute prior art.

Microgel is a nano-colloidal dispersion system with a three-dimensional network structure, which is composed of gelling materials (organic molecules or colloidal particles) connected to each other under certain conditions. Compared with other microstructured materials, microgels not only have a multi-layered, multi-scale structure, but also can swell and shrink to a certain degree. Therefore, microgels can be used to deliver one or more drugs, even including some biological molecules such as nucleic acids, proteins, peptides, and so on. In addition, microgels have certain modifiability both in structure and nature, and can be widely used in many fields (medicine, biology, food, chemical industry, etc.), which is also a frontier hot spot in current scientific research. At present, according to different needs, researchers have successfully prepared a variety of microgels, and summarized and summarized some common preparation methods, such as physical self-assembly method, monomer polymerization method, chemical cross-linking method, Template-assisted methods and more.

At present, there are many reports about microgels at home and abroad, and the methods for developing them into drug transport carriers are too numerous, but they are more inclined to the research of micron-loaded drug-containing hydrogels, and micron-loaded drug-containing organic Gels (or drug-loaded microorganic gels) have received relatively little attention. Whether it is a micron-loaded drug-loaded hydrogel or a drug-loaded organic gel previously studied by the applicant, they do not have the ability of temperature-controlled release, targeted localization, and the ability to label and trace drugs. Therefore, these microcoagulants Gum still needs to be functionally modified to become a more convincing drug delivery vehicle. In addition, the microorganic gel preparation methods, drug embedding strategies, and functional modification methods need to be further improved.

Summary of the Invention

Aiming at the shortcomings of the prior art drug-loaded microorganogels in preparation methods, embedding strategies, labeling and tracing, and targeting methods, a heat layer containing GQDs in the shell and Fe ₃ O ₄ NPs in the core was proposed. Preparation method of sensitive drug-loaded micro-organic gel, and a drug carrier with fluorescent labeling, targeted transmission, and temperature-controlled drug release obtained by the method.

The technical solutions adopted in this disclosure are as follows:

In a typical embodiment of the present disclosure, a method for preparing a heat-sensitive drug-loaded microorganic gel containing GQDs in a shell layer and Fe ₃ O ₄ NPs in a core layer is provided. The method includes:

(1) Disperse oleic acid-modified Fe ₃ O ₄ nanoparticles (OA-Fe ₃ O ₄ NPs) and a hydrophobic drug into an organogel having heat-sensitive properties to obtain an organogel phase, and then organogel The phase is mixed with water containing a polythiol protein or peptide and subjected to ultrasonic irradiation; after the irradiation is completed, the reaction solution is cooled and separated, and finally a microorganic gel carrying a hydrophobic drug and Fe ₃ O ₄ NPs is obtained;

(2) The microorganic gel carrying the hydrophobic drug and Fe ₃ O ₄ NPs is sequentially placed in a solution containing a cationic polyelectrolyte, a solution containing GQDs, and a solution containing a cationic polyelectrolyte, and the layers are adsorbed, and finally obtained Heat-sensitive drug-loaded microorganic gel containing GQDs in the shell and Fe ₃ O ₄ NPs in the inner core.

Wherein, the present disclosure provides a method for preparing the organic gel having heat-sensitive properties: dissolving a small molecule organic gelling agent in an oil phase at a high temperature, and cooling to obtain an organic gel having heat-sensitive properties.

In another exemplary embodiment of the present disclosure, a heat-sensitive drug-loaded micro-organic gel containing GQDs in a shell layer and Fe ₃ O ₄ NPs in a core layer prepared by the above method is provided.

In yet another exemplary embodiment of the present disclosure, a heat-sensitive drug-loaded microorganogel containing GQDs in the shell layer and Fe ₃ O ₄ NPs in the inner core is provided in a fluorescent label, targeted transmission, or temperature-controlled release drug. application.

Compared with the related technology known by the inventors, one technical solution in the present disclosure has the following beneficial effects:

The disclosed method has the advantages of simple process, short reaction time, controllable operation, etc., and can quickly and efficiently prepare a heat-sensitive drug-loaded microorganic gel containing GQDs in the shell layer and Fe ₃ O ₄ NPs in the inner core; The drug molecules dispersed in the organogel phase can be loaded into the heat-sensitive microorganic gel by the disclosed method, and the loading rate is high; the thiol crosslinked structure of the shell layer and the temperature-controlled phase of the gel core Variable properties can improve the stability of hydrophobic drugs in microorganogels; the fluorescent properties of GQDs on the shell can monitor the transport trends of drug-loaded microorganogels, and the magnetic responsiveness and magnetic properties of Fe ₃ O ₄ NPs in the core Mediating thermogenesis function can realize the targeted transportation and controlled release of drugs; In addition, Fe ₃ O ₄ NPs are located in the core, on the one hand, the three-dimensional network structure of the gel core can be used to effectively prevent it from falling off during transmission, ensuring that On the other hand, the magnetic responsiveness of the drug-loaded microorganic gel can also induce the phase change of the gel nucleus in an all-round way through its own magnetically mediated heat generation, and promote the rapid release of the drug.

BRIEF DESCRIPTION OF THE DRAWINGS

The accompanying drawings, which form a part of this disclosure, are used to provide a further understanding of the disclosure. The schematic embodiments of the disclosure and their descriptions are used to explain the disclosure, and do not constitute an improper limitation on the disclosure.

1 is an optical microscope image of the sample prepared in Example 1 in pure water;

2 is a transmission electron microscope image of the sample prepared in Example 2;

3 is a sunlight lamp diagram (A) and an ultraviolet lamp diagram (B) of the sample prepared in Example 3 in pure water;

FIG. 4 is a graph of the results of magnetic inspection of the sample prepared in Example 4. FIG.

detailed description

It should be noted that the following detailed descriptions are all exemplary and are intended to provide further explanation of the present disclosure. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

It should be noted that the terms used herein are only for describing specific embodiments, and are not intended to limit the exemplary embodiments according to the present disclosure. As used herein, the singular forms are intended to include the plural forms as well, unless the context clearly indicates otherwise, and it should also be understood that when the terms "including" and / or "including" are used in this specification, they indicate There are features, steps, operations, and / or combinations thereof.

As described in the background art, the drug-loaded microorganogels in the prior art do not have the capabilities of temperature-controlled release, targeted localization, and the ability to label and trace drugs. In order to solve the above technical problems, the present disclosure proposes A method for preparing a heat-sensitive drug-loaded microorganic gel containing GQDs in the shell layer and Fe ₃ O ₄ NPs in the core layer, the method includes:

(1) Disperse oleic acid-modified Fe ₃ O ₄ nanoparticles (OA-Fe ₃ O ₄ NPs) and a hydrophobic drug into an organogel having heat-sensitive properties to obtain an organogel phase, and then organogel The phase is mixed with water containing a polythiol protein or peptide and subjected to ultrasonic irradiation; after the radiation is completed, the reaction solution is cooled and separated, and finally a microorganic gel carrying a hydrophobic drug and Fe ₃ O ₄ NPs is obtained;

In one or some specific embodiments of the present disclosure, a method for preparing an organogel having heat-sensitive properties is provided: a small molecule organic gelling agent is dissolved in an oil phase at high temperature, and a heat-sensitive property is obtained after cooling. Organic gel. Among them, the high-temperature reaction temperature is 50 to 60 ° C, and further 55 ° C.

During the preparation of organogels with heat-sensitive properties, small molecule organic gelling agents in the oil phase will physically crosslink under the conditions of phase transition temperature, forming a three-dimensional network structure, which fixes the oil phase. Therefore, the content of small-molecule organic gelling agents often determines the stability of the three-dimensional network structure. In order to make the three-dimensional network structure stable and firm at a temperature lower than the phase transition temperature and a reversible thermal change at a temperature higher than the phase transition temperature, the content of the small molecule organic gelling agent in the oil phase is 10-300 mg / mL.

In the present disclosure, the small molecule organic gelling agent is an amino acid derivative, a fatty acid derivative, an anthracene derivative, an anthraquinone derivative, a steroid derivative, a sugar derivative, or an amide derivative having a hydrophobic gelation effect. .

In one or some specific embodiments of the present disclosure, in step (1), in the process of preparing a microorganic gel carrying a hydrophobic drug and Fe ₃ O ₄ NPs, the hydrophobic drug is in an organogel having heat-sensitive properties. The content in is not particularly limited, and it can be stably dispersed, but in order to ensure a high encapsulation rate and a high drug loading capacity of the drug in the microorganic gel, in step (1), the hydrophobicity The content of the drug in the organogel having heat-sensitive properties is 10 μg / mL-1 mg / mL.

In one or some specific embodiments of the present disclosure, in step (1), in the process of preparing a microorganic gel carrying a hydrophobic drug and Fe ₃ O ₄ NPs, the organic gel disperses the OA-Fe ₃ O ₄ NPs. The ability is limited, and the addition of OA-Fe ₃ O ₄ NPs will have a certain effect on the phase transition temperature of the organogel and the content of the hydrophobic drug. Therefore, in order to ensure that the microorganogel has good magnetic responsiveness, Does not affect its thermosensitivity and encapsulation efficiency for hydrophobic drugs. Therefore, in step (1), the content of the OA-Fe ₃ O ₄ NPs in the organogel with thermosensitive properties is 0.2 mg / mL -50 mg / mL.

In the present disclosure, the hydrophobic drug is one or more of paclitaxel, docetaxel, rifampicin, lomustine, indomethacin, 10-hydroxycamptothecin, and silymarin.

In one or some specific embodiments of the present disclosure, in the step (1), in the process of preparing a microorganic gel carrying a hydrophobic drug and Fe ₃ O ₄ NPs, a polythiol protein on the surface of an organic gel droplet or The peptide can undergo thiol cross-linking under the action of ultrasonic radiation to form a stable cross-linked film. However, the concentration of the polythiol protein or peptide needs to be a proper amount. It has been experimentally verified that an excessively high concentration of the polythiol protein or polypeptide can cause adhesion between microorganic gels, while an excessively low concentration of the polythiol protein or polypeptide cannot completely Encapsulating organic gel droplets is also not conducive to the formation of microorganic gels. Therefore, in step (1), the content of the polythiol protein or polypeptide in the water phase is 20-80 mg / mL.

In the present disclosure, the polythiol protein or polypeptide is one or more of hemoglobin, bovine serum albumin, human serum albumin, serum phosphocreatine kinase, ovalbumin, metallothionein, or a plant chelating peptide.

In one or some specific embodiments of the present disclosure, in the step (1), in the process of preparing a micro-organic gel carrying a hydrophobic drug and Fe ₃ O ₄ NPs, an organic gel phase / aqueous phase volume ratio, a reaction temperature The power and time of ultrasonic radiation will affect the synthesis and particle size of the microorganic gel. Therefore, in step (1), the volume ratio of the aqueous phase and the organic gel phase is 2: 1-15: 1 ; Placed in a water bath during ultrasonic irradiation, the temperature of the water bath is 20-60 ° C; the power of said ultrasonic radiation is 100-500W / cm ² , and the time of ultrasonic radiation is 0.5-8min.

In one or some specific embodiments of the present disclosure, in step (2), in the process of shell modification of a microorganic gel carrying a hydrophobic drug and Fe ₃ O ₄ NPs by GQDs, the electrostatic adsorption of the cationic polyelectrolyte may be Change the surface potential of the drug-loaded microorganic gel, and its concentration and adsorption time often determine the final surface potential. Therefore, in step (2), the concentration of the solution containing the cationic polyelectrolyte is 0.1-2 mg / mL; The electrostatic adsorption time is 5-60min / time.

In the present disclosure, the cationic polyelectrolyte is polyacrylamine hydrochloride, polydimethyldiallylammonium chloride, polyacryloxyethyltrimethylammonium chloride, polymethacryloxyethyl One of trimethylammonium chloride, poly-p-vinylbenzyltrimethylammonium chloride, polymethacrylamidopropyltrimethylammonium chloride or polyallyltrimethylammonium chloride or Multiple.

In one or some specific embodiments of the present disclosure, in step (2), in the process of GQDs shell modification of a microorganic gel loaded with a hydrophobic drug and Fe ₃ O ₄ NPs, the concentration and electrostatic deposition time of GQDs To a large extent, it can affect the content of GQDs on the microorganic gel, and then affect the fluorescent labeling ability of the product. Therefore, in step (2), the concentration of the GQDs-containing solution is 0.1-1 mg / mL; The stated deposition time is 5-60min.

In another exemplary embodiment of the present disclosure, a thermal sensitivity is provided in which the graphene-containing quantum dots (GQDs) of the shell layer and the ferric oxide nanoparticles (Fe ₃ O ₄ NPs) are prepared by using any of the above methods. Type drug-loaded micro-organic gel.

In one or some specific embodiments of the present disclosure, the heat-sensitive drug-loaded microorganic gel is spherical or ellipsoidal, has a particle diameter of 0.5-3 μm, and has a shell-core structure, wherein the shell layer is composed of a polythiol group. It consists of a protein or peptide cross-linked membrane, a cationic polyelectrolyte and GQDs. The core is an organic gel loaded with hydrophobic drugs and Fe ₃ O ₄ NPs.

In still another exemplary embodiment of the present disclosure, a heat-sensitive drug-loaded microorganogel containing GQDs in the shell layer and Fe ₃ O ₄ NPs in the inner core is provided in a fluorescent label, targeted transmission, or temperature-controlled release drug. Applications. For example, drug-loaded microorganic gels can use the fluorescence properties of GQDs on the shell to monitor the transport trends of drug-loaded microorganic gels, and can also use the magnetic responsiveness of Fe ₃ O ₄ NPs in the core to achieve targeted transmission. At the same time, it can also achieve the purpose of controlled drug release by virtue of the magnetically-mediated heat generation function of Fe ₃ O ₄ NPs.

Since the heat-sensitive organic gel and the core containing Fe ₃ O ₄ NPs are designed in this product, the heat-sensitive drug-loaded micro-organic gel products prepared by the two together have magnetic heat conversion triggering drug release. Function, so it has broad application prospects in temperature controlled release medicine.

The principle of the present disclosure: when the temperature is lower than a certain temperature, the small molecule organic gelling agent dissolved in the oil phase will be physically crosslinked to form a three-dimensional network structure, and the oil phase is fixed to obtain an organic gel having heat-sensitive properties; the use of ultrasound Acoustic cavitation can force polythiol proteins or peptides on the surface of organogel droplets to undergo sulfhydryl cross-linking to form a stable cross-linked membrane, and the organogel solution containing hydrophobic drugs and Fe ₃ O ₄ NPs The drug-loaded microorganic gel containing Fe ₃ O ₄ NPs in the core is encapsulated in drops, and the electrostatic adsorption of the cationic polyelectrolyte can change the surface potential of the drug-loaded microorganic gel from negative to positive. Negatively charged GQDs were deposited to obtain a drug-loaded microorganic gel containing GQDs in the shell. Therefore, the heat-sensitive drug-loaded microorganic gel containing GQDs in the shell layer and Fe ₃ O ₄ NPs in the inner core prepared by the method disclosed herein is a cationic polyelectrolyte / GQDs / protein or peptide complex as a shell, An organogel phase loaded with hydrophobic drugs and Fe ₃ O ₄ NPs is a microstructured material with a core.

In order to enable those skilled in the art to understand the technical solution of the present disclosure more clearly, the technical solution of the present disclosure will be described in detail below with reference to specific embodiments.

In the following examples, the oleic acid-modified Fe ₃ O ₄ nanoparticles prepared by the following method are used, but should not be limited to this preparation method.

(1) Prepare a mixed solution (100mL) containing Fe ³⁺ (0.1mol / L) and Fe ²⁺ (0.05mol / L); add concentrated ammonia water (5mL) to the mixed solution, and place it in a hot water bath to stir and crystallize After the reaction is completed, the reaction solution is cooled and centrifuged, and the Fe ₃ O ₄ nanoparticles in the lower layer are repeatedly washed and re-dispersed in deionized water to obtain Fe ₃ O ₄ magnetic fluid.

(2) Add hydrochloric acid dropwise to the Fe ₃ O ₄ magnetic fluid (25ml); then dropwise add oleic acid (1.25mL) to the acidified Fe ₃ O ₄ magnetic fluid and place in a 90 ° C hot water bath for rapid stirring; after the reaction is completed The reaction solution was cooled, centrifuged, and the lower oleic acid-modified Fe ₃ O ₄ nanoparticles (OA-Fe ₃ O ₄ NPs) were repeatedly washed with deionized water.

The following examples use graphene quantum dots (GQDs) prepared by the following methods, but they should not be limited to this method of preparation.

The graphene oxide (GO, 0.3 g) prepared by the Hummer method was placed in a mixed solution of concentrated sulfuric acid (10 mL) and concentrated nitric acid (3 mL) and pulverized by ultrasound (2h); the pulverized solution was charged into a miniature autoclave, and the temperature was high. The reaction was continued for 24 hours; after the reaction was completed, the reactants were dialyzed for 2-3 days to obtain graphene quantum dots, that is, GQDs.

Example 1 Preparation of a thermosensitive drug-loaded (10-hydroxycamptothecin) microorganic gel containing GQDs in the shell and Fe ₃ O ₄ NPs in the inner core

N-lauroyl-l-alanine methyl ester (80mg / mL) was dissolved in soybean oil at high temperature (55 ° C), and an organic gel with heat-sensitive properties was obtained after cooling; The aqueous phase of serum albumin (20 mg / mL) was mixed with an organic gel containing OA-Fe ₃ O ₄ NPs (1 mg / mL) and 10-hydroxycamptothecin (100 μg / mL), and then placed in a water bath ( 20 ℃); after the organic gel / water two-phase interface is subjected to ultrasonic irradiation (200W / cm ² , 2min), the reaction solution is cooled and centrifuged, and the adherent substances are repeatedly washed; the adherent substances are sequentially placed in the polymer In dimethyldiallylammonium chloride solution (0.5mg / mL, 10min) and GQDs solution (0.3mg / mL, 10min), the layers were adsorbed layer by layer; the product was placed in polydimethyldiallyl chloride again Ammonium chloride solution (0.5mg / mL, 10min), layer-by-layer adsorption, a thermosensitive micro-organic gel containing GQDs in the shell layer, Fe ₃ O ₄ NPs in the core layer and 10-hydroxycamptothecin can be obtained.

Optical microscopy showed that the constructed heat-sensitive drug-loaded microorganic gel was spherical or ellipsoidal, with an average particle diameter of about 2.5 μm (Figure 1); transmission electron microscopy showed that the internal distribution of the heat-sensitive drug-loaded microorganic gel Fe ₃ O ₄ NPs; under the ultraviolet lamp, the drug-loaded microorganic gel emits blue fluorescence of GQDs; UV-visible absorption spectrum shows that the heat-sensitive microorganic gel has an encapsulation rate of 82.1% for the drug; magnetic The test results show that the heat-sensitive drug-loaded microorganic gel has good magnetic response.

Example 2 Preparation of a heat-sensitive drug-loaded (rifampin) microorganic gel containing GQDs in the shell and Fe ₃ O ₄ NPs in the inner core

12-hydroxystearic acid (30mg / mL) was dissolved in peanut oil at high temperature (55 ° C), and an organic gel with heat-sensitive properties was obtained after cooling; human serum albumin (30mg / mL) was added at a volume ratio of 10: 1. ) The aqueous phase was mixed with an organogel containing OA-Fe ₃ O ₄ NPs (2mg / mL) and rifampicin (0.5mg / mL), and then placed in a water bath (40 ° C); After ultrasonic irradiation (300W / cm ² , 5min) at the water / water interface, the reaction solution was cooled and centrifuged, and the adherent substances were repeatedly washed; the adherent substances were sequentially placed in a polyacryloxyethyl trimethyl group Ammonium chloride solution (1mg / mL, 40min), GQDs solution (0.5mg / mL, 40min) layer-to-layer adsorption; the product was again placed in polyacryloxyethyltrimethylammonium chloride (1mg / mL) (40min), layer by layer adsorption, a thermosensitive microorganic gel containing GQDs in the shell, Fe ₃ O ₄ NPs in the core and rifampin can be obtained.

Optical microscopy showed that the thermosensitive drug-loaded microorganic gel was spherical or ellipsoidal, and the average particle size was about 1.5 μm. Transmission electron microscopy showed that Fe ₃ O was distributed inside the thermosensitive drug-loaded microorganic gel. ₄ NPs (Figure 2); under ultraviolet light, the drug-loaded microorganic gel emits blue fluorescence of GQDs; UV-visible absorption spectrum shows that the heat-sensitive microorganic gel has a drug encapsulation rate of 86.7%; magnetic The test results show that the heat-sensitive drug-loaded microorganic gel has good magnetic response.

Example 3 Preparation of a heat-sensitive drug-loaded (indomethacin) microorganogel containing GQDs in the shell and Fe ₃ O ₄ NPs in the inner core

N-lauroyl-l-alanine ethyl ester (250mg / mL) was dissolved in castor oil at high temperature (55 ° C), and an organic gel with heat-sensitive properties was obtained after cooling; the hemoglobin-containing content was 15: 1 by volume. (50 mg / mL) of the aqueous phase was mixed with an organic gel containing OA-Fe ₃ O ₄ NPs (3 mg / mL) and indomethacin (1 mg / mL), and then placed in a water bath (60 ° C.); After the organic gel / water two-phase interface was subjected to ultrasonic irradiation (300 W / cm ² , 5 min), the reaction solution was cooled and centrifuged, and the adherent substances were repeatedly washed; the adherent substances were sequentially placed in a polyallyltriamine-containing solution. Methyl ammonium chloride solution (1mg / mL, 20min), GQDs solution (0.7mg / mL, 20min) layer-to-layer adsorption; the product was again placed in a solution containing polyallyltrimethylammonium chloride (1mg / mL, 20min), layer-by-layer adsorption, a thermosensitive micro-organic gel containing GQDs in the shell and Fe ₃ O ₄ NPs in the core and indomethacin can be obtained.

Light microscopy showed that the heat-sensitive drug-loaded microorganic gel was spherical or ellipsoidal, with an average particle size of about 1.1 μm. Transmission electron microscopy showed that Fe ₃ O was distributed inside the heat-sensitive drug-loaded microorganic gel. ₄ NPs; under ultraviolet light, the drug-loaded microorganic gel emits blue fluorescence of GQDs (Figure 3, because the patent drawings are black and white, blue is not shown); UV-visible absorption spectrum shows that the heat-sensitive micro The encapsulation rate of the organic gel to the drug was 89.4%; the magnetic test results showed that the heat-sensitive drug-loaded microorganic gel had good magnetic response.

Example 4 Preparation of a heat-sensitive drug-loaded (indomethacin) microorganogel containing GQDs in the shell and Fe ₃ O ₄ NPs in the inner core

12-hydroxystearic acid (50mg / mL) was dissolved in hydroxy silicone oil at high temperature (55 ° C), and an organogel with heat-sensitive properties was obtained after cooling; bovine serum albumin (60mg / mL) of the aqueous phase was mixed with an organic gel containing OA-Fe ₃ O ₄ NPs (2 mg / mL) and indomethacin (1 mg / mL), and then placed in a water bath (40 ° C); After the glue / water two-phase interface is subjected to ultrasonic irradiation (500 W / cm ² , 8 min), the reaction solution is cooled and centrifuged, and the adherent substances are repeatedly washed; the adherent substances are sequentially placed in a solution containing polyacrylamine hydrochloride. (2mg / mL, 20min), GQDs solution (0.5mg / mL, 20min) layer-to-layer adsorption; the product was again placed in a solution containing polyacrylamine hydrochloride (2mg / mL, 20min), layer-by-layer adsorption, then A thermosensitive microorganic gel containing GQDs in the shell layer and Fe ₃ O ₄ NPs in the core layer and indomethacin can be obtained.

Optical microscopy showed that the heat-sensitive drug-loaded microorganic gel was spherical or ellipsoidal, and the particle size was about 0.8 μm. Transmission electron microscopy showed that Fe ₃ O _{4 was} distributed inside the heat-sensitive drug-loaded microorganic gel. NPs; under ultraviolet light, the drug-loaded microorganic gel emits blue fluorescence of GQDs; UV-visible absorption spectrum shows that the heat-sensitive microorganic gel encapsulates the drug at 95.1%; magnetic test results show that the heat The sensitive drug-loaded microorganic gel has good magnetic response (Figure 4).

The above embodiment is a preferred implementation of the present disclosure, but the implementation of the present disclosure is not limited by the above embodiments. Any other changes, modifications, substitutions, combinations, and modifications made without departing from the spirit and principle of the present disclosure, Simplifications should be equivalent replacements, and all are included in the protection scope of this disclosure.

Claims

A method for preparing a heat-sensitive drug-loaded microorganic gel containing graphene quantum dots (GQDs) in the shell layer and ferric oxide nanoparticles (Fe 3 O 4 NPs) in the core, which is characterized in that the method includes:

(1) Disperse oleic acid-modified Fe 3 O 4 nanoparticles (OA-Fe 3 O 4 NPs) and a hydrophobic drug into an organogel having heat-sensitive properties to obtain an organogel phase, and then organogel The phase is mixed with water containing a polythiol protein or peptide and subjected to ultrasonic irradiation; after the radiation is completed, the reaction solution is cooled and separated, and finally a microorganic gel carrying a hydrophobic drug and Fe 3 O 4 NPs is obtained;

(2) The microorganic gel carrying the hydrophobic drug and Fe 3 O 4 NPs is sequentially placed in a solution containing a cationic polyelectrolyte, a solution containing GQDs, and a solution containing a cationic polyelectrolyte, and the layers are adsorbed, and finally obtained Heat-sensitive drug-loaded microorganic gel containing GQDs in the shell and Fe 3 O 4 NPs in the inner core.
The preparation method according to claim 1, characterized in that in step (1), the preparation method of the organogel with heat-sensitive properties is: dissolving the small molecule organic gelling agent in the oil phase at high temperature, and obtaining after cooling Organic gel with heat-sensitive properties;

Further, the reaction temperature is 50-60 ° C;

Further, the content of the small molecule organic gelling agent in the oil phase is 10-300 mg / mL.
The preparation method according to claim 1, wherein in step (1), the content of the hydrophobic drug in the organogel having heat-sensitive properties is 10 μg / mL-1 mg / mL.
The production method as claimed in claim 1, wherein: step (1) in the OA-Fe content in the organic gel has a thermal property in 4 NPs 3 O is 0.2mg / mL-50mg / mL.
The method according to claim 1, wherein in step (1), the content of the polythiol protein or polypeptide in the water phase is 20-80 mg / mL.
The preparation method according to claim 1, characterized in that: in step (1), the volume ratio of the aqueous phase and the organogel phase is 2: 1-15: 1; and placed in a water bath during ultrasonic irradiation, The temperature of the water bath is 20-60 ° C; the power of the ultrasonic radiation is 100-500W / cm 2 , and the time of the ultrasonic radiation is 0.5-8min.
The preparation method according to claim 1, characterized in that: in step (2), the concentration of the cationic polyelectrolyte-containing solution is 0.1-2 mg / mL; and the electrostatic adsorption time is 5-60 min / times .
The method according to claim 1, wherein in step (2), the concentration of the GQDs-containing solution is 0.1-1 mg / mL; and the deposition time is 5-60 min.
The heat-sensitive drug-loaded microorganic gel containing GQDs in the shell layer and Fe 3 O 4 NPs in the inner core prepared by the method according to any one of claims 1 to 8, wherein: The drug microorganic gel is spherical or ellipsoidal, with a particle size of 0.5-3 μm, and has a shell-core structure. The shell layer is composed of a polythiol protein or peptide cross-linked membrane, a cationic polyelectrolyte, and GQDs. Organogels of hydrophobic drugs and Fe 3 O 4 NPs.
The heat-sensitive drug-loaded microorganic gel containing GQDs in the shell layer and Fe 3 O 4 NPs in the inner core according to claim 9 for fluorescent labeling, targeted transmission, or temperature-controlled drug release.