CN109078195B - Thermosensitive drug-loaded micro-organic gel with shell layer containing graphene quantum dots and core containing magnetic nanoparticles, and preparation method and application thereof - Google Patents
Thermosensitive drug-loaded micro-organic gel with shell layer containing graphene quantum dots and core containing magnetic nanoparticles, and preparation method and application thereof Download PDFInfo
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Abstract
The disclosure relates to a shell containing Graphene Quantum Dots (GQDs) and a core containing Fe3O4Nanoparticles (Fe)3O4NPs) and a preparation method and application thereof, and the heat-sensitive drug-loaded micro-organic gel which takes a compound of cationic polyelectrolyte/GQDs/multi-sulfhydryl protein or polypeptide as a shell and is loaded with Fe is obtained by experimental methods such as ultrasonic radiation, electrostatic adsorption and the like3O4The organic gel phase of the NPs and the hydrophobic drug is a core microstructure material. Preparation ofThe shell layer contains GQDs, and the core contains Fe3O4The thermosensitive drug-loaded micro-organogel of the NPs can improve the stability of hydrophobic drugs through the sulfydryl cross-linked structure of the shell and the temperature control phase change property of the gel core, and can also monitor the transmission direction of the drug-loaded micro-organogel by utilizing the fluorescence property of GQDs on the shell layer; and, by Fe in the core3O4The NPs have magnetic responsiveness and magnetic-mediated heat production function, and the drug-loaded micro-organogel can also realize targeted transportation and controlled release of drugs.
Description
Technical Field
The invention specifically relates to a shell containing Graphene Quantum Dots (GQDs) and a core containing Fe3O4Nanoparticles (Fe)3O4NPs) and a preparation method and application thereof.
Background
The statements herein merely provide background information related to the present disclosure and may not necessarily constitute prior art.
Microgel is a nano colloid dispersion system with three-dimensional network structure, which is formed by connecting gelled materials (organic molecules or colloid particles) under certain conditions. Compared with other microstructure materials, the microgel not only has a multi-layer and multi-scale structure, but also can swell and shrink to a certain degree. Thus, the microgel may be used to deliver one or more drugs, even including some biomolecules such as nucleic acids, proteins, peptides, and the like. Moreover, the microgel has certain modifiability in structure and property, can be widely applied to a plurality of fields (medicine, biology, food, chemical engineering and the like), and is a leading hot spot of current scientific research. At present, according to different requirements, researchers have successfully prepared various microgels, and have summarized and summarized some common preparation methods, such as a physical self-assembly method, a monomer polymerization method, a chemical crosslinking method, a template-assisted method and the like.
At present, many reports about microgel at home and abroad are available, and the methods for developing the microgel into a drug delivery carrier are not enumerated, but the microgel is more prone to the research of micron-sized drug-loaded hydrogel, and the micron-sized drug-loaded organogel (or drug-loaded micro-organogel) has relatively less attention. Both the micron-sized drug-loaded hydrogel and the drug-loaded organogel studied by the applicant before do not have the functions of temperature-controlled drug release and targeted positioning and the capability of marking tracer drugs, so that the microgel still needs to be functionally modified to become a more convincing drug delivery carrier. In addition, the preparation method of the micro-organogel, the drug embedding strategy and the functional modification means need to be further improved.
Disclosure of Invention
Aiming at the defects of the drug-loaded micro-organogel in the prior art in the aspects of preparation mode, embedding strategy, labeling tracing, targeting means and the like, a shell layer containing GQDs and an inner core containing Fe are provided3O4A preparation method of thermosensitive drug-carrying micro-organogel of NPs, and a drug carrier with fluorescence labeling, targeted delivery and temperature-controlled drug release functions obtained by the method.
The technical scheme adopted by the disclosure is as follows:
in an exemplary embodiment of the present disclosure, a shell layer comprising GQDs and a core comprising Fe is provided3O4A method for preparing thermosensitive drug-loaded micro-organogels of NPs, comprising:
(1) oleic acid-modified Fe3O4Nanoparticles (OA-Fe)3O4NPs) and hydrophobic drugs are dispersed into organogel with thermosensitive property to obtain an organogel phase, and then the organogel phase is mixed with aqueous phase containing multi-sulfhydryl protein or polypeptide to carry out ultrasonic radiation; after the radiation is finished, cooling and separating the reaction solution to finally obtain the hydrophobic drug and Fe3O4(ii) micro-organogels of NPs;
(2) loading the hydrophobic drug and Fe3O4The micro-organogel of NPs is sequentially placed in a solution containing cationic polyelectrolyte, a solution containing GQDs,Adsorbing the solution containing cationic polyelectrolyte layer by layer to obtain a shell containing GQDs and a core containing Fe3O4Thermosensitive drug-loaded micro-organogels of NPs.
The preparation method of the organogel with thermosensitive property comprises the following steps: dissolving the small molecular organic gelling agent into the oil phase at high temperature, and cooling to obtain the organogel with heat-sensitive property.
In still another exemplary embodiment of the present disclosure, there is provided a shell layer containing GQDs and a core containing Fe prepared by the above method3O4Thermosensitive drug-loaded micro-organogels of NPs.
In still another exemplary embodiment of the present disclosure, the shell layer is provided to contain GQDs and the core is provided to contain Fe3O4The thermosensitive drug-loaded micro-organogel of the NPs is applied to fluorescence labeling, targeted delivery or temperature-controlled drug release.
Compared with the related technology known by the inventor, one technical scheme in the disclosure has the following beneficial effects:
the method disclosed by the invention has the advantages of simple process, short reaction time, controllable operation and the like, and can be used for quickly and efficiently preparing the shell containing GQDs and the core containing Fe3O4Thermosensitive drug-loaded micro-organogels of NPs; all the drug molecules which can be stably dispersed in the organogel phase can be loaded into the thermosensitive micro-organogel by the method disclosed by the invention, and the entrapment rate is very high; the mercapto-crosslinking structure of the shell layer and the temperature-control phase change property of the gel core can improve the stability of the hydrophobic drug in the micro-organic gel; the fluorescence property of GQDs on the shell layer can monitor the transmission direction of the drug-loaded micro-organogel, and Fe in the core3O4The NPs have magnetic responsiveness and magnetic-mediated heat generation function, and can realize targeted transportation and controlled release of the medicine; further, Fe3O4The NPs are positioned in the inner core, on one hand, the NPs can be effectively prevented from falling off in the transmission process by virtue of the three-dimensional network structure of the gel core, the magnetic responsiveness of the drug-loaded micro-organogel is ensured, and on the other hand, the gel core can be induced to generate phase change in an all-round manner by self magnetic-mediated heat generation, so that the drug is rapidly released.
Drawings
The accompanying drawings, which are incorporated in and constitute a part of this disclosure, illustrate embodiments of the disclosure and, together with the description, serve to explain the disclosure and not to limit the disclosure.
FIG. 1 is an optical microscopic image of a sample prepared in example 1 in pure water;
FIG. 2 is a transmission electron micrograph of a sample prepared in example 2;
FIG. 3 is a graph of a solar light (A) and an ultraviolet light (B) in pure water for the sample prepared in example 3;
FIG. 4 is a graph showing the results of magnetic examination of the samples prepared in example 4.
Detailed Description
It should be noted that the following detailed description is exemplary and is intended to provide further explanation of the 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 is noted that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of example embodiments according to the present disclosure. As used herein, the singular forms "a", "an" and "the" are intended to include the plural forms as well, and it should be understood that when the terms "comprises" and/or "comprising" are used in this specification, they specify the presence of the stated features, steps, operations, and/or combinations thereof, unless the context clearly indicates otherwise.
As introduced in the background art, the drug-loaded micro-organogel in the prior art does not have the functions of temperature-controlled drug release and targeted positioning, the capability of labeling tracer drugs and the like, and in order to solve the technical problems, the disclosure provides a micro-organogel with a shell layer containing GQDs and an inner core containing Fe3O4A method for preparing thermosensitive drug-loaded micro-organogels of NPs, comprising:
(1) oleic acid-modified Fe3O4Nanoparticles (OA-Fe)3O4NPs) and hydrophobic drug into organogel having thermosensitive property to obtain organogelMixing the organic gel phase with the aqueous phase containing the multi-sulfhydryl protein or polypeptide, and carrying out ultrasonic radiation; after the radiation is finished, cooling and separating the reaction solution to finally obtain the hydrophobic drug and Fe3O4(ii) micro-organogels of NPs;
(2) loading the hydrophobic drug and Fe3O4Sequentially placing the micro-organogel of the NPs in a solution containing cationic polyelectrolyte, a solution containing GQDs and a solution containing cationic polyelectrolyte, adsorbing layer by layer to obtain a shell layer containing GQDs and a core containing Fe3O4Thermosensitive drug-loaded micro-organogels of NPs.
In one or some embodiments of the present disclosure, a method for preparing an organogel having thermosensitive properties is provided: dissolving the small molecular organic gelling agent into the oil phase at high temperature, and cooling to obtain the organogel with heat-sensitive property. Wherein the high-temperature reaction temperature is 50-60 ℃, and further 55 ℃.
In the process of preparing organogels with heat-sensitive properties, the small-molecule organogelator in the oil phase will undergo physical cross-linking at a temperature below the phase transition temperature to form a three-dimensional network structure, which fixes the oil phase, and therefore the content of the small-molecule organogelator often determines the stability of the three-dimensional network structure. In order to ensure that the three-dimensional network structure can be stable and firm below the phase transition temperature and can be subjected to reversible thermal change above 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 anthryl derivative, an anthraquinone derivative, a steroid derivative, a saccharide derivative, or an amide derivative having a hydrophobic gelling effect.
In one or more embodiments of the present disclosure, step (1) is to prepare a drug loaded with a hydrophobic drug and Fe3O4In the process of the micro-organogel of NPs, the content of the hydrophobic drug in the organogel having the thermosensitive property is not particularly limited, and the drug may be stably dispersed, but in order to ensure high encapsulation of the drug in the micro-organogelThe ratio and the drug loading are high, therefore, in the step (1), the content of the hydrophobic drug in the organogel with the thermosensitive property is 10 mu g/mL-1 mg/mL.
In one or more embodiments of the present disclosure, step (1) is to prepare a drug loaded with a hydrophobic drug and Fe3O4In the course of the micro-organogels of NPs, the organogels disperse OA-Fe3O4The capacity of NPs is limited, and OA-Fe3O4The addition of NPs has certain influence on the phase transition temperature of the organogel and the content of the hydrophobic drug, so that in order to ensure that the micro-organogel has good magnetic responsiveness without influencing the heat sensitivity and the encapsulation rate of the hydrophobic drug, in the step (1), the OA-Fe is used for preparing the organogel3O4The content of NPs in the organogel with thermosensitive property is 0.2mg/mL-50 mg/mL.
In the present disclosure, the hydrophobic drug is one or more of paclitaxel, docetaxel, rifampin, lomustine, indomethacin, 10-hydroxycamptothecin, and silymarin.
In one or more embodiments of the present disclosure, step (1) is to prepare a drug loaded with a hydrophobic drug and Fe3O4In the process of the micro-organogel of the NPs, the multi-sulfhydryl protein or polypeptide on the surface of the organogel liquid drop can generate sulfhydryl crosslinking under the action of ultrasonic radiation to form a stable crosslinking film. However, the concentration of the multi-thiol protein or polypeptide needs to be proper, and experiments prove that the multi-thiol protein or polypeptide with too high concentration can cause the adhesion phenomenon between the micro-organogels, and the multi-thiol protein or polypeptide with too low concentration can not completely encapsulate the organogel droplets, and is also not beneficial to the formation of the micro-organogels, so that in the step (1), the content of the multi-thiol protein or polypeptide in the water phase is 20-80 mg/mL.
In the present disclosure, the multi-thiol protein or polypeptide is one or more of hemoglobin, bovine serum albumin, human serum albumin, serum phosphocreatine kinase, ovalbumin, metallothionein, or phytochelatin.
In one or more embodiments of the present disclosureIn the formula, the step (1) is to prepare the carrier carrying the hydrophobic drug and Fe3O4In the process of the micro-organogel of NPs, the volume ratio of the organic gel phase to the water phase, the reaction temperature, the power and the time of ultrasonic radiation can influence the synthesis of the micro-organogel and the particle size thereof, so that in the step (1), the volume ratio of the water phase to the organic gel phase is 2:1-15: 1; placing in a water bath during ultrasonic radiation, wherein the temperature of the water bath is 20-60 ℃; the power of the ultrasonic radiation is 100-2The ultrasonic irradiation time is 0.5-8 min.
In one or more embodiments of the present disclosure, step (2) is carried out at GQDs pair carrying hydrophobic drug and Fe3O4In the process of modifying the shell layer of the organogel of the NPs, the electrostatic adsorption of the cationic polyelectrolyte can change the surface potential of the drug-loaded organogel, and the concentration and the adsorption time of the cationic polyelectrolyte often determine the final surface potential, so that in the step (2), the concentration of the solution containing the cationic polyelectrolyte is 0.1-2 mg/mL; the electrostatic adsorption time is 5-60 min/time.
In the present disclosure, the cationic polyelectrolyte is one or more of polyacrylamide hydrochloride, polydimethyldiallylammonium chloride, polyacryloyloxyethyltrimethylammonium chloride, polymethacryloxyethyltrimethylammonium chloride, poly-p-vinylbenzyltrimethylammonium chloride, polymethacrylamidopropyltrimethylammonium chloride, or polyallyltrimethylammonium chloride.
In one or more embodiments of the present disclosure, step (2) is carried out at GQDs pair carrying hydrophobic drug and Fe3O4In the process of shell modification of the micro-organogel of the NPs, the concentration and the electrostatic deposition time of the GQDs can influence the content of the GQDs on the micro-organogel to a great extent, and further influence the fluorescent marking capability of the product, so that in the step (2), the concentration of the solution containing the GQDs is 0.1-1 mg/mL; the deposition time is 5-60 min.
In another exemplary embodiment of the present disclosure, there is provided a shell containing Graphene Quantum Dots (GQDs) and a core containing ferroferric oxide nanoparticles prepared by any of the above methods(Fe3O4NPs) in a heat-sensitive, drug-loaded, micro-organogel.
In one or some embodiments of the present disclosure, the thermosensitive drug-loaded micro-organogel is spherical or ellipsoidal, has a particle size of 0.5-3 μm, and has a shell-core structure, wherein the shell layer is composed of a cross-linked membrane of a multi-thiol protein or polypeptide, a cationic polyelectrolyte and GQDs, and the core is loaded with a hydrophobic drug and Fe3O4Organogels of NPs.
In still another exemplary embodiment of the present disclosure, the shell layer comprises GQDs and the core comprises Fe3O4The thermosensitive drug-loaded micro-organogel of the NPs is applied to fluorescence labeling, targeted delivery or temperature-controlled drug release. For example, the drug-loaded micro-organogel can monitor the transmission direction of the drug-loaded micro-organogel by using the fluorescence property of GQDs on the shell layer, and can also use Fe in the core3O4The magnetic responsiveness of the NPs achieves the effect of targeted transmission and can also utilize Fe3O4The magnetic-mediated heat production function of the NPs achieves the purpose of controlled release of the medicine.
Because the organogel with heat-sensitive property and the Fe-containing organogel are designed in the product3O4The thermosensitive drug-loaded micro-organogel product prepared by the combined action of the NPs and the NPs has the function of triggering drug release by magnetic-thermal conversion, so that the thermosensitive drug-loaded micro-organogel product has a wide application prospect in temperature-controlled drug release.
The principle of the present disclosure: when the temperature is lower than a certain temperature, the small molecular organic gelling agent dissolved in the oil phase can be physically crosslinked to form a three-dimensional network structure, and the oil phase is fixed to obtain the organogel with the thermosensitive property; by using the acoustic cavitation of ultrasonic wave, the multi-sulfhydryl protein or polypeptide on the surface of the organogel liquid drop can be forced to generate sulfhydryl crosslinking to form a stable crosslinking membrane, and the stable crosslinking membrane is loaded with hydrophobic drugs and Fe3O4The organic gel droplets of the NPs are encapsulated into a cross-linked membrane to obtain a core containing Fe3O4Drug-loaded micro-organogels of NPs; the electrostatic adsorption of the cationic polyelectrolyte can change the surface potential of the drug-loaded micro-organogel from negative to positive, promote the deposition of negatively charged GQDs, and furtherObtaining the drug-loaded micro-organogel with a shell layer containing GQDs. Therefore, the shell layer prepared by the method disclosed by the invention contains GQDs, and the core contains Fe3O4The thermosensitive drug-loaded micro-organogel of NPs is a compound which takes cationic polyelectrolyte/GQDs/protein or polypeptide as a shell and is loaded with hydrophobic drugs and Fe3O4The organic gel phase of the NPs is the core microstructure material.
In order to make the technical solutions of the present disclosure more clearly understood by those skilled in the art, the technical solutions of the present disclosure will be described in detail below with reference to specific embodiments.
Oleic acid modified Fe prepared in the following examples by the following method3O4Nanoparticles, but should not be limited to this method of preparation alone.
(1) Preparation of a composition containing Fe3+(0.1mol/L) and Fe2+(0.05mol/L) of a mixed solution (100 mL); adding concentrated ammonia water (5mL) into the mixed solution, and placing the mixed solution in a hot water bath for stirring and crystallization; after the reaction is finished, cooling and centrifuging the reaction solution, and adding the lower layer of Fe3O4Repeatedly washing the nano particles, and re-dispersing the nano particles into deionized water to obtain Fe3O4And (4) magnetic fluid.
(2) To Fe3O4Adding hydrochloric acid dropwise into the magnetofluid (25ml) for acidification; then acidified Fe3O4Dropwise adding oleic acid (1.25mL) into the magnetofluid, and quickly stirring in a hot water bath at 90 ℃; after the reaction is finished, cooling and centrifuging the reaction liquid, and repeatedly washing the lower-layer oleic acid modified Fe by using deionized water3O4Nanoparticles (OA-Fe)3O4NPs)。
The following methods were used in the following examples to prepare Graphene Quantum Dots (GQDs), but should not be limited to this preparation method alone.
Putting graphene oxide (GO, 0.3g) prepared by a Hummer method into a mixed solution of concentrated sulfuric acid (10mL) and concentrated nitric acid (3mL), and carrying out ultrasonic crushing (2 h); putting the crushed liquid into a miniature high-pressure reaction kettle, and reacting for 24 hours at a high temperature; and after the reaction is finished, dialyzing the reactant for 2-3 days to obtain the graphene quantum dots, namely GQDs.
EXAMPLE 1 the shell layer contains GQDs,The core contains Fe3O4Preparation of thermosensitive drug-loaded (10-hydroxycamptothecin) micro-organogel of NPs (N-phosphoenolpyruvate carboxylase)
Dissolving N-lauroyl-l-alanine methyl ester (80mg/mL) into soybean oil at high temperature (55 ℃), and cooling to obtain organogel with heat-sensitive property; according to the volume ratio of 5:1 mixing an aqueous phase containing bovine serum albumin (20mg/mL) with an aqueous phase containing OA-Fe3O4NPs (1mg/mL) and 10-hydroxycamptothecin (100. mu.g/mL) were mixed together in an organogel and then placed in a water bath (20 ℃ C.); subjecting the organogel/water two-phase interface to ultrasonic irradiation (200W/cm)22min), cooling, centrifuging the reaction solution, and repeatedly washing adherent substances; placing adherent substances in polydimethyldiallyl ammonium chloride solution (0.5mg/mL, 10min) and GQDs solution (0.3mg/mL, 10min) in sequence, and adsorbing layer by layer; placing the product in poly dimethyl diallyl ammonium chloride solution (0.5mg/mL, 10min) again, adsorbing layer by layer to obtain the product with a shell layer containing GQDs and a core containing Fe3O4Thermosensitive organogels of NPs and 10-hydroxycamptothecin.
An optical microscope shows that the constructed thermosensitive drug-loaded micro-organogel is spherical or ellipsoidal, and the average particle size is about 2.5 microns (figure 1); transmission electron microscope shows that Fe is distributed in the thermosensitive drug-loaded micro-organogel3O4NPs; under an ultraviolet lamp, the drug-loaded micro-organogel emits GQDs blue fluorescence; the ultraviolet-visible absorption spectrum shows that the encapsulation rate of the heat-sensitive micro-organogel to the medicine is 82.1 percent; the magnetic test result shows that the thermosensitive drug-loaded micro-organogel has good magnetic responsiveness.
EXAMPLE 2 Shell containing GQDs and core containing Fe3O4Preparation of thermosensitive drug-loaded (rifampicin) micro-organogel of NPs
Dissolving 12-hydroxystearic acid (30mg/mL) into peanut oil at high temperature (55 ℃), and cooling to obtain organogel with heat-sensitive property; according to the volume ratio of 10: 1 mixing aqueous phase containing human serum albumin (30mg/mL) with aqueous phase containing OA-Fe3O4The organogels of NPs (2mg/mL) and rifampicin (0.5mg/mL) were mixed and then placed in a water bath (40 ℃ C.); subjecting the organogel/water two-phase interface to ultrasonic irradiation (300W/cm)2，5min)Then, cooling and centrifuging the reaction solution, and repeatedly washing adherent substances; placing the adherent substances in a solution (1mg/mL, 40min) containing poly acryloyloxyethyl trimethyl ammonium chloride and a GQDs solution (0.5mg/mL, 40min) in sequence for layer-by-layer adsorption; placing the product in polyacrylamide-containing polyoxyethylene trimethyl ammonium chloride (1mg/mL, 40min), adsorbing layer by layer to obtain the product with the shell layer containing GQDs and the core containing Fe3O4NPs and rifampicin.
An optical microscope shows that the constructed thermosensitive drug-loaded micro-organic gel is spherical or ellipsoidal, and the average particle size is about 1.5 mu m; transmission electron microscope shows that Fe is distributed in the thermosensitive drug-loaded micro-organogel3O4NPs (fig. 2); under an ultraviolet lamp, the drug-loaded micro-organogel emits GQDs blue fluorescence; the ultraviolet-visible absorption spectrum shows that the encapsulation rate of the heat-sensitive micro-organogel to the medicine is 86.7 percent; the magnetic test result shows that the thermosensitive drug-loaded micro-organogel has good magnetic responsiveness.
EXAMPLE 3 the shell contains GQDs and the core contains Fe3O4Preparation of thermosensitive drug-loaded (indometacin) micro-organogel of NPs
Dissolving N-lauroyl-l-alanine ethyl ester (250mg/mL) into castor oil at high temperature (55 ℃), and cooling to obtain organogel with heat-sensitive property; according to the volume ratio of 15:1 mixing the aqueous phase containing hemoglobin (50mg/mL) with the aqueous phase containing OA-Fe3O4NPs (3mg/mL) and indomethacin (1mg/mL) were mixed in an organogel and then placed in a water bath (60 deg.C); subjecting the organogel/water two-phase interface to ultrasonic irradiation (300W/cm)25min), cooling, centrifuging the reaction solution, and repeatedly washing adherent substances; placing the adherent substances in a solution (1mg/mL, 20min) containing poly-allyl trimethyl ammonium chloride and a GQDs solution (0.7mg/mL, 20min) in sequence for layer-by-layer adsorption; placing the product in solution containing poly allyl trimethyl ammonium chloride (1mg/mL, 20min), adsorbing layer by layer to obtain the product with shell containing GQDs and core containing Fe3O4Thermosensitive micro-organogels of NPs and indomethacin.
An optical microscope shows that the constructed thermosensitive drug-loaded micro-organogel is spherical or ellipsoidal,the average particle size was about 1.1 μm; transmission electron microscope shows that Fe is distributed in the thermosensitive drug-loaded micro-organogel3O4NPs; under an ultraviolet lamp, the drug-loaded micro-organogel emits GQDs blue fluorescence (FIG. 3, since the patent drawings are black and white, blue is not shown); the ultraviolet-visible absorption spectrum shows that the encapsulation rate of the heat-sensitive micro-organogel to the medicine is 89.4 percent; the magnetic test result shows that the thermosensitive drug-loaded micro-organogel has good magnetic responsiveness.
Example 4 the shell layer contains GQDs and the core contains Fe3O4Preparation of thermosensitive drug-loaded (indometacin) micro-organogel of NPs
Dissolving 12-hydroxystearic acid (50mg/mL) into hydroxyl silicone oil at high temperature (55 ℃), and cooling to obtain organogel with heat-sensitive property; according to the volume ratio of 15:1 mixing an aqueous phase containing bovine serum albumin (60mg/mL) with an aqueous phase containing OA-Fe3O4NPs (2mg/mL) and indomethacin (1mg/mL) were mixed in an organogel and then placed in a water bath (40 deg.C); subjecting the organogel/water two-phase interface to ultrasonic irradiation (500W/cm)28min), cooling, centrifuging the reaction solution, and repeatedly washing adherent substances; placing the adherent substance in a solution containing polyacrylamide hydrochloride (2mg/mL, 20min) and a GQDs solution (0.5mg/mL, 20min) for layer-by-layer adsorption; putting the product into solution containing polyacrylamide hydrochloride (2mg/mL, 20min) again, and adsorbing layer by layer to obtain the product with a shell layer containing GQDs and a core containing Fe3O4Thermosensitive micro-organogels of NPs and indomethacin.
An optical microscope shows that the constructed thermosensitive drug-loaded micro-organic gel is spherical or ellipsoidal, and the particle size is about 0.8 mu m; transmission electron microscope shows that Fe is distributed in the thermosensitive drug-loaded micro-organogel3O4NPs; under an ultraviolet lamp, the drug-loaded micro-organogel emits GQDs blue fluorescence; the ultraviolet-visible absorption spectrum shows that the encapsulation rate of the thermosensitive micro-organogel to the medicine is 95.1 percent; the magnetic test result shows that the thermosensitive drug-loaded micro-organogel has good magnetic responsiveness (figure 4).
The above embodiments are preferred embodiments of the present disclosure, but the embodiments of the present disclosure are not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present disclosure should be regarded as equivalent replacements within the scope of the present disclosure.
Claims (5)
1. The shell layer contains graphene quantum dots GQDs, and the core contains ferroferric oxide nano particles Fe3O4The preparation method of the thermosensitive drug-loaded micro-organogel of the NPs is characterized by comprising the following steps:
(1) oleic acid-modified Fe3O4Nanoparticle OA-Fe3O4Dispersing NPs and hydrophobic drugs into organogel with thermosensitive property to obtain an organic gel phase, then mixing the organogel phase with water phase containing multi-sulfhydryl protein or polypeptide, and carrying out ultrasonic radiation on an organogel/water two-phase interface; after the radiation is finished, cooling and separating reaction liquid to finally obtain the Fe loaded with the hydrophobic drug and the ferroferric oxide nano particles3O4(ii) micro-organogels of NPs;
(2) carrying the hydrophobic drug and ferroferric oxide nano particle Fe3O4Sequentially placing the micro-organogel of the NPs in a solution containing cationic polyelectrolyte, a solution containing graphene quantum dots GQDs and a solution containing cationic polyelectrolyte, adsorbing layer by layer to obtain a shell containing the graphene quantum dots GQDs and a core containing ferroferric oxide nano particles Fe3O4Thermosensitive drug-loaded micro-organogels of NPs;
the oleic acid-modified Fe3O4Nanoparticle OA-Fe3O4The content of NPs in the organogel with thermosensitive property is 0.2mg/mL-50 mg/mL;
the concentration of the solution containing the graphene quantum dots GQDs is 0.1-1 mg/mL; the adsorption time is 5-60 min;
the preparation method of the organogel with thermosensitive property comprises the following steps: dissolving the small molecular organic gelling agent into an oil phase at a high temperature, and cooling to obtain organogel with heat-sensitive property;
the content of the small molecular organic gelling agent in the oil phase is 10-300 mg/mL;
in the step (1), the content of the hydrophobic drug in the organogel with the thermosensitive property is 10 mu g/mL-1mg/mL；
In the step (1), the content of the multi-sulfhydryl protein or polypeptide in an aqueous phase is 20-80 mg/mL;
in the step (2), the concentration of the solution containing the cationic polyelectrolyte is 0.1-2 mg/mL; the adsorption time is 5-60 min/time.
2. The method of claim 1, wherein the shell layer contains graphene quantum dots GQDs, and the core contains ferroferric oxide nanoparticles Fe3O4The preparation method of the thermosensitive drug-loaded micro-organogel of the NPs is characterized in that in the preparation method of the organogel with the thermosensitive property, the reaction temperature is 50-60 ℃.
3. The method of claim 1, wherein the shell layer contains graphene quantum dots GQDs, and the core contains ferroferric oxide nanoparticles Fe3O4The preparation method of the thermosensitive drug-loaded micro-organogel of the NPs is characterized by comprising the following steps: in the step (1), the volume ratio of the water phase to the organic gel phase is 2:1-15: 1; placing in a water bath during ultrasonic radiation, wherein the temperature of the water bath is 20-60 ℃; the power of the ultrasonic radiation is 100-2The ultrasonic irradiation time is 0.5-8 min.
4. The shell layer containing graphene quantum dots GQDs and the core containing ferroferric oxide nano particles Fe prepared by the method of any one of claims 1 to 33O4The thermosensitive drug-loaded micro-organogel of the NPs is characterized in that: the thermosensitive drug-loaded micro-organogel is spherical or ellipsoidal, has a particle size of 0.5-3 μm, and has a shell-core structure, wherein the shell layer is composed of a multi-sulfhydryl protein or polypeptide cross-linked membrane, a cationic polyelectrolyte and graphene quantum dots GQDs, and the core is loaded with a hydrophobic drug and ferroferric oxide nanoparticles Fe3O4Organogels of NPs.
5. The method of4, the shell layer contains graphene quantum dots GQDs, and the core contains ferroferric oxide nano particles Fe3O4The thermosensitive drug-carrying micro-organogel of the NPs is applied to the preparation of fluorescent labeling, targeted delivery or temperature-controlled drug release preparations.
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| CN107096474A (en) * | 2017-05-11 | 2017-08-29 | 青岛大学 | A kind of method that the preparation and encapsulating material of organic microgel are realized in synchronization |
| CN107603591A (en) * | 2017-08-29 | 2018-01-19 | 浙江理工大学 | A kind of fluorescence microcapsules and preparation method thereof |
| CN107875390A (en) * | 2017-10-31 | 2018-04-06 | 青岛大学 | A kind of shell contains micro- organogel of load medicine of ferroso-ferric oxide and its preparation method and application |
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| CN107096474A (en) * | 2017-05-11 | 2017-08-29 | 青岛大学 | A kind of method that the preparation and encapsulating material of organic microgel are realized in synchronization |
| CN107603591A (en) * | 2017-08-29 | 2018-01-19 | 浙江理工大学 | A kind of fluorescence microcapsules and preparation method thereof |
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