KR102004333B1 - Nanospheres having cavities therein and use thereof - Google Patents

Abstract

The present invention relates to a second layer comprising mesoporous nanoparticles and magnetic nanoparticles and a second layer comprising poly (N-isopropylacrylamide-co-1-butyl-3-vinylimidazolium bromide-co- Wherein the second layer surrounds the outer surface of the first layer, and a drug carrier using the same, wherein the nanoparticles of the present invention Has the advantage of being able to enclose the drug in the cavity and to control drug release according to pH and temperature.

Description

Nanospheres having cavities in the interior and uses thereof [0002]

The present invention relates to a second layer comprising mesoporous nanoparticles and magnetic nanoparticles and a second layer comprising poly (N-isopropylacrylamide-co-1-butyl-3-vinylimidazolium bromide-co- Layer, wherein the first layer has a cavity formed therein, and the second layer surrounds the outside of the first layer, and a use thereof.

Nanotransporters capable of excellent cell targeting have recently received much attention in the field of drug delivery systems. These properties are attributed to the nature of the nanoscale, which pass through various biological boundaries, resulting in improved permeability and retention. Nano carriers of a particular size and target type (e.g., liposomes and nanoparticles) often have a tendency to accumulate in cancer tissue. However, targeting and delivering accurate doses of drugs to designed tissues without side effects is an important challenge in cancer therapy. Nano carriers, including liposomes, dendrimers, polymeric nanoparticles and inorganic nanoparticles, are potential candidates in the field of drug delivery. However, there are certain limitations in utilizing most nano-carriers. Since liposomes are expensive to produce, they have disadvantages in use in the medical field, and polymeric nanoparticles are being used as alternative nanomaterials for drug delivery. However, they are difficult to regulate and release the encapsulated drug under physiological conditions.

Recently, research on smart inorganic material-based drug delivery system is underway and attracts much attention. Mesoporous silica nanoparticles (MSN) are potential carriers for both drugs and genes due to their large surface area, large pore volume and biodegradability. However, they have drawbacks in terms of stimulus-responsiveness and targeting. Introduction of quantum dots (QD) into gate keeper to control drug release from MSN to the aqueous environment is still limited due to irreversibility of pore opening and toxicity of QD gate material. Therefore, since many cancer tissues accumulate lactic acid through hypoxic metabolism and exhibit a relatively low extracellular pH value compared to normal tissues, the optimal strategy is to use polymer-coated MSN carriers with stimulation-reactive (pH, temperature and magnetic stimulation) Lt; / RTI > In addition, it has been shown that high temperatures at temperatures above 42 ° C are toxic to cancer cells over time. Ultimately, the manufacture of nano-carriers of pH and temperature variables is a reasonable approach to effectively treat cancer. Recent developments of ECM-reactive drug delivery systems have taken into account variables such as pH and temperature. Much of this effort has been limited to the use of single stimuli and could not prevent pre-release in the blood vessels.

Therefore, there is a need to develop nanoparticles for drug delivery which are easy to control drug release and have improved problems such as toxicity.

SUMMARY OF THE INVENTION An object of the present invention is to overcome the technical limitations of the prior art as described above and to provide a drug delivery vehicle which is easy to control the release of drug encapsulated in the drug delivery vehicle and is easy to apply to the treatment of cancer cells .

It is another object of the present invention to provide nanoparticles capable of controlling drug release in response to both temperature, pH and magnetism, and a drug delivery system containing the nanoparticles.

The inventors of the present invention have developed a nanoparticle drug delivery system which is sensitive to pH and temperature and is capable of controlling the position of drug release in response to magnetism, thereby completing the present invention. The means are as follows.

1. A first layer comprising mesoporous nanoparticles and magnetic nanoparticles and a second layer comprising poly (N-isopropylacrylamide-co-1-butyl-3-vinylimidazolium bromide-co-acrylic acid) Wherein a cavity is formed in the first layer, and the second layer surrounds the outside of the first layer.

2. A drug delivery system comprising nanoparticles of 1.

The drug delivery system of the present invention can control the release of drug contained therein in response to pH and temperature conditions, and the position of the drug release can be controlled by using an external magnetic field.

1 is a TEM image of MNP, FIG. 1 (b) is a SEM image of MSN / MNP, FIG. 1 (c) is a TEM image of MSN / MNP TEM image, and (d) TEM image of pNIBIm-AA / MSN / MNP.
2 shows FT-IR spectra, thermogravimetric analysis, XRD analysis and magnetization curves of the nanoparticles prepared in Example 1 of the present invention. Specifically, (a) is the FT-IR spectrum of fMSN / MNP and pNIBIm-AA / MSN / MNP (C) is the XRD of MNP, and (d) is the magnetization curve of MNP and pNIBIm-AA / MSN / MNP.
FIG. 3 is a graph showing the movement of pNIBIm-AA / MSN / MNP in the magnetic field sealed with doxorubicin prepared in Example 2. FIG.
FIG. 4 is a graph showing the results of a rod adsorption graph (a) and a release graph (b) at 37-42 ° C and pH 5-7 according to the concentrations of pNIBIm-AA / MSN / MNP sealed with doxorubicin prepared in Example 2 at 10 ° C )to be.
AA / MSN / MNP (= MSN / MNP / P) and doxorubicin-sealed pNIBIm-AA / MSN / MNP (= MSN / MNP) in human breast adenocarcinoma cells in 2D medium. MNP / P / Dox) at various concentrations and at two temperatures (white = 37 ° C, black = 42 ° C).
Figure 6 shows the content of pNIBIm-AA / MSN / MNP and the release of doxorubicin in doxorubicin-sealed MCF7 cells at 37 < 0 > C and 42 < 0 > C. (a) shows that the red fluorescence in the nucleus and near the nucleus is due to DOX. (b) shows contrast dyeing with actin thread (Alexa Fluor 546-labeled phalloidin, green) and DAPI, showing a round shape and regular shape destruction in the experimental group compared to the control group.

The present invention relates to a first layer comprising mesoporous nanoparticles (hereinafter referred to as MSN) and magnetic nanoparticles (hereinafter referred to as MNP) and a first layer comprising poly (N-isopropylacrylamide-co-1- -Vinyl imidazolium bromide-co-acrylic acid) (hereinafter referred to as p-NIBIm-AA), wherein a cavity is formed in the interior of the first layer, and the second layer Wherein the first layer surrounds the outside of the first layer.

The cavity means an empty space, and the drug can be enclosed in the cavity.

The first layer means the inner layer of the nanoparticles. The first layer includes MSN and MNP, and the MSN is preferably coated on the outer surface of the MNP. Since the first layer has pores, the drug enclosed in the cavity can be released to the outside through the pores, and the nanoparticles of the present invention can be adjusted to an external magnetic field due to the magnetism due to the contained MNP.

The second layer means the outer layer of the nanoparticles. The second layer comprises p-NIBIm-AA. The p-NIBIm-AA is a copolymer comprising repeating units derived from three kinds of monomers such as acrylic acid (AAc), 1-butyl-3-vinylimidazolinium bromide (BVIm) and N-isopropylacrylamide It is united. The copolymer may be prepared by mixing three kinds of monomers. The ratio of the three monomers may be NIPAAm: BVIm: AAc = 70-80: 10-25: 5-10, preferably 75: 19: 6. The p-NIBIm-AA is modified in its structure in response to pH and temperature, so that the pore size of the first layer can be controlled to control the drug release in the cavity.

Therefore, the nanoparticles are suitable for use as a drug delivery system, and the present invention provides a drug delivery system comprising the nanoparticles.

The drug may be enclosed in the cavities of the nanoparticles.

The drug delivery system of the present invention can deliver various drugs, for example, the drug delivery system can deliver an immunosuppressant, an anticancer agent or an antibiotic agent, but is not limited thereto. Drugs that can be delivered by the drug delivery system of the present invention may be all drugs that do not react with p-NIBIm-AA on the surface.

The immunosuppressive agent includes all substances that can be used to prevent rejection of organ transplantation or to suppress autoimmune diseases. Examples of such immunosuppressants include prednisone, azathiopurine, RS61443, cyclosporine, FK506, rapamycin, and the like.

The above-mentioned anticancer agent refers to a medicament having anticancer activity intervening in various metabolic pathways of cancer cells, and includes all substances capable of exhibiting an anticancer effect. Examples of the anticancer agent include doxorubicin, paclitaxel, and the like.

The antibiotic refers to a substance that inhibits or kills the growth of microorganisms and includes all substances capable of exhibiting an antibiotic effect. Examples of the antibiotics include penicillin antibiotics, aminoglycoside antibiotics, tetracycline antibiotics and quinolone antibiotics. Examples of the penicillin antibiotics include ampicillin, amoxicillin, penicillin, oxacillin and temocillin. Examples of aminoglycoside antibiotics include kanamycin, gentamicin, neomycin, tobramycin, amikacin, and abecacin. Examples of the tetracycline antibiotics include demeclocycline, tetracycline, doxycycline, oxytetracycline And examples of the above-mentioned quinolone antibiotics include enosacin, gatifloxacin, levofloxacin, lomeproxasin, and ophrosacin.

Example

Hereinafter, preferred embodiments for facilitating understanding of the present invention will be described. The following examples are provided only for the purpose of easier understanding of the present invention, and the present invention is not limited thereto.

material

Iron chloride (III), iron (II) chloride, glycine and sodium hydroxide (Sigma-Aldrich, USA) were used for MNP preparation. Tetraethyl orthosilicate (TEOS), hexaethyltrimethylammonium bromide (CTAB) (Sigma-Aldrich, USA), and 3- (trimethoxysilyl) propylmethacrylate (TMSPMA) Particle synthesis and their functionalization. Reaction was carried out using N-isopropylacrylamide (NIPAAm), N-vinylimidazole (NVIm), 1-bromobutane, ammonium persulfate (APS) and acrylic acid (AAc) (Sigma-Aldrich, USA) To prepare a copolymer. NVIm and 1-bromobutane were used to synthesize 1-butyl-3-vinylimidazolium bromide (BVIm). NIPAAm was filtered before recrystallization using hexane (HPLC grade, Sigma-Aldrich, USA). Doxorubicin hydrochloride (DOX, Sigma-Aldrich, USA) was used as a model anticancer agent in this example. Dulbecco's Modified Eagle's Medium (DMEM), penicillin-streptomycin, fetal calf serum (Gibco, USA), trypsin-EDTA (Invitrogen, Basel, Switzerland), MTS assay kit [3- (4,5- (AMRESCO, Solon, OH), Alexa Fluor 546 conjugated phalloidin, DAPI (Molecular Probes, USA), and Rat tail type I collagen (First Link, 2.05 mg / ml ) Were used in the experiments on human breast adenocarcinoma cells (MCF7, American Type Culture Collection, Rockville, Md., USA).

Example 1. Preparation of p-NIBIm-AA / MSN / MNP

900 mg of iron (II) chloride and 2300 mg of iron chloride (I) were dissolved in glycine / water solution (35% v / v) and sodium hydroxide solution (41% w / v) was added dropwise, Solution (MNP sol). Silica sol dissolved in 5.6 ml of TEOS and 200 mg of CTAB in ethanol was added to homogeneous MNP-sodium hydroxide solution to effect MSN coating. After that, it was washed with ethanol-acetone and dried overnight, followed by calcination at 600 ° C for 4 hours to remove the surfactant and obtain MSN-coated MNP. The calcined MNP / MSN particles were then functionalized with TMSPMA (fMSN / MNP) for 12 hours at 50 ° C and dried by centrifugation. The dried fMSN / MNP was homogeneously dispersed (~ 2 mg / ml) in distilled water using an ultrasonic bath and transferred to a two-necked flask with a condenser. The monomer solution; was mixed with the nanoparticle solution (NIPAAm / BVIm / AAC = 75/19/6 5% by weight of the fMSN / MNP) at room temperature, the gas was removed using N _2. The APS solution (10 wt.% In water) was then added and stirred at 600 rpm and the reaction temperature was raised to 60 ° C, after which TEMED (3% of reaction volume) was added. The reaction mixture was cooled to room temperature after 16 hours, centrifuged at 15000 rpm, washed three times with deionized water, and dried at 70 ° C overnight to obtain pNIBIm-AA / MSN / MNP particles.

Example 2. Preparation of pNIBIm-AA / MSN / MNP encapsulating doxorubicin

The nanoparticles prepared in Example 1 were added to different concentrations of doxorubicin solution (0.1-1.2 mg / ml for distilled water) to give a final concentration of 1 mg / ml, and stirred at a temperature below 10 ° C for 24 hours Respectively. After incubation, centrifugation was used to obtain pNIBIm-AA / MSN / MNP nanoparticles encapsulating doxorubicin.

Experimental Example 1. Physical and Chemical Characterization

The nanoparticles prepared in Example 1 were analyzed by an electron transmission microscope (TEM; JEM-3010, JEOL). Thermogravimetric analysis was performed with TGA N-1500 instrument (Scinco, South Korea) in nitrogen gas at a rate of 10 ° C / min. In the region of 4000-400 cm ^-1 Infrared spectral analysis was performed at a resolution of 4 cm ^-1 using a Varian 640-IR FT-IR spectrometer (Varian, Australia). The zeta potential values were obtained using Zeta Sizer (ZEN 3600, Malvern, UK) at room temperature and pH 4-10. The size, volume, and surface area of the pores were measured using a Quadasorb SI automated suface area and pore size analyzer (Quantachrom Instruments, UK) via N ₂ adsorption isotherm at 77K. Prior to the experiment, the MSN was degassed at 300 ° C for 4 hours and the pNIBIM-AA / MSN / MNP was placed at room temperature overnight to obtain a final pressure of 10 -5 Torr or less.

The TEM and SEM results of various nanoparticles prepared in the procedure of Example 1 are shown in FIG. Figure 1 (a) is a TEM image of MNP, b) is an SEM image of MSN / MNP, c) is a TEM image of MSN / MNP, and d) is a TEM image of pNIBIm-AA / MSN / MNP. In FIG. 1A, glycine was used as a shielding agent to prevent self-aggregation, and it was confirmed that monodispersed MNP of about 8 nm was produced. The high resolution TEM image showed that the measured spacing of the crystallographic plane is about 0.48 nm, which fits well with the distance between the lattice planes of Fe ₃ O ₄ crystals. The internal MSN / MNP spheres of the mesopores had a uniform size, shape and mesopore structure of 150 nm and walls of 20 nm thickness (see FIGS. 1B and 1C). The MNP dispersion inside the shell wall represented a small block of nanocrystals (Fig. 1C). When pNIBIM-AA was used as a thermally reactive polymer in a ratio of 5%, a thickness increase of up to about 20 nm was observed (Fig. 1d).

FT-IR analysis results are shown in Fig. The fMSN-functionalized MNP to TMSPMA is exhibited increases in the C = O 1722cm ^-1, CH ₂ showed an elongation at 2958cm ^-1, which means that a successful functionalization jyeotdaneun achieved. various vibration peaks of 1650 cm ^-1 , 1538 cm ^-1 (C═O extension of the secondary amide) and 1380 cm ^-1 (decomposition of the methyl group of -C (CH ₃ ) ₂ ) in the case of pNIBIm-AA / MSN / . In addition, the silica skeleton of MSN in hybrid nanoparticles remained unchanged despite the polymer coating, which was confirmed by conservation of peaks at 441 cm ^-1 , 796.4 cm ^-1 and 1066.4 cm ^-1 . Also, a shoulder peak of C = O stretching of the carboxylic acid was observed at 1710.5 cm ^-1 of pNIBIm-AA / MSN / MNP indicating that successful copolymerization of NIPAAm, BVIm and AA was achieved. The molar ratio of AA / NIPAAm reflected the strength of the shoulder peak at 1720 cm-1, indicating that the AA content was successfully achieved as the intensity increased.

The result of the thermogravimetric analysis is shown in Fig. 2B. FIG. 2B shows that the content of inorganic components of nanoparticles measured by TGA was 98.5, 89.9 and 84.25% by weight in MSN / MNP, fMSN / MNP and pNIBIm-AA / MSN / MNP, respectively. Total weight-loss in fMSN / MNP and pNIBIm-AA / MSN / MNP indicates the presence of a polymer shell.

The results of the XRD analysis are shown in Fig. 2C. The six characteristic peaks of Fe3O4 are their exponents [(2 2 0), (3 1 1), (4 0 0), (4 2 2), (5 1 1) ] And showed the purity of the synthesized Fe ₃ O ₄ nanoparticles as evidenced by the database of the JCPDS file (PDF No. 65-3107).

The results of the analysis of the magnetization curve are shown in Fig. 2d. The magnetic curves show that all samples have typical superparamagnetic properties. The saturation magnetization value of Fe ₃ O ₄ was 73.71 emu / g, but decreased to 32.06 emu / g for MSN / MNP, which is due to the protective effect of the hybrid nanoparticles on silica and polymer.

BET pore volume, surface area, pore diameter and zeta potential values are summarized in Table 1 below.

characteristic MSN / MNP pNIBIm-AA / MSN / MNP Pore volume (cm ³ / g) 1.18 0.98 Surface area (m ² / g) 648 124 Pore Diameter (nm) 4.23 2.23 Zeta potential (mV) -16 -7

Experimental Example 2. Analysis of migration of pNIBIM-AA / MSN / MNP nanoparticles by magnetic field in a collagen matrix

The pNIBIM-AA / MSN / MNP nanoparticles (corresponding to 4.46% Fe ₃ O ₄ concentration) prepared in Example 1 were dispensed in a petri dish on a 5 mm thick type 1 collagen gel, The magnet was placed on the opposite side. The movement of the particles within the influence range of the magnets was observed with a digital camera (Kodak DX6490) over time. The centerline corresponding to the distance between the initial point of administration and the point of the final particle was considered to be the distance traveled by the particle and was approximately similar to the width of the magnet used (3 cm). This is shown in FIG. In this experiment, to obtain a simple experimental model, we excluded variables such as inter-particle mutual attraction, friction during fluid movement, and binding with cells. The information obtained in this experiment was used in the 3D cell survival experiment.

Experimental Example 3. Confirmation of Temperature Dependence of Isovirucin Inclusion and Release

To confirm the amount of doxorubicin encapsulated in doxorubicin-encapsulated pNIBIM-AA / MSN / MNP prepared in Example 2, the supernatant of the solution was optically measured at 520 nm using a UV-Vis spectrometer (1601PC, Shimadzu, Japan) Respectively. The inclusion rate was calculated using Langmuir isotherm.

For temperature-dependent release of doxorubicin, an appropriate amount of 1 mg / ml doxorubicin-encapsulated nanoparticle solution was prepared in PBS and incubated at 37 < 0 > C and 42 < 0 > C for up to 10 days. At each incubation temperature, supernatants were collected at predetermined time intervals and their optical density was measured at 520 nm using a UV-Vis spectrometer (1601 PC, Shimadzu, Japan).

The results of experiments of the incorporation and release of doxorubicin in nanoparticles are shown in Fig. The inclusion of doxorubicin was carried out at pH 7.4 and 10 ° C for 4 hours (Fig. 4A). Drug release experiments were performed in body fluids at 37-42 ° C and pH 5.0-7.4 (LCST = 38-42 ° C for stimuli-responsive polymers). About 50% of doxorubicin was released after 24 hours at 37 ° C and pH 7, and 36% was released during the first 10 hours. When the temperature was raised to 42 ° C at the same pH, doxorubicin was released at a faster rate. The amount released for 24 hours rose to about 78%, and nearly 95% was released for 45 hours. When the pH was reduced to 5 at 37 ° C, toxin rubicin release increased to about 96% during the first 24 hours. At the highest temperature and low pH values (42 ° C and pH 5), the release rate of doxorubicin was the fastest, with a release of about 92% within 9 hours. As a control, doxorubicin was injected into MSN / MNP and the same release experiment was carried out, and it was revealed that doxorubicin was completely released within 36 hours. This means that external pNIBIm-AA and internal MSN can regulate the diffusion of doxorubicin from void space and mesopore passages. The process of doxorubicin release from pNIBIm-AA / MSN / MNP followed a distance-limiting mechanism. The polymer shell at pH 7.4 and 37 ° C was in a closed state, which appeared at a slow release rate. In addition, the electrical attraction between the positively charged drug molecule and the negatively charged MSN interfered with the release of doxorubicin. Therefore, except for the initial release, it was confirmed that doxorubicin is stable inside the hybrid nanoparticles and will leak to the minimum even when circulating through the blood. Rapid doxorubicin release from hybrid nanoparticles is possible due to heat generated by an external magnetic field or local inflammation when the target's magnetic field is reached using an external magnetic field. The reduction of the external polymer layer due to this heat changed the surface charge of the nanoparticle passages and void spaces in the center to reduce the electrostatic attraction of doxorubicin and release a large amount of doxorubicin.

Experimental Example 4. Measurement of cell survival rate in 2D medium

Human breast carcinoma cells (MCF 7) to 37 ℃ and 5% CO ₂ fetal bovine serum in a humidified atmosphere up to 70% of the fusion (10% v / v, Gibco , USA) and phenethyl cylinder / streptomycin (1% v / v, Invitrogen, USA) (Welgene, South Korea). The cell monolayer was then trypsinized and collected in suspension and further analyzed.

After direct contact with the nanoparticles in an incubator humidified with 5% CO ₂ , the MTS assay kit [3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium Bromide] (AMRESCO, Solon, OH) was used to measure cell viability at different temperatures (37 < 0 > C and 42 < 0 > C). For thermal shock, the nanoparticles and cells were incubated at 42 ° C for 4 hours, then incubated at 37 ° C for 20 hours to have recovery. Cells were distributed in 96-well plates (~ 5 x 10 ³ cells / well) and treated with different concentrations of nanoparticle dilutions (25-500 μg / ml) for 24 h. The cell viability was determined as the optical density (OD) at 490 nm as measured using a microplate reader (iMark (TM), Miorad, Hongkong). The results are shown in Fig.

Visual inspection of cell debris on MNP treated cells was used as an indicator of toxicity induced by MNP (> 25 μg / ml) and cell viability as measured by MTS analysis supported this. The cell viability was significantly decreased after 4 hours of heat treatment at 42 ° C and after 20 hours of recovery at 37 ° C. The survival rate was maintained at about 43% at 37 ° C and 38% at 42 ° C. These results indicate that the temperature-dependent release of doxorubicin contributed to cytotoxicity.

Experimental Example 4. Measurement of cell viability and cell imaging in 3D medium in a fixed magnetic field

Such that the MCF7 cells were distributed in sterile agarose (2g, 60μl / well in 100ml DNEM) pre-coated 96-well plates (~ 5x10 ³ cells / well), the formation of aggregates of the 3D spheroid shape 5% CO ₂ Humidified atmosphere and 37 ° C. After 3 days of incubation, each 3D spheroid-like cell aggregate was transferred to a well of a 48-well plate and immediately covered with 2 mm thick Type I collagen gel. Type I collagen gel was prepared by mixing collagen (2 mg / ml) with sterilized acetic acid (0.02 N), DMEM (10 ×) and neutralizing to pH 7.4 at 37 ° C with sodium hydroxide. After polymerization (~ 30 min), 200 μl of the medium was covered and incubated overnight. The magnet was then placed near the spoleoid along the wall of the plate and 200 μg of nanoparticles containing 5 μl of MSN / MNP / P / DOX were injected into the other side of the well. It was then incubated at 37 and 42 ° C for 24 hours in a 5% CO ₂ -humidified atmosphere. Cell viability in the collagen matrix after incubation was measured by MTS analysis. Collagen gels containing MCF7 spheroids not exposed to DOX-encapsulated nanoparticles were used as controls. All collagen gel MTS values not containing cells were used for normalization.

After incubation for 24 hours, the gel containing the spoloids was washed with cold PBS, fixed with 4% (v / v) paraformaldehyde and observed using an Olympus fluorescence microscope equipped with a DP72 microscope digital camera. To observe F-actin, the structure was stained with Alexa Fluor 546 conjugated phalloidin (Molecular Probes, USA) and fluorescently imaged with an Olympus fluorescence microscope equipped with a DP72 microscope digital camera. This is shown in FIG.

The red fluorescence of the nucleus and nucleus region is due to the internalization of the nanoparticles by the cells. Doxorubicin forms a pi-pi bond with the aromatic ring of the DNA base to increase the fluorescence inside the cell. As the temperature increased, cell shrinkage and decrease in cell number were observed, which is consistent with an increase in DOX-positive cells due to rapid DOX release at 42 ° C. Furthermore, morphological analysis confirmed the amount of nanoparticles in the cells. The degree of cytoplasmic condensation and cellular contraction was significant in the cells subjected to heat shock treatment. Cells observed in small pieces were used as indicators of dead cells. Whereas control cells showed large, flat nuclei with increased actin seals. Therefore, it has been confirmed that the nanoparticles of the present invention can target cancer cells and their doxorubicin release can cause fluorescence for cell imaging.

The structure and operation principle of the nanoparticles prepared in the present invention are summarized in FIG. The nanoparticles prepared in Example 1 have an empty space in the center layer, MSN and MNP are mixed, and the polymer layer on the surface can control the release of the drug contained therein by varying the shape depending on the temperature.

Claims (10)

A first layer comprising mesoporous nanoparticles and magnetic nanoparticles;
And a second layer comprising poly (N-isopropylacrylamide-co-1-butyl-3-vinylimidazolium bromide-co-acrylic acid)
The mesoporous nanoparticles are coated on the outer surface of the magnetic nanoparticles,
A cavity is formed in the first layer,
The poly (N-isopropylacrylamide-co-1-butyl-3-vinylimidazolium bromide-co-acrylic acid) is preferably selected from the group consisting of N-isopropylacrylamide, And a repeating unit derived from the repeating unit,
Wherein the second layer surrounds the outside of the first layer. delete delete The method of claim 1, wherein the ratio between the repeating units derived from N-isopropylacrylamide, 1-butyl-3-vinylimidazolium bromide, and acrylic acid is 70-80: 10-25: particle. A drug carrier comprising nanoparticles of claim 1 or 4. 6. The drug delivery system of claim 5, wherein the drug is enclosed within the cavity of the nanoparticle. The drug delivery system according to claim 6, wherein the drug is selected from the group consisting of an immunosuppressant, an anti-cancer agent, and an antibiotic. 8. The drug delivery system according to claim 7, wherein the immunosuppressive agent is selected from the group consisting of prednisone, azathiopurine, RS61443, cyclosporine, FK506 and rapamycin. 8. The drug delivery system according to claim 7, wherein the anticancer agent is paclitaxel or doxorubicin. 8. The drug delivery system according to claim 7, wherein the antibiotic is selected from the group consisting of penicillin antibiotics, aminoglycoside antibiotics, tetracycline antibiotics and quinolone antibiotics.

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