KR20130081428A - Synthesis method of magnetic nanoparticles for targetable drug delivery system and drug delivery vector using the same - Google Patents

Abstract

PURPOSE: A magnetic nanoparticle is provided to enable adsorption or desorption of a desired material through the interaction with a specific material, and to deliver and release a specific material to a specific site. CONSTITUTION: A method for preparing a magnetic nanoparticle comprises the steps of: mixing a phospholipid solution and a solution containing Fe^3+ to prepare a Fe^3+-impregnated liposome dispersion; reacting the liposome dispersion with a silica precursor, and preparing a silica-coated Fe^3+-impregnated liposome particle; and reducing the silica-coated Fe^3+-impregnated liposome particle under a hydrogen atmosphere. The phospholipid is lecithin. A method for manufacturing a targeted drug delivery system comprises the steps of: modifying the surface of the magnetic nanoaprticles and applying double bond; and binding a temperature-sensitive polymer onto the surface of the magnetic nanoparticles.

Description

Synthesis method of magnetic nanoparticles for targetable drug delivery system and drug delivery vector using the same}

The present invention relates to a magnetic nanoparticles for target-oriented drug delivery and a method for producing a drug carrier using the same, in detail, a spherical magnetic nanoparticles by coating and reducing the surface of the Fe ^{3 +} impregnated liposome formed in aqueous solution with silica The present invention relates to a method for preparing a target-oriented drug delivery system by combining the prepared magnetic nanoparticle surface with a temperature-responsive polymer.

Drug Delivery System (DDS) is a drug delivery system designed to effectively reduce the side effects of drugs, improve patient compliance with drugs, and maximize the efficacy and effectiveness of drugs by efficiently delivering drugs to the treatment area. Generic term for techniques to optimize treatment.

Drug delivery systems can be categorized as sustained drug release systems, controlled release systems, and target-oriented drug delivery systems, which provide a rate of drug release when the bioavailability is low, or when the drug is absorbed too slowly or is lost too quickly. The formulation is designed to compensate for the problem by slowing down, and the controlled release system is a formulation designed to control the actual therapeutic effect by controlling the concentration of the target site.

Target-oriented drug delivery systems have been developed to deliver drugs to desired sites to minimize side effects on other parts of the body and maximize their effectiveness, and are particularly used to reduce the side effects of highly toxic anticancer drugs. Target-oriented drug delivery systems are divided into two types: active and passive systems. Passive uses the looseness of vascular tissue around cancer cells and active uses ligands such as antibodies or aptamers that recognize specific proteins expressed by cancer cells. .

Means to be attempted for drug delivery systems include the manufacture of patches that deliver drugs through the skin, the production of microcapsules from lipids to work only on specific parts of the body, the injection of non-aqueous drugs into solids, and the solids. Solid dispersions, gels, nanoparticles, liposomes, microemulsions, pellets, matrix tablets, osmotic pressures, etc. .

Liposomes, on the other hand, have been the subjects of great interest in biofilm simulation and drug delivery since Bangham et al. Discovered their structure through electron microscopy in the early 1960s. The structure of the liposome is composed of a closed bilayer membrane and a water-soluble space inside the membrane spontaneously formed when the polar lipids are dispersed in water, as shown in FIG. Bilayer membranes of liposomes can interact with and permeate or capture molecular materials. Hydrophobic molecules are distributed between the bilayer membranes of liposomes and are anchored as if anchored by chains extending to the polar portion, while hydrophilic molecules are trapped in the aqueous space of liposomes and move relatively freely therein.

This trapping ability allows the material to be trapped in the liposomes for days to weeks, and small ions can diffuse between the bilayer membranes or pass through the bilayer membranes with the help or pores of carriers. In particular, liposomes can easily capture various drugs, hormones and enzymes, and the captured drugs can be used as a sustained-release agent that continuously releases the drug when injected into the body by oral cavity, muscle, or blood vessel injection, or target sites. It has a different pharmacological property than when it is not captured, such as to reach the drug to reduce the toxic expression and increase the efficacy. Therefore, liposomes have been studied for their application in the fields of drug carriers and targeting in addition to simulation studies of biological membranes.

On the other hand, the 'temperature-sensitive polymer' refers to a polymer in which the phase of the polymer is transferred in accordance with temperature change, and changes from a sol to a gel or a gel to a sol. At this time, when the temperature is changed to a gel at a temperature below a predetermined temperature and is exceeded, the temperature at this time is referred to as a low critical solution temperature (LCST). As shown in Fig. 2, the polymer hydrogel having LCST condenses to become a gel when the temperature increases above LCST, and this class is called a temperature hydrogel.

These temperature-sensitive polymers have been extensively studied over the last decade, and many polymers exhibit low critical solution temperature (LCST) in aqueous solution, with a balance of hydrophilic and hydrophobic groups. Temperature sensitive polymers are very important in drug delivery systems because they have a sensitive response to temperature changes. Examples of the functional groups among the polymers exhibiting a sensitive reaction by temperature are shown in Table 1 below.

Functional Group Polymer Ester Group Poly (ethylene oxide) (PEO)
Poly (EO-propylene oxide) random copolymer
PEO-PPO-PEO triblock surfactants
Alkyl-PEO block surfactant
Poly (vinyl methyl ether) Alcohol group Hydroxypropyl acrylate
Hydroxypropyl methylcellulose
Hydroxypropyl cellulose
Hydroxyethyl cellulose
Methylcellulose
Poly (vinyl alcohol) derivatives Amide Group Poly (N-substituted acrylamide)
Poly (N-acryloyl pyrrolidine)
Poly (N-acryloly piperidine)
Poly (acryl-L-amino acid amides)
Poly (ethyl oxazoline)

PNIPAm, a typical temperature-sensitive polymer, exhibits a low-critical solution temperature due to hydrophobic interactions in the vicinity of body temperature of about 30 to 35 ° C, and precipitates the polymer, and at a temperature below that, it turns into a transparent aqueous solution. In general, PNIPAm can be used as drug delivery, and PNIPAm hydrogels use the phenomenon of condensing the gel by raising the temperature above the low critical solution temperature after supporting the drug in the swollen state under the low critical solution temperature. Can release the drug.

In temperature-sensitive polymers, LCST changes according to the balance of hydrophobic groups and hydrophilic groups bonded to the polymer backbone. Generally, when the content of the hydrophilic group increases, the phase transition temperature increases, and when the hydrophobic group increases, the phase transition temperature decreases. Application of such temperature-sensitive polymers is being actively conducted in various fields such as medical materials, environmental fields, and cosmetics.

In the present invention, by using a liposome and a temperature sensitive polymer useful as a drug carrier, various functional groups are bonded to a surface to allow adsorption or desorption of a desired substance through interaction with a specific substance, as well as to move a desired substance to a desired target site by Target oriented drug carriers have been developed that can facilitate loading and release of drugs in response to changes.

An object of the present invention is to target a variety of functional groups on the surface by the adsorption or desorption of the desired material through interaction with a specific material, the magnetic is a target-oriented that can be transported to a specific place to transport the specific material combined Magnetic nanoparticles for drug delivery and to provide a method for producing a drug delivery using the same.

In addition, an object of the present invention is a magnetic nanoparticles and a drug using the same for the target-oriented drug delivery to facilitate the loading and release of the drug according to the temperature change by coupling the polymer in which the phase of the polymer with the temperature change to the magnetic nanoparticles It is to provide a method for producing a carrier.

According to an aspect of the present invention as described above, the present invention is to prepare a i) phospholipids (phospholipid) solution with an Fe ³⁺ is mixed with Fe ³⁺ is impregnated with an aqueous solution containing a liposomal dispersion; Ⅱ) to prepare the Fe ^{3 +} of the liposome dispersion and by reacting the impregnated silica precursors are silica coated Fe ^{3 +} impregnated liposome particle; And iii) reducing the silica-coated Fe ^{3 +} impregnated liposome particles in a hydrogen atmosphere; provides a method for producing magnetic nanoparticles comprising.

In this case, as an example, lecithin may be used as the phospholipid, and the reaction of the liposome dispersion and the silica precursor is preferably performed under acidic conditions of pH 2 to 4 to reduce destruction of the liposomes. the coated Fe ^{3 +} impregnated liposome particles, it is preferred that the reduction in the 600 ~ 1000 ℃ to indicate a sufficient magnetic properties.

In addition, the present invention provides a magnetic nanoparticle that can be transported to a specific material and released to a specific place through the manufacturing method. At this time, the size of the magnetic nanoparticles is 300 ~ 500nm, the saturation magnetization (Ms) value of the magnetic nanoparticles is preferably 20 ~ 30emu / g.

On the other hand, the present invention i) modifying the surface of the prepared magnetic nanoparticles to give a double bond; And ii) bonding a temperature-sensitive polymer to the surface of the magnetic nanoparticles to which the double bonds are imparted.

Modification of imparting a double bond to the surface of the magnetic nanoparticles may be performed using 3-MOP (3- (trimethoxysilyl) propyl methacrylate) which is a silane coupling reagent. In addition, the temperature-sensitive polymer is a substance capable of releasing the drug in the body by transferring the phase of the polymer between the sol-gel with the temperature change, in one embodiment PNIPAm (poly ( N- isopropylacrylamide)) may be used, The PNIPAm may be bound to the surface of the magnetic nanoparticles using an NIPAm ( N -isopropylacrylamide) monomer, NMBA ( N, N'- Methylenebisacrylamide) crosslinker, and KPS (Potassium persulfate) initiator. At this time, the NMBA / NIPAm concentration is preferably 3 to 11% so that the temperature sensitive polymer is sufficiently polymerized.

The magnetic nanoparticles of the present invention are stacked on the surface of the silica to combine the various functional groups of interest to the adsorption or desorption of the desired material through interaction with a specific material, is magnetic, and carries a specific material that is bound to a specific place Can be released. In addition, the present invention can implement a target-oriented drug carrier to facilitate the loading and release of the drug according to the temperature change by coupling the polymer in which the phase of the polymer with the temperature change to the magnetic nanoparticles.

Figure 1-Schematic diagram showing the formation of the double membrane structure of liposomes
Figure 2-Schematic showing the phase transfer mechanism of the temperature sensitive polymer
3-Schematic diagram showing the synthesis of MNPs
4-Schematic diagram showing the synthesis of PNPPAm-bound MNPs
5, 6-Scheme and schematic showing the manufacturing process of MNPs bound to PNIPAm
Figure 7-(a) Fe ^{3 +} is Impregnated with a liposome, (b) a silica-coated Fe ^{3 +} FT-IR spectra of the impregnating liposomes
Figure 8 - (a) Fe ^{3 +} is impregnated with a liposome, (b) Fe ^{3 +} is impregnated with a liposome, (c) a silica-coated Fe ^{3 +} impregnated liposomes and (d) a silica-coated Fe ^{3 +} the impregnated liposomes TEM image
9, 10-silica-coated Fe ^{3 +} FT-IR and TGA spectra of the different reduction temperatures of the impregnation liposomes
11-silica-coated Fe ^{3 +} impregnated image after reduction of the liposomes
Figure 12 - (a) SEM images of the silica-coated Fe ^{3 +} impregnated with liposomes, (b) a silica-coated Fe ^{3 +} impregnated liposomes and (c) TEM image of MNPs
EDAX analysis data of (a) impregnating a Fe ^{3 +} liposomes and (b) coating silica MNPs - 13
Figure 14 - (a) silica-coated Fe ^{3 +} impregnated liposomes and (b) XRD pattern of MNPs
Figure 15-TEM image of (a) MNPs, (b) 3-MOP modified MNPs and (c) MNPs bound to PNIPAm
Figure 16-SQUID results of (a) MNPs and (b) MNPs with PNIPAm bound
17, 18-FT-IR and TGA spectra of PNPPAm-coupled MNPs according to weight ratio change of NIPAm / 3-MOP-MNPs
19, 20-FT-IR and TGA spectra of PNPPAm-coupled MNPs with NMBA concentration changes

With reference to the accompanying drawings, the magnetic nanoparticles for the target-oriented drug delivery and the drug delivery method using the same according to an aspect of the present invention will be described in detail as follows.

The magnetic nanoparticles of the present invention to prepare a i) the phospholipid solution and the Fe ³⁺ is mixed with Fe ^{+ 3} is impregnated with an aqueous solution containing the liposome dispersion liquid as shown in Figure 3, ⅱ) the Fe ^{3 +} impregnation by reacting a liposome dispersion and the silica precursor is prepared through the steps, and ⅲ) step of the silica is reduced in a hydrogen atmosphere, the coated Fe ^{3 +} impregnated liposome particles for producing the Fe ³⁺ impregnating the silica-coated liposomes.

In this case, lecithin may be used as an example of the phospholipid, and the present invention provides a silica precursor such as TEOS (tetraethyl orthosilicate) to Fe ³⁺ impregnated liposomes to prepare magnetic nanoparticles using liposomes as a framework. The silica coating is characterized in that the hydrolysis and the condensation reaction (condensation) using.

Wherein the Fe ³⁺ is impregnated liposomes may be prepared to replace the Na ^+, which can reduce the electrostatic repulsion between the phosphate anion in the phospholipid molecules which constitute the liposomes as Fe ^{+ 3,} often in the process of coating the silica Since the reaction under basic conditions using ammonia water used tended to destroy the produced liposomes themselves, it is preferable to disperse the liposome solution in an ethanol solution or the like and react in an acid solution having a pH of 2-4.

By providing organic functionality to the coated silica material, control of surface polarity (hydrophilicity, hydrophobicity, binding to guest molecules), change of surface reactivity, protection of surface from external attack, change of bulk properties (mechanical and scientific properties) of the material, etc. Can bring The silica, like amorphous silica, has many silanol (Si-OH) groups on its surface, which serves as a point for fixing organic functionality.

The silica-coated Fe ^{3+ -impregnated} liposomes can be finally reduced to a magnetic atmosphere, thereby obtaining magnetic nanoparticles. The silica-coated Fe ³⁺ impregnated liposomes are preferably reduced at 600 to 1000 ° C. in order to exhibit sufficient magnetic properties, and below 600 ° C., it is difficult to show magnetism, and at 1000 ° C., the structure of the nanoparticles themselves may collapse. Can be. The prepared nanoparticles may have a particle size of 300 to 500 nm and a saturation magnetization (Ms) value of 20 to 30 emu / g so as to be suitable for delivering the contained drug to a desired place.

The magnetic nanoparticles prepared as described above are stacked with silica to bind a desired functional group to interact with a specific material, thereby adsorbing or desorbing the desired material, and having a magnetic property to transport the bound material to be released to a specific place. .

On the other hand, the target-oriented drug carrier of the present invention as shown in Figure 4 i) modifying the surface of the magnetic nanoparticles prepared as described above to impart a double bond, and ii) the magnetic nanoparticles are given the double bond It can be prepared through the step of bonding the temperature-sensitive polymer to the surface of the particles.

Modification of imparting a double bond to the surface of the magnetic nanoparticles may use 3-MOP (3- (trimethoxysilyl) propyl methacrylate) which is a silane coupling reagent, and the temperature-sensitive polymer may have a different sol-gel of the polymer according to temperature change. Various substances may be used which are transferred to each other and release the drug in the body. In one embodiment, PNIPAm (poly ( N- isopropylacrylamide)) may be used.

The PNIPAm may be bonded to the surface of the magnetic nanoparticles using NIPAm ( N -isopropylacrylamide) monomer, NMBA ( N, N'- Methylenebisacrylamide) crosslinker, KPS (Potassium persulfate) initiator, and the temperature sensitive polymer is sufficiently polymerized. The NMBA / NIPAm concentration is preferably 3-11%. 5 and 6 show a double bond to the particle surface using 3-MOP (silane coupling agent) to the magnetic nanoparticles, NIPAm (monomer), NMBA (cross linker), KPS (initiator) using PNIPAm The synthesis principle of the bonded magnetic nanoparticles is shown.

Hereinafter, examples and experimental examples of the magnetic nanoparticles and the drug carrier using the same for target-oriented drug delivery prepared according to the present invention will be described in detail. However, the following examples are merely to aid the understanding of the present invention, and the scope of the present invention is not limited to the following examples.

On the other hand, the experiments of the following examples were made by the following methods.

Fourier transform-infrared (FT-IR) spectroscopy: FT-IR was analyzed by the FT-IR-460 PLUS spectrometer (JASCO, Tokyo, Japan) using the KBr method in the wavenumber range of 4000cm ^-1 and 650cm ^-1.

2) Transmission electron microscopy (TEM): The particle morphology was measured using JEM-2000EX (JEOL, Tokyo, Japan). The specimen was dispersed in ethanol in a powder state, dropped into microgrid (Cu) and dried.

3) Field-emission scanning electron microscopy / Energy-dispersive X-ray spectroscopy (FE-SEM / EDX): EDX connected to FE-SEM (JSM-6700F, JEOL, Tokyo, Japan) was analyzed by elemental 15KV AC voltage. The samples were coated with Pt in Cressington scientific instruments 108 Auto sputter coater (Cranbery Tep., PA, USA).

4) X-ray diffraction (XRD): Using a Rigaku D / MAX-RB apparatus (Tokyo, Japan) powder diffractometer, CuKa (λ = 1.1542Å) radiation measured at 2 ^o / min in the range of 10 ^o to 80 ^o Was

5) Thermogravimetric analysis (TGA): SDT Q-600 (TA Instruments, Delaware, USA) was used to measure the thermal properties of N2 at 10 / min.

6) Scanning electron microscopy (SEM): The shape of silica-coated Fe ³⁺ impregnated liposomes was observed using SM-300 (Topcon).

7) Superconducting quantum interference device (SQUID): The magnetic properties were measured in the field range: -1 T to +1 T, 300 K using MPMS-7 (Quantum design, USA).

[ Example  1] Fe ³⁺ Preparation of this impregnated liposome

5 g of lecithin was dissolved in 50 g of methanol, and 45 g of 0.1 M FeCl ₃ aqueous solution was added to the lecithin solution, followed by stirring.

[ Example  2] Fe ³⁺ Silica coating of this impregnated liposome

Put in 100mL of ethanol produced a liposome dispersion of Fe ^{3 +} impregnation 20g (pH 2) to give a well stirred with a magnetic stirrer. While stirring the mixed solution vigorously at room temperature, add 4 mL of tetraethyl orthosilicate (TEOS) dropwise. Since the reaction under basic conditions using ammonia water, which is commonly used for coating silica, tended to destroy the generated liposomes themselves, the liposome solution was dispersed in ethanol to adopt a reaction process in an acidic solution (pH 3).

The reaction solution was stirred at room temperature for 6 hours, and the pH of the solution was about 3 after the reaction was over. After stirring was complete, centrifuge at 3000rpm for 10 minutes, discard the filtrate, wash the precipitate three times with ethanol to remove unreacted TEOS, and then wash the dried product at room temperature to give silica-coated Fe ^{3 +} Impregnated liposomes were obtained.

[ Example  3] silica coated Fe ^{3 +} Impregnation Liposomal  Hydrogenation reaction

Hydrogen gas for Fe ^{3 +} impregnating the silica-coated liposome at 600 ℃ flow for 1 hour is reduced to Fe ^3+. After cooling to room temperature. The nanoparticles change from light brown to black with the reduction of Fe ^{3 +} .

[ Example  4] 3- MOP Modification of Magnetic Nanoparticles Using

In order to modify the surface of the prepared magnetic nanoparticles with 3-MOP, after dispersing the magnetic nanoparticles in toluene, 2,6-Lutidine and 3-MOP (Silane coupling agent) are added. After refluxing at 110 ° C. for 6 hours, washing with methanol removes unreacted 3-MOP. And vacuum dried at room temperature.

[ Example  5] PNIPAm this Combined  Manufacture of magnetic nanoparticles

After dispersing the magnetic nanoparticles whose surface is modified with 3-MOP in a small amount of ethanol, an aqueous solution containing NIPAm (monomer) and NMBA (cross linker) is added and stirred. Then add KPS (initiator) and N ₂ Allow 30 minutes for bubbling. After stirring for 12 hours at room temperature, the temperature is raised to 70 ° C and polymerized.

After the polymerization is complete, washing with methanol removes unreacted NIPAm. After washing, vacuum drying at room temperature is performed for 24 hours to prepare magnetic nanoparticles having PNIPAm bound thereto. The experimental conditions are shown in Table 2 below. The molecular ratio (%) of KPS / NIPAm is 1.05.

Condition NIPAm / 3MOP-MNPs
(Weight Ratio) NMBA / NIPAm
(Molar Ratio) (%) One 4 5.5 2 2 5.5 3 8 5.5 4 4 2.75 5 4 11.0

[ Experimental Example  One] Fe ^{3 +} this Impregnated Liposomes and  Silica coated Fe ^{3 +} Impregnation Liposomal FT - IR  And TEM  result

Figure 7 is a FT-IR (Fourier transform-infrared spectroscopy) spectrum of the resulting Fe ³⁺ Fe ³⁺ is impregnated with a liposome and the liposome-impregnated silica coating. (a) Fe ³⁺ is 2921cm ^-1 of the impregnated liposomes, 1467cm ^-1, the C = O bond in the CH, 1744cm ^-1 was confirmed at 1416cm ^-1. In addition, the CO, 1014cm ^-1 PO bond in NH, 1236cm ^-1 was confirmed at 1647cm ^-1. Since the Fe—O bond peak is shown at 580 cm ⁻¹ , it is not shown in FIG. 7. (b) Silica coated Fe ³⁺ impregnated liposomes could be confirmed that silica was coated by confirming the strong peak showing the Si-O-Si bond at 1061cm ^-1 .

Figure 8 is a photograph by observation using a Fe ³⁺ Fe ³⁺ is impregnated with a liposome and the liposome-impregnated silica coated (Transmission electron microscopy) TEM. In liposomes impregnated with Fe ³⁺ (a) and (b), it was confirmed that the lecithin constituting the liposome was in the bilayer form. (c), (d) is silica coated Fe ^{3 +} In the form of impregnated liposomes, the difference between before and after silica coating was confirmed.

[ Experimental Example  2] silica coated Fe ^{3 +} Impregnation Liposomal  According to various hydrogen reaction temperature FT - IR  And TGA  result

The silica-coated Fe ³⁺ impregnated liposomes were hydrogen reduced at 25 ° C., 200 ° C., 400 ° C. and 600 ° C., respectively, in order to confirm the characteristics of reducing the Fe ^{3 +} by using hydrogen gas.

9 is an FT-IR spectrum when the silica-coated Fe ³⁺ impregnated liposomes are reduced to respective hydrogen reaction temperatures. As the hydrogen reaction temperature increases, the CH bonds around 2920cm ^-1 , 1460cm ^-1 and NH bond peaks around 1647cm ^-1 gradually decreased. In addition, the C = O bond peak near 1740cm ^-1 was confirmed to disappear after the hydrogen reaction at 400 ℃. This was confirmed that the lecithin component constituting liposomes disappear as the hydrogen reaction temperature increases.

FIG. 10 shows thermogravimetric analysis (TGA) with increasing temperature from room temperature to 1000 ° C. (10 ° C./min) in a nitrogen atmosphere when the silica coated Fe ³⁺ impregnated liposomes are reduced to respective hydrogen reaction temperatures. .

Samples subjected to hydrogen reduction at high temperature were less likely to lose weight. Samples subjected to hydrogen reduction at 600 ° C. show a 10.81% weight loss, and hydrogen reduction reactions at 25 ° C. show a 56.78% weight loss. At 200 ° C., there is a rapid thermogravimetric loss and weight loss up to 800 ° C. occurs. This is caused by the breakdown of the liposome structure composed of lecithin.

Figure 11 shows the color change of the sample when the silica-coated Fe ^{3 +} impregnated liposomes are reduced to the respective hydrogen reaction temperature. As the reaction temperature increases, it was confirmed that the color changed from pale brown to black. The magnetism did not appear up to 400 ° C. and showed magnetic properties from 600 ° C.

Experimental Example 3 Silica Coated Fe ³⁺  Impregnated liposomes SEM, TEM, FESEM-EDX, before and after hydrogen reaction XRD  result

Figure 12 (a) was observed the morphology of silica coated Fe ³⁺ impregnated liposomes by scanning electron microscopy (SEM). The synthesized liposomes had a size of about 400 nm and were confirmed to be produced as uniform particles. 12 (b) and (c) are transmission electron microscopy (TEM) images before and after hydrogen reaction of silica coated Fe ³⁺ impregnated liposomes. After the hydrogen reaction, the change of the particle was confirmed, and the size of the particle was reduced to about 350 nm.

Figure 13 is an elemental analysis of the hydrogen reaction before and after the silica-coated Fe ^{3 +} impregnated liposomes using FESEM-EDX (Field-emission scanning electron microscopy / Energy-dispersive X-ray spectroscopy). In terms of wt% of the element, it was confirmed that the distribution of Fe components in the particles increased after the hydrogen reaction.

An important point in silica coated Fe ³⁺ impregnated liposomes is the presence or absence of magnetic production according to hydrogen reduction. A coating that is not tinged with magnetic silica Fe ^{3 +} impregnated liposome particles and have the magnetic hydrogen reduction treatment at 600 ℃, due to the magnetism can be used in various fields, and particularly, drug delivery is moved to a desired portion by using a magnetic There is an advantage that can be.

Figure 14 shows the XRD analysis before and after hydrogen reaction of silica coated Fe3 + impregnated liposomes. Figure 14 (a) silica-coated Fe ^{3 +} impregnated liposome particles, as shown in is a, as shown in Figure 14 to check out the 2θ = 22 ° of the amorphous without the characteristics of the magnetic Si peak, (b) amorphous The peak of Si was confirmed at 2θ = 22 ° and the peak of Fe was confirmed at 2θ = 44.76 ° and 65.16 °. In addition, it can be seen that 2θ = 35 °, which is a peak appearing in the compound of Fe and Si, can also be confirmed. Through this, it could be confirmed that the silica-coated Fe ^{3 +} can be magnetic through hydrogen reduction of impregnated liposome particles.

[ Experimental Example  4] NIPAm  Effect of monomer and magnetic nanoparticle ratio

FIG. 15 is a TEM observation of magnetic nanoparticles, magnetic nanoparticles modified with 3-MOP, and magnetic nanoparticles bound to PNIPAm. (a) magnetic nanoparticles, (b) magnetic nanoparticles modified with 3-MOP, and (c) magnetic nanoparticles to which PNIPAm is bound. The surface of the particles before and after 3-MOP binding showed no significant difference. After PNIPAm binding, the presence of PNIPAm on the surface of the magnetic nanoparticles was clearly confirmed.

FIG. 16 shows the results of measuring magnetic nanoparticles combined with magnetic nanoparticles and PNIPAm using a super conducting quantum interference device (SQUID). The heating run and the cooling run were the same, and the super-paramagnetic properties were maintained. The change in the magnetic hysteresis curves of the SQUID magnetic nanoparticles and PNIPAm-coupled magnetic nanoparticles measured at 300K shows that the saturation magnetization (Ms) value is 25.57 emu / g for magnetic nanoparticles and magnetic nanoparticles with PNIPAm. 3.38 emu / g. It was found that the saturation magnetization (Ms) value decreased after PNIPAm binding. This is interpreted to decrease as the coating becomes thicker with the PNIPAm layer in the magnetic susceptibility of the magnetic nanoparticles.

17 shows FT-IR magnetic nanoparticles, magnetic nanoparticles modified with 3-MOP, and PNIPAm-coupled magnetic nanoparticles synthesized by NIPAM and 3-MOP-MNPs according to weight ratio conditions (conditions 1 to 3). It is represented by a spectrum. Through FT-IR analysis, 3-MOP binding to magnetic nanoparticles and PNIPAm binding were confirmed. As a result of binding 3-MOP to the magnetic nanoparticles, the carbonyl peak (C = O) of 3-MOP was confirmed at 1720cm ^{- 1} , indicating that 3-MOP was successfully bound to the magnetic nanoparticles. As a result of synthesizing PNIPAm to magnetic nanoparticles according to NIPAm / 3MOP-MNPs (weight ratio), 2972cm ^-1 and 2882cm ^-1 showed CH bond, and CC bond was confirmed at 1360cm ^{- 1} to show isopropyl. NH bonding at 3320cm ^-1 1650cm ^- C = O bond, 1570cm ^-1 CNH mixed combination of ¹ was characterized by the amides. Therefore, it was confirmed that PNIPAm was bound to magnetic nanoparticles in all of NIPAm / 3MOP-MNPs (weight ratio) conditions 1 to 3.

18 shows magnetic nanoparticles, magnetic nanoparticles modified with 3-MOP, and PNIPAm-coupled magnetic nanoparticles synthesized with NIPAM and 3-MOP-MNPs according to weight ratio conditions (conditions 1 to 3) in a nitrogen atmosphere. Thermogravimetric analysis (TGA) is shown with increasing temperature from room temperature to 1000 ° C. (10 ° C./min). TGA analysis revealed the amount of PNIPAm bound to the magnetic nanoparticles modified with 3MOP. The weight reduction rates of magnetic nanoparticles from 110 ℃ to 1000 ℃, magnetic nanoparticles modified with 3-MOP, and magnetic nanoparticles with PNIPAm (conditions 1,2,3) were 9.56%, 15.23%, 68.39%, and 58.1, respectively. %, 75.98%.

The weight loss from 25 ℃ to 110 ℃ was confirmed that PNIPAm bonded magnetic nanoparticles were larger than magnetic nanoparticles before bonding. It can be considered that PNIPAm bound to the surface of magnetic nanoparticles has more water molecules than magnetic nanoparticles before binding. This is because PNIPAm is characterized by the inclusion of water molecules in crossed network structures.

[ Experimental Example  5] Cross-linking agent NMBA Effect of concentration on

Figure 19 shows the synthesis results according to the concentration of the crosslinking agent NMBA in the FT-IR spectrum. 2970cm ^-1 and 2875cm ^-1 showed CH bonds, and CC bonds were confirmed at 1380cm ^-1 , indicating isopropyl. NH bonding at 3430cm ^-1, C = O bond, 1568cm ^-1 CNH mixed bonding at 1644cm ^-1 was characterized by the amide. Therefore, it was confirmed that PNIPAm was bound to the magnetic nanoparticles in conditions 1, 4, and 5 of the concentration of the crosslinking agent NMBA.

20 was analyzed the amount of PNIPAm bound through the thermogravimetric analysis (TGA) of the synthesis results according to the concentration of the crosslinking agent NMBA. The weight loss was measured from 110 ° C to 1000 ° C since the amount of water contained in each sample was different until 110 ° C. The weight loss was 79.97% when the concentration of NMBA / NIPAm was 11% (condition 5), and 68.39% and 62.26% when the concentration of NMBA / NIPAm was 5.5% (condition 1) and 2.75% (condition 4), respectively. Showed a loss. Therefore, when NMBA / NIPAm concentration is 11%, it was confirmed that the most polymerization of PNIPAm was made.

As can be seen in the above Examples and Experimental Examples, the present invention is prepared by impregnating Fe ^{3 +} in spherical liposomes formed by self-assembly of phospholipid molecules, and coating silica with silica and coating the surface of liposomes with silica. the Fe ^{3 +} by reduction of liposome particle impregnated with hydrogen gas presents a simple and easy method of producing the nanoparticles magnetically. In addition, the magnetic nanoparticles of the present invention are stacked with silica to combine various functional groups of interest, and the adsorption or desorption of a desired substance through interaction with a specific substance is possible. You can.

The magnetic nanoparticles can be given temperature-sensitivity by binding PNIPAm in which the polymer phase is transferred in accordance with temperature change. It was magnetic even after binding with PNIPAm and showed different synthesis rate according to the amount of NIPAm and the amount of crosslinking agent NMBA. PNAPAm-coupled magnetic nanoparticles prepared as described above are materials for use in delivery materials such as pharmaceuticals and antibodies, and may be usefully used not only in the medical field but also in environmental fields such as the separation of heavy metals.

The present invention is not limited to the above-described specific embodiments and descriptions, and various modifications can be made to those skilled in the art without departing from the gist of the present invention claimed in the claims. And such modifications are within the scope of protection of the present invention.

Claims (12)

i) mixing to prepare a liposome dispersion is impregnated with Fe ^{3 +} phospholipids (phospholipid) solution and the aqueous solution containing Fe ^{3 +;}
Ⅱ) to prepare the Fe ^{3 +} of the liposome dispersion and by reacting the impregnated silica precursors are silica coated Fe ^{3 +} impregnated liposome particle; And
Ⅲ) the step of reducing in a hydrogen atmosphere for Fe ^{3 +} liposome particles impregnated with the silica coating;
Method of producing a magnetic nanoparticle comprising a. The method of claim 1,
The phospholipid is lecithin (lecithin) characterized in that the manufacturing method of the magnetic nanoparticles. The method of claim 1,
Method for producing a magnetic nanoparticles, characterized in that the reaction of the liposome dispersion impregnated with Fe ^{3 +} and the silica precursor is carried out under acidic conditions of pH 2 ~ 4. The method of claim 1,
The method of producing magnetic nanoparticles, characterized in that to reduce the silica coated spherical nanoparticles at 600 ~ 1000 ℃. Magnetic nanoparticles prepared by the method of any one of claims 1 to 4. The method of claim 5,
Magnetic nanoparticles having a particle size of 300 ~ 500nm. The method of claim 5,
Magnetic nanoparticles having a saturation magnetization (Ms) value of 20 ~ 30emu / g. i) modifying the magnetic nanoparticle surface of claim 5 to impart a double bond; And
Ii) bonding a temperature sensitive polymer to the surface of the magnetic nanoparticles to which the double bond is given;
Method for producing a target-oriented drug delivery agent comprising a. 9. The method of claim 8,
The method of manufacturing a target-oriented drug carrier, characterized in that the modification of the magnetic nanoparticles is made using 3-MOP (3- (trimethoxysilyl) propyl methacrylate) which is a silane coupling reagent. 9. The method of claim 8,
Method for producing a target-oriented drug carrier, characterized in that the temperature-sensitive polymer is PNIPAm (poly ( N- isopropylacrylamide)). The method of claim 10,
The PNIPAm is a method of producing a target-oriented drug carrier, characterized in that the binding to the magnetic nanoparticles surface using NIPAm ( N -isopropylacrylamide) monomer, NMBA ( N, N ' -Methylenebisacrylamide) crosslinking agent, KPS (Potassium persulfate) initiator. 12. The method of claim 11,
The NMBA / NIPAm concentration of 3 ~ 11% characterized in that the manufacturing method of the target-oriented drug carrier.

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