KR101136190B1 - Magnetic nano-particles coated by biocompatible polymer and method for manufacturing the same - Google Patents

Abstract

The present invention relates to paramagnetic nanoparticles coated with a biocompatible polymer and a method of manufacturing the same. The present invention includes at least a synthesis step of reacting by supplying air (or oxygen) to a mixture of a polar organic solvent, a metal precursor, and a biocompatible polymer. According to the present invention, paramagnetic nanoparticles are synthesized (coated) in ultra-fine size in one step. Accordingly, the manufacturing is simple, the synthesis cost is low, and because of the ultra fine size, high human body absorption is fast.

Description

Paramagnetic nanoparticles coated with biocompatible polymer and method for manufacturing the same {MAGNETIC NANO-PARTICLES COATED BY BIOCOMPATIBLE POLYMER AND METHOD FOR MANUFACTURING THE SAME}

The present invention relates to paramagnetic nanoparticles coated with a biocompatible polymer and a method of manufacturing the same, and more particularly, to synthesize paramagnetic nanoparticles coated with a biocompatible polymer on a surface of a metal oxide. The present invention relates to a paramagnetic nanoparticle coated with a biocompatible polymer and to a method of manufacturing the same, which is synthesized to an ultrafine size, and is simple to manufacture and fast to absorb in the human body.

In general, paramagnetic nanoparticles are used for various purposes such as data storage, radio absorbers, contrast agents of magnetic resonance imaging devices (hereinafter referred to as 'MRI'), and drug delivery systems.

Paramagnetic nanoparticles are coated with various materials to solve problems such as water insolubility and toxicity and to introduce functional groups applicable to surfaces. Paramagnetic nanoparticles, for example, are coated with biocompatible polymers when used as contrast media for MRI. In MRI, contrast agents are used as substances introduced into an imaged anatomical or functional area by varying the relaxation time through higher contrast in the generated image, to increase the difference between different tissues, or between normal and abnormal tissues. . As negative contrast agents that appear dark on MRI, particulate superparamagnetic iron oxides (SPIOs) are used. Superparamagnetic iron oxides (SPIOs) produce a spin relaxation effect, resulting in shorter T ₁ relaxation times and T ₂ relaxation times. In general, superparamagnetic iron oxides (SPIOs) and smaller microscopic superparamagnetic oxides (USPIONs) are composed of a core of crystalline iron oxide containing iron atoms and a shell of a polymer coated on the core. Tiny superparamagnetic iron oxides (USPIONs) smaller than 300 nm exhibit very high relaxation.

These paramagnetic nanoparticles heat a solution containing a polymer and a surfactant to a high temperature, and then administer a metal oxide such as iron oxide for a short time to form uniform nuclei induced, and then lower the temperature to prevent new nucleation. It is synthesized in a manner that induces the growth of particles uniformly. Another method involves heating a solution containing a metal, an alkoxide and a surfactant and then rapidly injecting a metal halide compound at a high temperature.

In addition, Korean Patent Publication No. 10-2008-0066999 discloses nanoparticles prepared by a wet method from a metal oxide, reacts nanoparticles with an azide-containing reagent to introduce an azide group, and an organic complex having metal ions bonded thereto. A method for preparing an agent by reacting is provided. In addition, the Republic of Korea Patent Publication No. 10-2008-0084102 discloses a step of converting the polarity of the target particles (iron compound, etc.), adsorbing the first polymer material having a polarity opposite to the polarity conversion particles, the first after washing A method for preparing nanoparticles coated with a polymer is disclosed, including adsorbing a second polymer material having a polarity opposite to that of the polymer-bound particle.

However, the manufacturing method of the nanoparticles according to the prior art including the prior document, there is a problem that the production is complicated, accompanied by several steps of the process. It is also pointed out that it is difficult to produce nanoparticles having a distribution of ultrafine size, for example, an average particle size of 3 nm or less.

The present invention is to solve the problems of the prior art as described above, in the production of paramagnetic nanoparticles (biosynthesis) coated with a biocompatible polymer on the surface of the metal oxide, one-step ultra-fine size Produced by coating (synthesizing) with a simple, easy to manufacture, fast absorption of the human body due to the ultra-fine size provides a paramagnetic nanoparticles coated with a biocompatible polymer and a method of manufacturing the same can be usefully applied in the bio or medical field The purpose is to.

The present invention to achieve the above object,

In the production method of paramagnetic nanoparticles coated with a metal oxide biocompatible polymer,

Method of producing paramagnetic nanoparticles comprising a synthetic step of supplying and reacting a mixture of a polar organic solvent, a metal precursor and a biocompatible polymer by supplying air (or oxygen) in a bubbling manner by inserting a glass tube below the mixture and injecting to provide.

At this time, subsequent to the synthesis step, it may further comprise a separation step of precipitating and separating the paramagnetic nanoparticles coated with the biocompatible polymer from the reaction product, this separation step is synthesized by adding a precipitant such as acetone to the reaction product It is preferable to precipitate the separated paramagnetic nanoparticles. In the synthesis step, according to a preferred embodiment, at a temperature of 210 ℃ ~ 290 ℃, it is preferable to react for 12 hours to 48 hours.

In addition, the present invention is prepared by the above method, to provide paramagnetic nanoparticles coated with a biocompatible polymer on the surface of the metal oxide.

According to the invention, the coating (synthesized) to the ultrafine size in one step (One-step), the effect of action is simple and, due to the micro size can be a human body absorbs faster useful applications in the bio and medical fields Has

Hereinafter, the present invention will be described in more detail.

In the method for preparing paramagnetic nanoparticles according to the present invention, air (or oxygen) is injected into a mixture of a polar organic solvent, a metal precursor, and a biocompatible polymer by a bubbling method in which a glass tube is inserted under the mixture and then injected into a reaction. (Synthesis step). According to the present invention, the metal precursor is oxidized to the metal oxide of the nano-sized particles by one-step synthesis, and at the same time, the surface of the nano-sized metal oxide particles is coated with the biocompatible polymer (synthesis). )do. In addition, according to the above synthesis process, it is possible to produce ultra-fine nanoparticles (coated with biocompatible polymer) of 3nm or less.

In the synthesis step, it is preferable to react for 12 hours to 48 hours at a temperature of 21 0 ℃ ~ 290 ℃. At this time, when the reaction temperature is less than 21 0 ° C., the reactivity decreases, and the yield and coating amount of the nanoparticles (the weight of the biocompatible polymer coated on the surface of the nanoparticles) become small. When the reaction temperature exceeds 290 ° C, the synergistic effect of excessively elevated temperature is not so great and is not preferable in terms of thermal energy use. That is, even if the reaction temperature is increased, the coating amount of the biocompatible polymer does not increase by the temperature increase amount. In addition, when the reaction time is less than 12 hours, the yield of the nanoparticles coated with the biocompatible polymer may be reduced, and when it exceeds 48 hours, it may be difficult to obtain nanoparticles of ultra fine size by causing particle growth. At this time, by controlling the reaction temperature and / or time, the metal oxide is 30 to 70% by weight based on the total weight of the nanoparticles, the biocompatible polymer is preferably coated (synthesized) to have a weight distribution of 30 to 70% by weight. That is, the mass ratio of Magnetic nanoparticles constituting the metal oxide and the biocompatible polymer is 3-7: good to 3 to 7. Further, through the control of the reaction temperature and / or time, the nanoparticles (coated with biocompatible polymers) have an average particle size distribution of 1 nm to 5 nm in average size, preferably 1 nm to 3 nm in average size. It is good to make it ultra-miniature with distribution. Most preferably in the above synthesis step, it is not particularly limited but may be reacted at a temperature of 260 ° C. for 24 hours. Under these temperature / time conditions (260 ° C./24 hours), nanoparticles with a mean particle size distribution of 1.7 ± 0.3 nm can be prepared.

In the synthesis step, the polar organic solvent used as the reactant may be used as long as it has a polarity, for example, one or more selected from the group consisting of polar alcohols (ethyl alcohol, isopropyl alcohol, etc.) and glycols Or a mixture of two or more kinds). Preferably, the polar organic solvent may be one of diethylene glycol and triethylene glycol as glycols.

In addition, in the synthesis step, the metal precursor used as the reactant may be used as long as it is a precursor that can be transferred to the metal oxide after the reaction, for example, metal salts (including inorganic salts and organic salts) and / or hydrates thereof. (hydrate) and the like can be used. In this case, the metal element constituting the metal precursor may be selected from iron (Fe), titanium (Ti), manganese (Mn), aluminum (Al), zirconium (Zr) and silicon (Si). More specifically, for example, the metal precursor may use at least one selected from iron chloride (FeCl ₃ ) and hydrates thereof (FeCl ₃ .6H ₂ O) as iron (Fe) precursors. As the metal precursor, when using the iron (Fe) precursor as described above, the synthesized nanoparticles contain iron (Fe), is useful as a contrast medium of MRI, as well as can be used as a source of iron (Fe) of the human body.

In addition, in the synthesis step, the biocompatible polymer used as a reactant does not have heterogeneity in the living body, and can be used if it is water-soluble, for example polyethylene glycol (PEG; polyethylene glycol), polylactic glycolic acid (PLGA; Poly (D At least one selected from the group consisting of L-latic-co-glycolic acid and dextrin may be used.

After the synthesis step, the reaction product may include a polar organic solvent and an unreacted material depending on the amount of the reactant together with the nanoparticles coated with the biocompatible polymer. A separation step is performed to separate and obtain the nanoparticles coated with the biocompatible polymer from the reaction product.

The separation step may be obtained by separating and obtaining the nanoparticles coated with the biocompatible polymer from the reaction product using a membrane filtration method, preferably using a precipitation separation method. Specifically, a precipitant is added to the reaction product to precipitate paramagnetic nanoparticles coated with the biocompatible polymer. Then, the supernatant is removed from the reactor to separate and obtain a precipitate (nanoparticle coated with biocompatible polymer). Although the said precipitant is not specifically limited, Ketones, such as acetone and methyl ethyl ketone, can be used. At this time, the precipitate (nanoparticle coated with biocompatible polymer) may be dried and commercialized in powder form. In addition, the dried powder may be dissolved in distilled water or the like to be commercialized in a liquid state. The dried powder has excellent dispersibility in distilled water.

According to the production method (synthesis method) of the present invention described above, paramagnetic nanoparticles coated with biocompatible polymers are simply manufactured by one-step, ie, one-step synthesis. . That is, as described above, the metal precursor is oxidized to the metal oxide of the nano-sized particles by the synthesis step involving the reaction, and at the same time the biocompatible polymer is coated on the particle surface of the metal oxide. In addition, it is manufactured in an ultra fine size, so that the absorption of the human body is fast and the cost is low. In addition, since the synthesis takes place in the reactor at once, a large design of the reactor scale enables mass production.

On the other hand, the paramagnetic nanoparticles according to the present invention, as prepared according to the production method (synthesis method) of the present invention as described above, the core-shell structure (core-shell) structure in which the biocompatible polymer is coated on the surface of the metal oxide Has In this case, the metal oxide is paramagnetic, for example, selected from iron (Fe), titanium (Ti), manganese (Mn), aluminum (Al), zirconium (Zr), silicon (Si) and the like. Selected from oxides having at least one metal element. More specifically, the metal oxide may be selected from iron oxide, titanium dioxide, manganese dioxide, aluminum oxide, zirconium oxide, silicon dioxide, and the like, preferably iron oxide (magnetite, Fe ₃ O ₄ ). The size of the paramagnetic nanoparticles according to the present invention may be very small having an average particle size distribution of 1 nm to 5 nm, preferably of 1 nm to 3 nm.

The paramagnetic nanoparticles according to the present invention can be used in various applications such as, but not limited to, MRI contrast agents (including positive and negative contrast agents) and drug delivery systems. For example, when the metal oxide constituting the core is iron oxide, it can be usefully used as a contrast agent of T ₁ and T ₂ in MRI, and also a drug for supplying iron (Fe) to the human body (anemia treatment agent and And / or as a prophylactic agent).

Hereinafter, embodiments of the present invention will be exemplified. In the following examples, iron chloride hydrate (FeCl ₃ · 6H ₂ O) is used as the metal precursor, and polyethylene glycol (PEG) is used as the biocompatible polymer, and polyethylene glycol (USPIONs) is formed on the surface of the micro iron oxide (USPIONs). Experimental example for preparing superparamagnetic nanoparticles (hereinafter referred to as "PEG-USPIONs") coated with PEG) is exemplified.

[Example]

<Synthesis Example>

Into the reactor, 1351 mg (5 mmol) of iron chloride hydrate (FeCl ₃ · 6H ₂ O, 99%), 2.6 ml (5 mmol) of polyethylene glycol (PEG, molecular weight = 600), and 20 ml of triethylene glycol as a polar organic solvent were added. . The mixture was allowed to react for 24 hours at 260 ° C. while stirring with a magnetic rod while flowing air in a bubbling manner by inserting a glass tube into the mixture. The reaction mixture was then cooled to room temperature and then acetone was added to the reaction mixture to precipitate PEG-USPIONs. The solvent in the upper layer was slowly removed, and the precipitate was dried at room temperature in air to obtain powder specimens (PEG-USPIONs). Such a reaction mechanism is shown in the following [Scheme 1].

Scheme 1

TEM micrographs and hydration diameter distributions of the prepared specimens (PEG-USPIONs) are shown in FIG. 1. In Fig. 1, (a) is in contrast to a scale of 50 nm, and (b) and (c) are in contrast to a scale of 5 nm. As shown in (a)-(c) of Figure 1, it can be seen that PEG-USPIONs have a uniform particle size distribution. And an average particle size distribution of 1.7 ± 0.3 nm. The hydrodynamic diameter of PEG-USPIONs was 5.4 nm in the hydration diameter distribution diagram shown in FIG. This was much larger than the results of TEM micrographs due to the moisture present around PEG-USPIONs. In addition, Figure 2 is the X-ray diffraction (XRD) pattern results of the prepared specimen (PEG-USPIONs). 2 shows the XRD pattern results of iron oxide (Fe ₃ O ₄ ) and PEG.

<Evaluation of Weight Distribution of PEG-USPIONs>

On the other hand, to determine the iron oxide (Fe ₃ O ₄ ) and PEG content (wt%) in the PEG-USPIONs, PEG-USPIONs were synthesized in the same manner as in the synthesis example. At this time, it was measured using a thermal analyzer (TGA), the results are shown graphically in FIG. As shown in the weight distribution graph of Figure 3, the final PEG content is 69.35% by weight, it can be seen that the content of iron oxide (Fe ₃ O ₄ ) is 30.65% by weight.

<Evaluation of Applicability to MRI Contrast Agents>

In addition, to evaluate whether the prepared PEG-USPIONs can be used as a contrast agent of MRI was evaluated as follows.

Synthesis was carried out in the same manner as in Synthesis Example, but the concentration of iron (Fe) was 0.0625, 0.125, 0.25, 0.5, and 1.0 mM to obtain PEG-USPIONs specimens according to the respective concentrations. 4 (a) is a graph showing 1 / T ₁ of each specimen according to the concentration, Figure 4 (b) is a graph showing 1 / T ₂ of each specimen according to the concentration. In FIG. 4, the slopes r ₁ (= 4.46 mM ⁻¹ s ⁻¹ ) and r ₂ (= 15.01 mM ⁻¹ s ⁻¹ ) mean spin relaxation rates of T ₁ and T ₂ , respectively. In addition, Figure 5 (a) is a T ₁ map image of each specimen according to the concentration, Figure 5 (b) is a T ₂ map image. At this time, the relaxation ratio (r ₂ / r ₁ ) was evaluated as low as 3.4, it can be seen that the map image of T ₁ and T ₂ depends on the concentration, as shown in (a) and (b) of FIG. 5. This result means that both T ₁ and T ₂ can be used as contrast medium.

In addition, in FIG. 5, (c) is a photograph of a solution in which a specimen (1.0 mM iron concentration) is dispersed in distilled water, and (d) is a photograph of a powder specimen before dispersion. As shown in the photograph shown in (c) of Figure 5, it can be seen that the prepared PEG-USPIONs specimen has excellent water dispersibility.

1 is a TEM micrograph and hydration diameter distribution diagram of PEG-USPIONs prepared according to an embodiment of the present invention.

2 is an XRD pattern of PEG-USPIONs prepared according to an embodiment of the present invention.

Figure 3 is a graph of the weight distribution measured by using a thermal analyzer (TGA) PEG-USPIONs prepared according to an embodiment of the present invention.

Figure 4 is a graph showing 1 / T ₁ and 1 / T ₂ according to the iron (Fe) concentration of PEG-USPIONs prepared according to an embodiment of the present invention.

5 is a map image and photograph of T ₁ and T ₂ according to iron (Fe) concentration of PEG-USPIONs prepared according to an embodiment of the present invention.

Claims (12)

In the production method of paramagnetic nanoparticles coated with a metal oxide biocompatible polymer, A method for producing paramagnetic nanoparticles comprising the step of reacting by supplying air (or oxygen) to a mixture of a polar organic solvent, a metal precursor, and a biocompatible polymer which is diethylene glycol or triethylene glycol. The method of claim 1, A method for producing paramagnetic nanoparticles, further comprising a separation step of precipitating and separating the paramagnetic nanoparticles coated with the biocompatible polymer from the reaction product. The method of claim 1, Synthesis step is a method for producing paramagnetic nanoparticles, characterized in that for 12 hours to 48 hours at a temperature of 210 ℃ to 290 ℃. 3. The method of claim 2, The separation step is a method for producing paramagnetic nanoparticles, characterized in that by adding a precipitant to the reaction product to precipitate the paramagnetic nanoparticles coated with a biocompatible polymer. The method of claim 1, Metal precursor is a method for producing paramagnetic nanoparticles, characterized in that the iron (Fe) precursor. The method of claim 1, The biocompatible polymer is one or more selected from the group consisting of polyethylene glycol (PEG), polylactic glycolic acid (PLGA; Poly (D, L-latic-co-glycolic acid) and dextrin). Manufacturing method. delete delete delete delete delete delete

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